Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement

INTRODUCTION — Prostate cancer is among the most common cancers in males worldwide, and while many present with clinically localized low- or very low-risk disease there is evidence that patients are being diagnosed at a later stage given reduced rates of screening [1]. Some males with newly diagnosed prostate cancer have no demonstrable distant metastases, but have an extensive primary tumor (T2b or higher), regional lymph node metastases (N1), or other factors associated with an increased risk of local recurrence or progression to disseminated disease (serum prostate-specific antigen ≥10 ng/mL or Gleason grade group 3 or higher) (table 1A-B) [2]. (See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

This topic discusses the initial management approach for prostate cancer at intermediate and high risk for recurrence and dissemination based on clinical and radiographic staging. The approaches to the treatment of low-risk prostate cancer and to males with distant metastases are discussed separately. The management of patients who are managed with radical prostatectomy and are considered to be at increased risk following pathologic staging is also discussed separately.

●(See "Initial approach to low- and very low-risk clinically localized prostate cancer".)

●(See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer".)

●(See "Prostate cancer: Postoperative management of pathologic stage T3 disease, positive surgical margins, and lymph node involvement following radical prostatectomy".)

OVERVIEW OF THE APPROACH TO INITIAL TREATMENT — The approach to initial treatment is based on the initial risk stratification and an assessment of the patient's suitability for definitive local therapy. Our suggested approach is outlined in the algorithm (algorithm 1), and summarized in the sections below.

Risk stratification and staging — For males with newly diagnosed prostate cancer, treatment selection is based on several factors including digital rectal examination, serum levels of prostate-specific antigen (PSA), results from prostate biopsy, and the results of imaging studies, including prostate magnetic resonance imaging (MRI):

●Clinical staging is based on a digital rectal examination by an experienced clinician which contributes to assessing the extent of disease, a pretreatment serum PSA, the Gleason score/grade group (table 2) in the initial biopsy, and the number and extent of cancer involvement in the biopsy cores. This information allows the stratification of males with localized disease into clinical risk categories according to the primary tumor.

Most North American clinicians use the risk stratification system of the National Comprehensive Cancer Network (NCCN) to define clinical risk categories (table 3). This risk stratification system has been utilized in guidelines for treatment of clinically localized prostate cancer from the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO), which have been largely endorsed by the American Society of Clinical Oncology (ASCO) [3,4]. It will be utilized for the remainder of this topic review.

By contrast, European guidelines for risk stratification combine very low- or very high-risk disease, and otherwise, definitions for low-, intermediate-, and high-risk disease differ modestly [5]:

•Low risk – PSA <10 ng/mL and International Society of Urological Pathology (ISUP) grade 1 (Gleason score <7) and cT1-2a localized

•Intermediate risk – PSA 10-20 ng/mL or ISUP grade 2/3 (Gleason score 7) or cT2b

•High risk

-PSA >20 ng/mL or ISUP grade 4/5 (Gleason score >7) or cT2c or

-Any PSA, any ISUP grade, cT3-4 or cN+ (locally advanced (table 3))

●Imaging studies (radionuclide bone scan, computed tomography [CT] of the abdomen and pelvis, multiparametric MRI, positron emission tomography [PET] using prostate specific radionuclides such as prostate-specific membrane antigen (PSMA) PET are used selectively to assess for extraprostatic extension, regional adenopathy, or distant metastases, depending on the initial clinical stage and estimate of risk. Imaging for distant disease is not routinely recommended for very low- and low-risk prostate cancer according to the risk-based clinical staging system described above, while radionuclide bone scan (for unfavorable but not favorable intermediate-risk) and cross-sectional imaging (of the pelvis with or without abdominal imaging) are recommended for those with intermediate- and high-risk disease [3]. However, recent FDA approval of PSMA PET scanning for staging of localized high-risk disease may replace bone scans and the method of staging particularly since it may also serve to identify nonosseous metastases. Indications for prostate MRI are evolving, but it is often recommended for males with high-risk disease. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'High- and very high-risk disease' and "The role of magnetic resonance imaging in prostate cancer".)

The tumor, node, metastasis (TNM) staging system of the American Joint Committee on Cancer uses the clinical stage of disease (or pathologic stage, in those who have undergone prostatectomy), the baseline serum PSA, the histologic grade group (based on the Gleason score), and the extent of prostate involvement (as assessed at the time of surgery) to divide patients into prognostic stage groups (table 1A and table 1B). Among patients without distant metastases, these groups can also be used for selection of initial treatment according to risk, although we prefer to use the clinical risk categories as defined by the NCCN. It should be noted that a detailed evaluation of histology, and the impact of tumor size (rather than just the number of positive cores) and gene expression profiling are not fully captured by these risk groups. (See "Molecular prognostic tests for prostate cancer".)

Taken together, information derived from clinical staging and imaging studies are used to inform treatment options. Guidelines from AUA/ASTRO and ASCO endorse shared decision making, which explicitly considers not only risk stratification but also patient values and preferences, life expectancy, pretreatment general functional status and genitourinary symptoms, expected post-treatment functional status, and potential for salvage treatment [3,4]. (See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

A major problem is that current stratification systems to estimate risk of progression were based on data from patients who did not undergo MRI or targeted (MRI/transrectal ultrasound) prostate biopsy. As this is becoming more of a standard of care internationally, it is believed that the accuracy of estimating disease risk according to pretreatment assessment (especially the underestimation of disease risk) will improve over time.

Options for intermediate-risk disease — Intermediate-risk patients are divided into favorable and unfavorable subsets (table 3). (See "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'Favorable versus unfavorable intermediate-risk disease'.)

Treatment options for males with intermediate-risk prostate cancer include the following:

●Radiation therapy (RT), which may be administered using external beam radiation therapy (EBRT) alone, EBRT combined with a brachytherapy boost, or brachytherapy alone. Brachytherapy alone for intermediate-risk disease is primarily limited to those with favorable intermediate-risk disease (FIR). Patients with unfavorable intermediate-risk (UIR) disease can be treated with RT alone (EBRT with or without brachytherapy), but for most patients we suggest combined RT plus androgen deprivation therapy (ADT). (See 'EBRT alone' below and 'EBRT with brachytherapy boost' below and 'Brachytherapy alone' below and 'Role of concurrent ADT' below.)

●Radical prostatectomy (RP) with pelvic lymph node dissection. (See 'Radical prostatectomy' below.)

●Active surveillance (AS) is an option for those with FIR, but patients should be informed that this comes with a higher risk of developing metastases compared with definitive treatment [3]. AS is not indicated for males with UIR. AS for intermediate-risk disease is discussed below, and other issues relating to the selection of males for AS in males with localized prostate cancer are discussed in detail elsewhere. (See 'Active surveillance' below and "Active surveillance for males with clinically localized prostate cancer", section on 'Indications'.)

Options for high- and very high-risk disease — Males with clinically localized prostate cancer have more extensive disease based on the presence of extraprostatic extension (cT3a) or seminal vesicle invasion (cT3b). In addition, patients with less extensive disease may be classified as being at high risk because of a serum PSA ≥20 ng/mL or a histologic grade group of 4 or 5 (Gleason score of 8 to 10). Patients whose initial evaluation suggests locally advanced disease with seminal vesicle involvement, tumor fixation, or invasion of adjacent organs are classified as being at very high risk for progression or recurrence (cT3a/b or cT4). In addition, patients with grade group 5 disease are classified as very high risk. (See 'Risk stratification and staging' above.)

Treatment options for males with clinically localized high- or very high-risk prostate cancer include the following:

●EBRT for high-/very high-risk disease should always be administered with long-term ADT. RT may be administered using EBRT alone or EBRT combined with a brachytherapy boost. (See 'EBRT alone' below and 'EBRT with brachytherapy boost' below and 'Role of concurrent ADT' below.)

For males with grade group 5 disease, some observational data suggest that dose escalation with EBRT plus brachytherapy decreases prostate cancer-specific mortality and is associated with decreased all-cause mortality compared with either EBRT alone or RP. (See 'Patients with grade group 5 disease' below.)

●RP with pelvic lymph node dissection is an option for males with locally advanced disease without tumor fixation to adjacent structures. Patients who initiate treatment for locally advanced disease should be counseled preoperatively that adjuvant therapy may be recommended following RP based on the histologic findings of the removed prostate and surrounding tissues, as well as margin status. (See 'Radical prostatectomy' below.)

●Patients who are managed with RP are staged pathologically based on the resection specimen. Following RP, patients with more extensive local disease, positive surgical margins, or microscopic involvement of regional lymph nodes may require additional treatment or a change in their treatment plan. The management of patients with significant changes in their staging based on examination of the surgical resection specimen is discussed separately. (See "Prostate cancer: Postoperative management of pathologic stage T3 disease, positive surgical margins, and lymph node involvement following radical prostatectomy", section on 'Lymph node involvement'.)

Radiation therapy versus prostatectomy — The choice of RT or RP for intermediate-, high-, or very high-risk disease depends on an informed patient decision incorporating knowledge about the potential advantages and disadvantages associated with each approach, contraindications to each of these approaches, and personal preferences (table 4 and table 5 and table 6) [6]. The specific side effects associated with each approach are discussed separately, as are their relative frequencies. (See "Radical prostatectomy for localized prostate cancer", section on 'Functional outcomes' and "External beam radiation therapy for localized prostate cancer", section on 'Complications'.)

There are no data from adequately powered randomized trials that compare RP with RT specifically for males with intermediate-, high-, or very high-risk prostate cancer, although approximately one-fourth of patients included in the phase III Prostate Testing for Cancer and Treatment (ProtecT) trial had such disease [7]. (See "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'ProtecT trial'.)

Published comparisons between different treatment modalities often rely on interpretation of large observational databases [8,9]. Interpretation of such data requires that studies use optimal contemporary techniques, have adequate follow-up, stratify patients based on pretreatment criteria, utilize standard definitions for treatment success or failure, and contain adequate numbers of patients.

Surgery may be preferred over RT for males with intermediate- or high-risk disease who have a prior history of bladder or rectal cancer, or severe intractable non-cancer-related lower urinary tract obstructive symptoms that are not amenable to medical therapy (eg, obstruction related to benign prostatic hyperplasia or detrusor instability) or surgical therapy (eg, severe benign prostatic hyperplasia with median lobe hyperplasia). Prior transurethral resection of the prostate (TURP) is a relative contraindication for brachytherapy (either alone or in combination with EBRT).

The sections below will review the data for efficacy of RT, brachytherapy, and prostatectomy in males with intermediate- and high-risk localized prostate cancer. Although these studies provide information about long-term outcomes for these patients, the results cannot be used for definitive comparisons of different modalities.

Benefits of definitive treatment — The benefit of definitive treatment, rather than either observation/AS or ADT alone, for intermediate- and high-risk regionally localized prostate cancer has been demonstrated in multiple large trials; as examples:

●In a National Cancer Institute of Canada intergroup phase III trial, 1205 males with locally advanced or high-risk prostate cancer were randomly assigned to RT plus lifelong ADT or lifelong ADT alone [10-12]. The total RT dose was 65 to 69 Gy over 7 to 7.5 weeks. With a median follow-up of eight years, the 10-year overall survival was significantly increased with the combination of RT plus ADT compared with ADT alone (55 versus 49 percent, hazard ratio [HR] 0.70, 95% CI 0.57-0.85). Similarly, the death rate due to prostate cancer was decreased (15 versus 26 percent, HR 0.46, 95% CI 0.34-0.61). These results were obtained using a radiation dose that is lower than that considered optimal by modern standards.

A quality of life (QOL) analysis of this trial found that bowel symptoms, diarrhea, urinary function, and erectile function were worse at six months for those given RT; however, these differences were not statistically significant three years after treatment [12]. (See "External beam radiation therapy for localized prostate cancer", section on 'Complications'.)

●In the Scandinavian Prostate Cancer Group 7 trial, 875 males with locally advanced or high-risk prostate cancer were randomly assigned to three months of combined androgen blockade followed by RT (minimum cumulative dose 70 Gy) with lifelong ADT or to three months of combined androgen blockade followed by lifelong ADT alone without RT [13]. Enrollment was carried out between 1996 and 2002. With a median observation time of 12 years, the 15-year prostate cancer-specific mortality was significantly lower in those treated with ADT plus RT compared with ADT alone (17 versus 34 percent). Benefits persisted long term, and largely outweighed the increased risk of secondary cancers (including urinary bladder cancer) in the RT group [14]. (See "External beam radiation therapy for localized prostate cancer", section on 'Secondary malignancies'.)

●In the Prostate Cancer Intervention Versus Observation Trial (PIVOT), 731 males with localized prostate cancer were randomly assigned to RP or to observation [15]. At a median follow-up of 10 years, prostate cancer mortality was lower in those assigned to RP compared with observation in males with a serum PSA ≥10 ng/mL (5.6 versus 12.8 percent, p = 0.02) and among males with high-risk prostate cancer (9.1 versus 17.5 percent, p = 0.04). These results were maintained with long-term follow-up [16].

Despite these data, there are significant barriers, especially related to insurance status and race/ethnicity, that may limit decision making for definitive local therapy [17].

Active surveillance — For patients with favorable intermediate-risk disease (table 3) who do not have of areas of cribriform or intraductal histology, who are willing to accept a potentially higher risk of developing metastases, who are comfortable with the psychosocial burden of living with an indolent cancer without active treatment, and willing to undergo monitoring for disease progression, AS is an alternative to RT or RP, especially for patients with a shorter life expectancy (ie, <10 years).

AS is based on the assumption that initial assessment (particularly if it incorporates new tools such as prostate MRI) is reasonably accurate for risk stratification, and that serial monitoring can successfully identify subclinical progression at a time when treatment is still curative in intent, and no more morbid than definitive treatment delivered at the time of diagnosis. The primary concerns with AS are twofold:

●Disease may be misclassified at diagnosis, such that a patient with an aggressive cancer is incorrectly classified as having a low-risk cancer.

●Favorable-risk cancer may evolve into higher-grade cancer during AS.

A major advantage of AS is the avoidance or deferral of treatment-associated side effects. (See "Active surveillance for males with clinically localized prostate cancer", section on 'Quality of life issues and psychologic comfort with surveillance'.)

There are no trials directly comparing AS versus definitive treatment for intermediate-risk prostate cancer. None of the studies described above examining the benefits of definitive treatment had a control arm that included modern AS. (See 'Benefits of definitive treatment' above and "Active surveillance for males with clinically localized prostate cancer", section on 'Active surveillance versus watchful waiting' and "Active surveillance for males with clinically localized prostate cancer", section on 'Monitoring and triggers for intervention with treatment'.)

The available data from prospective AS cohorts specifically reporting outcomes for intermediate-risk patients managed with AS have been mixed [18-28]. While some institutions have shown that males with intermediate-risk prostate cancer have progression-free rates similar to those with lower-risk disease (in which AS is often the preferred strategy), others, including the PIVOT trial described above [16,20,22,29], suggest inferior outcomes. (See "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'Treatment approaches' and 'Benefits of definitive treatment' above.)

As an example, the group from Toronto found significantly poorer outcomes at 15 years in males undergoing AS for intermediate-risk disease compared with those with low-risk tumors [20,22]. In this analysis comparing outcomes in 237 patients with intermediate-risk disease with those in 708 patients with low-risk disease, metastasis-free, overall, cause-specific, and treatment-free survival rates were all significantly poorer at 15 years for those with intermediate-risk disease (eg, for metastasis-free survival, HR 3.14, 95% CI 1.51-6.53, 82 versus 95 percent, HR 3.75, 95% CI 1.37-10.28), and there was an increased risk of developing metastatic disease (4.6 versus 0.8 percent) [22]. However, this finding was driven primarily by males with predominant Gleason pattern 4 cancer in the biopsy, rather than males who were categorized as intermediate-risk based on PSA or T stage. Notably, MRI of the prostate was not used in this study to select males for AS and this might help in the detection of high-grade disease. (See "Active surveillance for males with clinically localized prostate cancer", section on 'Multiparametric MRI of the prostate'.)

Specific subgroups of males with intermediate-risk disease (ie, those with "unfavorable-risk disease") are perceived as being at higher risk of inferior outcomes if definitive therapy is deferred. While a number of retrospective studies have sought to refine protocols for selecting males with intermediate-risk disease for AS by utilizing large datasets to examine associations of clinical risk factors with adverse pathology at RP [27,29-32], it remains unclear whether extrapolating these data to separate males into FIR and UIR disease for decisions about AS is valid. This uncertainty has led to different groups having different definitions of FIR versus UIR disease and disparate recommendations for which patients are appropriate for AS (table 7). The one area of agreement is that individuals with unfavorable-risk disease, regardless of definition, are not appropriate candidates for AS.

Tissue-based genomic prognostic markers can be used in males with FIR disease to discover those who might have more aggressive disease, and better served by definitive therapy. However, while these tests are currently being used for treatment decision-making, better evidence is needed before they can be considered a standard component of the decision-making process for or against AS. This subject is presented in detail elsewhere. (See "Molecular prognostic tests for prostate cancer" and "Active surveillance for males with clinically localized prostate cancer", section on 'Tissue-based genomic prognostic markers'.)

QOL and psychologic issues associated with AS; specific tools to refine the selection of patients for AS, including prostate histology and prostate MRI; as well as monitoring and triggers for definitive therapy for individuals undergoing AS are also discussed in more detail elsewhere. (See "Active surveillance for males with clinically localized prostate cancer", section on 'Quality of life issues and psychologic comfort with surveillance' and "Active surveillance for males with clinically localized prostate cancer", section on 'Tools to refine the selection of males for AS' and "Active surveillance for males with clinically localized prostate cancer", section on 'Monitoring and triggers for intervention with treatment'.)

Males who are not candidates for definitive local therapy — Primary ADT alone may be a reasonable approach if males are not candidates for definitive local therapy (eg, if the patient has a limited life expectancy due to age or comorbidity) but have local symptoms [3]. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Benefits and methods for androgen deprivation therapy'.)

Both TURP and simple prostatectomy can provide short-term palliation of lower urinary tract obstructive symptoms in males with locally advanced prostate cancer. These procedures may have a role in older adults and in those with substantial comorbidities and a limited life expectancy. However, prolonged local disease control is unlikely. These approaches should never be employed if definitive treatment is the therapeutic goal. (See "Prostate cancer in older males".)

DEFINITIVE THERAPY FOR LOCALIZED DISEASE — Outcomes from definitive local therapy for males with intermediate- or high-risk prostate cancer will be reviewed in the following sections.

Radical prostatectomy — Radical prostatectomy (RP) is an accepted standard option for otherwise healthy males with intermediate-risk regionally localized prostate cancer and an option for males with high-risk regionally localized or locally advanced prostate cancer without tumor fixation to adjacent structures. For males with intractable non-cancer-related severe lower urinary tract obstructive symptoms (American Urological Association [AUA]/International Prostate Symptom Score >20 (table 8) (calculator 1) [33]), surgery may be preferred over radiation therapy (RT) [3]. Pelvic lymphadenectomy is recommended for those with high- or unfavorable intermediate-risk (UIR) disease [3]. (See "Radical prostatectomy for localized prostate cancer".)

Intermediate-risk disease — The results using radical retropubic prostatectomy are illustrated by a series of 2795 males with intermediate-risk prostate cancer treated at the Mayo Clinic between 1987 and 2003 [34]. Approximately 50 percent of these cases had clinical stage T2b disease, while the rest were classified as intermediate risk based on a serum prostate-specific antigen (PSA) of 10 to 20 ng/mL or a Gleason score of 7; the median follow-up was 7.7 years.

At five years, 78 percent were free from biochemical relapse, and at 10 years, 65 percent remained biochemically progression free. Even among those who experienced a biochemical relapse, the prognosis for these patients was highly favorable. The overall rates of freedom from local recurrence were 96 and 92 percent at 5 and 10 years, respectively, and freedom from systemic progression was 96 and 89 percent at 5 and 10 years, respectively.

High- or very high-risk disease — In the presence of high-risk features, appropriately selected patients have a relatively favorable prognosis after RP, both in terms of disease control and cancer-specific mortality:

●Radical retropubic prostatectomy was used to treat 1513 males with high-risk prostate cancer at the Mayo Clinic between 1987 and 2003 [34]. Median follow-up was 7.7 years. The biochemical recurrence-free survival (RFS) rates at 5 and 10 years were 68 and 55 percent, respectively. For high-risk patients, the 10-year local RFS rate was 90 percent, and the 10-year systemic progression-free survival (PFS) rate was 89 percent.

●In a multi-institution series of 3828 patients who underwent RP for high-risk prostate cancer between 1987 and 2010, the 10-year cancer-specific mortality rate varied from 5 to 13 percent depending on age and specific high-risk factors [35]. By contrast, the mortality rate from other causes ranged from 4 to 37 percent, with variation due to age and comorbidities. The only age group in which cancer-specific mortality exceeded other causes of mortality was males less than 60 years old with no comorbidity.

●Similar results were seen in a single-institution analysis of patients undergoing RP for high-risk disease, although the majority of patients in that series were high risk based on the degree of PSA elevation or a biopsy Gleason score of 8 or greater [36]. These results appear to be similar to those with RT in historical series.

Neoadjuvant ADT approaches — For males with regionally localized intermediate-, high-, or very high-risk prostate cancer who choose RP as their primary therapy, a role for any form of neoadjuvant therapy remains uncertain, but is under active investigation. We concur with current guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) that do not recommend this as a standard approach [3,37] outside of the context of a clinical trial. However, newer phase II data on the combination of an luteinizing hormone-releasing hormone (LHRH) agonist plus abiraterone in the neoadjuvant setting from two large cancer centers are very encouraging, reporting relatively high rates of complete or near complete pathologic response at the time of prostatectomy. While randomized trials proving benefit from this approach are lacking, some clinicians, including some of the authors and editors associated with this topic review, inform patients of these data and individualize decision making.

●ADT – Neoadjuvant androgen deprivation therapy (ADT) may decrease tumor volume and improve the rate of complete resection in males with clinical T3 prostate cancer [38,39], but there are no randomized trials compared with prostatectomy alone, and there is no high-quality evidence that long-term outcomes are improved. In a review of the available literature, neoadjuvant ADT decreased the serum PSA in almost all males and decreased the incidence of positive resection margins in six of seven randomized prospective studies [38]. However, this was not accompanied by significant differences in operative time, blood loss, transfusion rates, or length of hospital stay. Moreover, there was no improvement in the rate of lymph node metastasis, biochemical RFS, or overall survival.

●ADT plus newer antiandrogens – A possible role for newer antiandrogens (eg, abiraterone, enzalutamide, apalutamide) and the orally active gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix in the neoadjuvant setting is under investigation [40-47]. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Relugolix' and "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus second-generation antiandrogens'.)

Early results are promising; as examples:

•In a single center randomized trial, 65 males with high-risk prostate cancer were randomly assigned to three months of abiraterone acetate plus prednisone and an LHRH agonist or LHRH agonist alone followed by RP [48]. Although there was no significant difference in organ confinement between the two groups, serum PSA depletion to ≤0.1 ng/mL was observed in >80 percent of males treated with abiraterone plus the LHRH agonist, And these patients had significantly lower tumor volumes. At a median follow-up of four years, males receiving abiraterone had a significantly lower rate of PSA recurrence (44 versus 59 percent), and a lower tumor epithelial volume correlated with better outcomes.

•Additional information is available from a multicenter phase II trial in which 118 males with Gleason score ≥4+3 = 7, PSA >20 ng/mL, or T3 disease (by prostate MRI) and lymph nodes <20 mm were randomly assigned to six months of abiraterone acetate plus prednisone plus apalutamide and leuprolide (APAL) or abiraterone acetate plus prednisone and leuprolide (APL) [46]. The primary endpoint was rate of pathologic complete response (pCR) or minimal residual disease (MRD; ≤5 mm). Overall, 111 of the 118 males had NCCN high-risk disease. The median preprostatectomy PSA nadir was <0.01 versus 0.02 with APAL and APL, respectively, and the time to nadir was 4.2 versus 4.6 months. The combined pCR/MRD rate was 22 percent with APAL and 20 percent with APL.

●Chemohormonal therapy – Other investigational approaches have added neoadjuvant chemotherapy to ADT (chemohormonal therapy), based primarily on the activity of docetaxel in patients with advanced disease. One phase III clinical trial (Cancer and Leukemia Group B [CALGB] 90203 [ALLIANCE]) compared neoadjuvant docetaxel plus ADT followed by RP versus immediate RP in 788 males with locally advanced prostate cancer [49]. Unfortunately, no significant improvement was seen in the primary endpoint with neoadjuvant therapy (three-year biochemical RFS 0.89 versus 0.84, 95% CI for the difference, -0.01 to 0.11, p = 0.11).

Adjuvant therapy — Additional information from the examination of the surgical specimen is used for pathologic staging, which replaces clinical staging for postsurgical treatment decisions.

For patients with adverse histologic features (extraprostatic extension, seminal vesicle involvement, positive margins, or unsuspected lymph node disease), postoperative adjuvant therapy may be indicated. This topic is discussed in detail elsewhere. (See "Prostate cancer: Postoperative management of pathologic stage T3 disease, positive surgical margins, and lymph node involvement following radical prostatectomy".)

Importantly, if the PSA fails to fall to undetectable levels or if the PSA subsequently rises following prostatectomy, patients are presumed to have residual or recurrent disease. Such patients should be evaluated for evidence of metastatic disease, and subsequent therapy is dictated by the results of that evaluation. Low levels of persistently elevated PSA following prostatectomy may reflect retained normal prostate tissue rather than residual disease, but these patients cannot be identified except with long-term follow-up. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation" and "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management".)

Radiation therapy

Indications and selection of treatment approach — RT is an accepted standard option for both intermediate- and high-risk prostate cancer. For most males with intermediate risk and all males with high risk, ADT is given in combination with RT. (See 'Role of concurrent ADT' below.)

RT may be administered using external beam radiation therapy (EBRT) alone, EBRT combined with a brachytherapy boost, or brachytherapy. Guidelines from ASCO/Cancer Care Ontario recommend that males with unfavorable intermediate- and high-risk localized prostate cancer be offered combined brachytherapy when receiving EBRT [50], a position that is endorsed by the American Brachytherapy Society/American Radium Society Appropriate Use Criteria Genitourinary Committee [51]. However, this is a controversial area, and not all agree that combined therapy provides clinically superior outcomes [52]. Guidelines from AUA/American Society for Radiation Oncology (ASTRO) suggest either dose-escalated hypofractionated EBRT or combined EBRT plus brachytherapy in this setting, along with a risk-appropriate course of ADT [53]. We would endorse shared decision making, informing males that combined treatment may improve clinical outcomes (mainly biochemical recurrence rates but not overall survival) but may also worsen treatment-related toxicity. One setting in which we prefer EBRT plus brachytherapy over EBRT alone is in males with prognostic grade group 5 disease (table 2). (See 'EBRT with brachytherapy boost' below.)

If combined therapy is chosen, multiple different brachytherapy isotopes for permanent prostate brachytherapy and varying fractionation regimens for high-dose rate (HDR) brachytherapy have been shown to be effective, are acceptable, and are consistent with recommendations from the American College of Radiology, the American Brachytherapy Society [54], and AUA/ASTRO [53].

At some institutions, males without clinical evidence of pelvic lymphadenopathy who have an estimated risk of nodal involvement >15 percent are offered elective treatment of the pelvic lymph nodes (whole-pelvis radiation therapy [WPRT]). In our view, this is acceptable but not mandatory. (See 'Whole-pelvis versus prostate-only radiation therapy' below.)

EBRT alone — Contemporary EBRT for prostate cancer utilizes three-dimensional conformal techniques (three-dimensional conformal radiation therapy [3D-CRT]), generally delivered by intensity-modulated radiation therapy (IMRT) with image guidance, often referred to as "image-guided" radiation therapy. For most males who have chosen EBRT for treatment of localized prostate cancer, professional guidelines from ASTRO, ASCO, and the AUA suggest moderate hypofractionation RT over conventional fractionation RT [53,55,56]. (See "External beam radiation therapy for localized prostate cancer", section on 'External beam radiation therapy techniques'.)

The results with EBRT alone can be illustrated by a single-institution series of 2047 males treated between 1998 and 2004 [57]. RT was administered by 3D-CRT IMRT, with doses ranging from 66 to 86 Gy:

●In the 849 males with intermediate-risk disease, the seven-year PSA relapse-free survival rate was 72 percent. The distant metastasis-free and cause-specific survival rates at seven years for males with intermediate-risk disease were 92 and 94 percent, respectively.

●In the 752 patients with high-risk disease, the seven-year PSA RFS rate was 54 percent. The distant metastasis-free survival rate was 76 percent at seven years, and the cause-specific survival rate was 81 percent.

EBRT with brachytherapy boost — The benefits of adding a brachytherapy boost to EBRT remain uncertain. Several randomized trials have shown that the addition of a brachytherapy boost to EBRT reduces local recurrence and improves biochemical control, but does not significantly reduce the development of metastatic disease or improve survival [58-62]. We would endorse shared decision making, informing males that combined treatment may improve clinical outcomes (mainly biochemical recurrence rates but not overall survival) but may also worsen treatment-related toxicity. One setting in which we prefer EBRT plus brachytherapy over EBRT alone is in males with prognostic grade group 5 disease (table 2).

●LDR brachytherapy plus EBRT – The benefit of combined EBRT with low-dose rate (LDR) brachytherapy (which uses implanted sealed sources) was addressed in the Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) trial, 398 males with intermediate- (n = 122) or high-risk (n = 276) disease were treated with 12 months of ADT, including eight months prior to RT [59]. Patients received WPRT (46 Gy in 23 fractions) and then were randomly assigned to EBRT to the prostate (32 Gy in 16 fractions) either alone or with LDR brachytherapy. All patients received 12 months of ADT beginning eight months prior to RT.

At a median follow-up of 6.5 years, RFS was significantly longer with EBRT plus brachytherapy compared with EBRT alone (five-year biochemical RFS 89 versus 84 percent, seven-year RFS 86 versus 75 percent, and nine-year RFS 83 versus 62 percent). Although biochemical failure was associated with increased mortality and randomization to combined therapy doubled the rate of biochemical failure, this did not translate into an improvement in overall survival. There was an increase in grade 3 toxicities with the addition of brachytherapy, although serious late toxicities were similar in the two treatment arms. Overall survival data were not provided.

●HDR brachytherapy plus EBRT – Similarly, the efficacy of high-dose rate (HDR) brachytherapy plus EBRT has been compared with EBRT alone in two small, randomized trials, both of which failed to demonstrate an improvement in overall survival with combined therapy:

•In one trial, 104 males with clinical T2 or T3 prostate cancer were randomly assigned to EBRT alone (66 Gy in 2 Gy fractions) or EBRT (40 Gy) preceded by a single, transperineal, temporary implantation of iridium-192 brachytherapy (35 Gy) given over 48 hours [60,61]. At a median follow-up of eight years, the rate of biochemical or clinical failure was significantly lower in the brachytherapy plus EBRT group (29 versus 61 percent). The improvement in biochemical control was maintained at a median follow-up of 14 years (hazard ratio [HR] 0.53, 95% CI 0.31-0.88). However, there was no statistically significant difference in overall survival, even with prolonged follow-up [61]. It should also be noted that the EBRT regimen of conventionally fractionated 66 Gy in 33 fractions is considered suboptimal.

•In the other trial, 218 patients were randomly assigned to EBRT alone (55 Gy in 20 fractions over four weeks) or EBRT (35.75 Gy in 13 fractions over 2.5 weeks) plus HDR brachytherapy (17 Gy divided into two fractions over 24 hours) [63]. In a secondary report with follow-up extending up to 10 years, RFS was significantly longer with the combined treatment, but there was no improvement in overall survival [62].

The interpretation of these trials is complicated by the variable dose and fractionation schedules used with the EBRT plus HDR brachytherapy combination, as well as the small size of these trials.

Patients with grade group 5 disease — Patients with histologic grade group 5 disease (table 2) constitute a subset of those with very high-risk prostate cancer that may derive particular benefit from combining EBRT with brachytherapy.

A retrospective analysis of 1809 patients with grade group 5 disease from 12 tertiary cancer centers compared the clinical outcomes in patients treated with EBRT combined with brachytherapy, EBRT alone, or RP (436, 734, and 639 patients, respectively) [9]. ADT was administered in approximately 90 percent of the patients managed with RT. Brachytherapy was administered using either an LDR or HDR technique (62 and 38 percent, respectively).

●The adjusted five-year prostate cancer-specific mortality rates were 3, 13, and 12 percent for EBRT plus brachytherapy, EBRT alone, or RP, respectively (HR 0.41, 95% CI 0.24-0.71, versus EBRT and HR 0.38, 95% CI 0.21-0.68, versus RP).

●The propensity-matched adjusted five-year incidence rates of distant metastasis were 8, 24, and 24 percent, respectively (HR 0.30, 95% CI 0.19-0.47, versus EBRT and HR 0.27, 95% CI 0.17-0.43, versus RP).

These observational data need to be interpreted with caution given the potential for unknown confounders in a propensity-matched analysis, the high percentage of patients receiving ADT in conjunction with RT, and the long natural history of prostate cancer.

Whole-pelvis versus prostate-only radiation therapy — At some institutions (including those of some, but not all, of the authors and editors of this topic), males with localized prostate cancer who have chosen RT, who are without clinical evidence of pelvic lymphadenopathy, and who have an estimated risk of nodal involvement >15 percent are offered elective treatment of the pelvic lymph nodes (whole pelvis RT, WPRT) in conjunction with prostate RT and ADT, whereas others have suggested different thresholds [64]. However, this is a controversial area, and many radiation oncologists do not treat the pelvic lymph nodes electively. In our view, WPRT is acceptable but not mandatory in these cases.

By contrast, WPRT is generally recommended for males with clinical or pathologic node-positive disease. (See 'Clinical evidence of lymph node involvement' below.)

Pelvic lymph node dissection is the only accurate means of assessing pelvic lymph node involvement and is generally performed in conjunction with RP for those patients at significant risk for lymph node involvement based on local extent of disease, serum PSA, and Gleason grade group (generally for those with intermediate- or high-risk disease (table 3)). Among males with clinical T3 prostate cancer who are managed with RP and thus have full pathologic staging, approximately one-quarter will be found to have radiographically occult lymph node metastases [65]. (See "Radical prostatectomy for localized prostate cancer", section on 'Pelvic lymph node dissection'.)

Pelvic lymph node dissection is generally not performed in patients who will be treated with RT rather than surgery. In this setting, the decision whether or not to treat the pelvic lymph nodes electively is often based on the estimated probability of lymph node involvement. In some cases, there may be radiographic suspicion of pelvic lymph node involvement, which may be confirmed by biopsy. Imaging studies, such as pelvic CT or MRI, can be used to assess regional lymph node enlargement prior to planned definitive treatment for localized prostate cancer. However, cross-sectional imaging, which uses shape and size criteria (typically 8 to 10 mm is the threshold) to define malignant nodes, has a low sensitivity. Micrometastases can be detected in as many as 30 percent of radiographically "normal" pelvic lymph nodes [65,66]. However, it is highly likely that newer more sensitive imaging techniques, such as positron emission tomography (PET) imaging with prostate-specific tracers (eg, gallium-68 prostate-specific membrane antigen [Ga-68 PSMA-11], piflufolastat F-18, flotufolastat F-18), will better identify males with subclinical node positivity at an earlier stage. These two PSMA-based PET radiotracers are approved in the United States for males with newly diagnosed prostate cancer and suspected metastases who are candidates for initial definitive therapy, and are now widely available. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'PET imaging using PSMA-based radiotracers'.)

However, for males without clinical or biopsy-proven node-positive disease, there is no consensus on what tool to use to estimate which males have an estimated risk of nodal involvement that exceeds 15 percent, and might therefore benefit from elective WPRT. Options include the Partin tables, the Roach formula [67,68], or other methods [69]. At some institutions, males with grade group 4 or 5 disease (table 2) or a PSA >20 ng/mL are referred for WPRT. (See "External beam radiation therapy for localized prostate cancer", section on 'Whole-pelvis versus prostate-only radiation therapy'.)

Elective RT to the pelvic lymph nodes (WPRT) has been advocated in males with a significant estimated likelihood of having disease in the regional nodes. This was mainly on the basis of multicenter randomized trials in favor of combining prostate EBRT and ADT, most of which included pelvic RT in the RT field. However, no randomized trial has shown a clear advantage for WPRT over ADT plus prostate RT alone, and WPRT adds more toxicity to the RT regimen. Thus, this practice remains controversial [70,71].

Three randomized trials have directly addressed the role of WPRT compared with prostate-only RT, none of which demonstrates a clear benefit for WPRT [72-78]. In the largest one, the Radiation Therapy Oncology Group (RTOG) trial 9413, 1323 males with regionally localized disease and an estimated risk of nodal metastasis ≥15 percent [72] were randomly assigned to WPRT (1.8 Gy per fraction, with 50.4 Gy to the pelvis and 70.2 Gy to the prostate) or prostate-only RT (70.2 Gy) [72-74]. Patients were further randomized, using a two-by-two factorial design, to neoadjuvant plus concurrent ADT (goserelin or leuprolide plus flutamide) administered for two months before and during RT, or to adjuvant ADT with the same drugs given for the same length of time but starting after the completion of RT. The majority of enrolled males had stage T2c or higher disease, a serum PSA <30 ng/mL, and a Gleason score of 7 or higher; thus, these males were categorized as either intermediate or high risk.

In the latest update, at a median follow-up of 8.8 years (14.8 years for living patients), there were no significant differences in PFS or overall survival when males treated with WPRT were compared with those managed with prostate-only RT [75]. However, there appeared to be an interaction between ADT and RT field size. Within the group that received WPRT, there was a trend toward better PFS and overall survival with neoadjuvant plus concurrent (two months before and during) ADT as compared with only adjuvant ADT (median PFS 30.2 versus 28.4 months, HR 1.21, 95% CI 1.03-1.43). Furthermore, when comparing neoadjuvant hormonal therapy with either prostate-only RT or WPRT, WPRT is associated with better PFS (28.4 versus 23.5 percent, HR 1.21, 95% CI 1.02-1.43), albeit at the cost of increased late grade ≥3 gastrointestinal toxicity (7 versus 2 percent). However, the study was insufficiently powered to show a statistically significant difference between these two treatment arms.

Results with adjuvant versus neoadjuvant ADT are discussed below. (See 'Sequencing and duration' below.)

Additional information is expected from another phase III RTOG trial (RTOG 0924, NCT01368588) in which patients with high-risk or locally advanced prostate cancer are receiving ADT in conjunction with either prostate-only or WPRT.

Brachytherapy alone — Brachytherapy alone can be used as a single RT technique to treat selected patients with favorable intermediate-risk prostate cancer (FIR; (table 9)). However, few trials have directly compared brachytherapy alone versus EBRT with or without a brachytherapy boost. In the phase III RTOG 0232 trial (NCT00063882), 588 males with intermediate-risk prostate cancer were randomly assigned to pelvic plus prostate RT plus brachytherapy or to brachytherapy alone [58]. The patient population was limited to males with a Gleason score ≤6 and a PSA 10 to 20 ng/mL or those with a Gleason score of 7 and a PSA <10 ng/m.

Results are only available from presentations at the 2016 and 2018 ASTRO meetings [79]. The results were released by the Data Monitoring Committee based on an interim analysis at a median follow-up of 6.7 years. In the latest analysis, which included 443 patients with a minimum of five years of follow-up, there was no significant difference in PFS with EBRT and brachytherapy compared with brachytherapy alone (five-year rate 85 versus 86 percent, hazard ratio [HR] 1.02). Without further follow-up and a peer-reviewed publication, it cannot be concluded based on these data that the two approaches are equivalent in terms of cancer-related outcomes.

Clinicians should inform patients considering brachytherapy that it appears to have similar effects to EBRT with regard to erectile dysfunction and proctitis, but that it can exacerbate urinary obstructive symptoms [3]. As a result, for males with clinically localized prostate cancer and intractable non-cancer-related lower urinary tract obstructive symptoms or who have undergone a "significant" transurethral resection of the prostate, brachytherapy is relatively contraindicated, and prostatectomy is preferred for appropriate surgical candidates. Techniques, patient selection and oncologic outcomes with brachytherapy alone are discussed in detail elsewhere. (See "Brachytherapy for low-risk or favorable intermediate-risk, clinically localized prostate cancer".)

Role of concurrent ADT — ADT has an established role in conjunction with EBRT for males with regionally localized high-risk or very high-risk prostate cancer, although its role is less well defined for those with intermediate-risk disease. Patients with UIR disease can be treated with RT alone (EBRT with or without brachytherapy), but for most patients, we suggest combined RT plus short-duration ADT.

Our approach is consistent with year 2018 ASCO guidelines, which advocate ADT in conjunction with EBRT (with or without brachytherapy) for males with high- or very high-risk prostate cancer but do not provide guidance on this issue for intermediate-risk disease [3]. Consensus-based guidelines from the NCCN and AUA/ASTRO advocate ADT in conjunction with EBRT for males with high-risk and UIR disease but not for those with FIR [37,53].

High-risk disease — For males with high-/very high-risk disease treated with EBRT with or without brachytherapy, we recommend long-term ADT (ie, 12 to 36 months versus 2 to 4 months) plus RT rather than RT alone. The optimal duration of ADT has not been definitively determined, but we prefer a 24-month duration of ADT for most males. Individuals who place a greater value on quality of life (QOL) during treatment might reasonably choose to limit ADT to 12 to 18 months of therapy. (See 'Duration' below.)

For most males we suggest initiating ADT prior to rather than concurrent with RT. There is no consensus as to the optimal duration of neoadjuvant ADT, and practice varies from two to eight months prior to the initiation of RT. (See 'Sequencing and duration' below.)

Benefits — The use of ADT in combination with EBRT has traditionally been the standard treatment for males receiving RT for regionally localized high-risk prostate cancer, based on the improvements in cancer-specific and overall survival observed in multiple randomized trials [80-84].

These findings are best demonstrated by the results of an individual patient data meta-analysis of six trials examining ADT use in conjunction with RT for high- or intermediate-risk prostate cancer [85]. Across seven randomized trials (5136 patients, median follow-up 12.9 years), the addition of ADT to RT significantly prolonged metastasis-free survival (HR 0.83, 95% CI 0.77-0.89), corresponding to a 10-year absolute benefit of 8.6 percent (95% CI 5.8-11.4). Use of ADT also improved overall survival (HR 0.85, 95% CI 0.80-0.92), corresponding to an absolute 10-year benefit of 7.7 percent (95% CI 4.9-10.4). The benefits were seen regardless of risk group, patient age, or radiotherapy dose.

Males receiving a brachytherapy boost — Although practice patterns demonstrate that receipt of a brachytherapy boost is associated with omission of ADT [86,87], there is insufficient evidence to support the omission of ADT in these males, and we suggest against this practice in males undergoing EBRT with a brachytherapy boost. (See 'EBRT with brachytherapy boost' above.)

The benefits of ADT versus brachytherapy in males undergoing EBRT for intermediate- or high-risk prostate cancer were addressed in a network meta-analysis of nine trials comparing EBRT with or without ADT, and three trials comparing EBRT with or without a brachytherapy boost (one of which excluded the use of ADT [60]) [88]. The addition of ADT to EBRT significantly improved overall survival (HR 0.71, 95% CI 0.62-0.81), whereas the addition of brachytherapy to EBRT did not (HR 1.03, 95% CI 0.78-1.36). Bayesian modeling demonstrated an 88 percent probability that EBRT resulted in superior overall survival compared with EBRT plus brachytherapy. The authors concluded that if a brachytherapy boost was added to EBRT, that the addition of ADT was needed to prevent the inferior overall survival that would result from the omission of ADT.

Risks — The addition of ADT to EBRT clearly increases the likelihood and severity of treatment-related effects on sexual function in most males [89,90], and it can cause other systemic side effects, including vasomotor symptoms, decreased muscle strength, and fatigue. (See "Side effects of androgen deprivation therapy".)

All of these risks are increased with a longer duration of therapy. Efforts to minimize the impact of prolonged ADT have led to several trials that have compared shorter with longer courses of ADT. (See 'Duration' below.)

The available evidence from randomized trials suggests that the vast majority of males with nonmetastatic prostate cancer are not at risk for an excess of ADT-associated cardiovascular problems [80,91-94]. However, at least some data suggest that the benefit of combining RT with ADT may be limited to patients who have no or minimal comorbidity, while it may in fact increase the risk of death by a small amount in patients with moderate or severe comorbidity:

●Some retrospective studies had suggested that all-cause mortality may be higher with the use of neoadjuvant ADT in males with a history of severe coronary artery disease as manifested by heart failure or myocardial infarction [95].

●In a trial in 206 males with unfavorable-risk prostate cancer in which patients were randomly assigned to RT with or without a six-month course of ADT, at a median follow-up of 16.6 years, RT plus ADT was associated with better overall survival than RT alone for the 157 males with no or minimal comorbidity (15-year survival rate 43.8 versus 30.5 percent, p = 0.04) [96-98]. By contrast, for the 49 males with moderate or severe comorbidity, RT plus ADT was associated with worse overall survival (15-year survival rate 8.3 versus 20.0 percent, p = 0.07).

Although the benefits of ADT appear to outweigh the risks in most patients, the potential risks for those with moderate or severe comorbidity should be considered when planning therapy.

Duration — For males with high-/very high-risk disease treated with EBRT with or without brachytherapy, we recommend long-term ADT (ie, 12 to 36 months versus 2 to 4 months) plus RT rather than RT alone. The optimal duration of ADT has not been definitively determined, but we typically continue ADT for 24-months. Individuals who place a greater value on QOL during treatment might reasonably choose to limit ADT to 12 to 18 months of therapy.

The optimal duration of ADT has not been definitively determined. Guidelines from ASCO, which largely endorse year 2018 guidelines from the AUA/ASTRO/Society of Urologic Oncology [3,99], generally recommend treatment for 24 to 36 months rather than a shorter duration of treatment. Updated year 2022 guidelines from AUA/ ASTRO recommend treatment for 18 to 36 months in this setting [53].

The main drawback of prolonged ADT is the higher incidence of clinically important side effects, such as impotence, loss of libido, long-term hypogonadism, osteoporosis, and possibly, cardiovascular issues, although there does not appear to be an increase in cardiovascular mortality. Importantly, testosterone recovery rates have not been consistently assessed in the available studies comparing short versus longer duration of ADT. ADT regimens of various lengths have the potential for long-term and potentially life-long castration. (See 'Risks' above.)

Efforts to minimize the impact of prolonged ADT have led to several trials that have compared shorter with longer courses of ADT [100-112]. These included comparisons of 24 versus 4 months (RTOG 9202 and DART01/01 GICOR), 18 versus 6 months (RADAR), and 36 versus 6 months (EORTC 22961). (See "Side effects of androgen deprivation therapy".)

The issue of ADT duration was addressed in an individual patient data meta-analysis of trials examining adjuvant ADT prolongation when used in conjunction with RT for high- or intermediate-risk prostate cancer [85]. Across four randomized trials (3774 patients, median follow-up 10.9 years), the addition of prolonged ADT (ie, 13 to 36 versus 2 to 6 months) to RT significantly prolonged metastasis-free survival (HR 0.84, 95% CI 0.78-0.91), corresponding to a 10-year absolute benefit of 7.7 percent (95% CI 4.0-11.4). Prolonged ADT also improved overall survival (HR 0.85, 95% CI 0.78-0.94), corresponding to an absolute 10-year benefit of 5.6 percent (95% CI 2.0-9.2). The benefits extended to all risk group, patient age, or radiotherapy dose, and the p-value for interaction in all subsets was significant.

In the only trial comparing two different "prolonged therapy" ADT options, 630 males with high-risk (T3/4, PSA >20 ng/mL, or Gleason score >7), node-negative prostate cancer were randomly assigned to either 18 or 36 months of ADT beginning prior to RT [108]. At a median follow-up of 9.4 years, there were no statistically significant differences between 18 and 36 months of ADT in 5-year (86 versus 91 percent) or 10-year overall survival (62 percent in both groups), the global HR for death (1.02, 95% CI 0.81-1.29), or the rates of biochemical treatment failure (31 versus 25 percent). QOL analysis showed a significant difference in 6 of 21 scales (physical, emotional, and social functioning; fatigue; hormone treatment-related symptoms; and sexual activity) and 13 items favoring 18 months of therapy, with two scales (hot flushes and enjoyable sex) judged as clinically relevant given the difference in mean scores of over 10 points.

The authors concluded that 36 months was not superior to 18 months of ADT. However, the trial was not designed as a noninferiority trial, and we believe that such trials will need to meet noninferiority criteria to supplant the current standard of a longer duration of ADT. As a result, we continue to prefer a longer duration of ADT for most males (typically 24 rather than 36 months, based on RTOG 9202 [100,101]), particularly those with very high-risk disease. Nevertheless, individuals who place a greater value on QOL during treatment and a relatively lesser value on the uncertainty of prostate cancer-related outcomes might reasonably choose to limit ADT to 12 to 18 months of therapy, an approach that was used in the ASCENDE-RT trial [59]. (See 'EBRT with brachytherapy boost' above.)

Gleason grade group 5 disease — We do not advocate lifelong ADT after RT for males with grade group 5 prostate cancer without distant metastatic spread. We treat most of these males with 24 months of ADT, followed by close PSA monitoring. Patients receiving definitive treatment for prostate cancer with histologic grade group 5 disease have a worse outcome than do those with lower grade group scores. However, in general, this is not a failure to control disease locally and, instead, reflects a high rate of micrometastases present at diagnosis. (See "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'Biopsy grade group 5 (Gleason score 9 or 10)'.)

At least some data suggest that lifelong ADT may be beneficial in this population. In an individual patient data meta-analysis of 992 males (593 with Gleason grade group 4 and 399 with Gleason grade group 5 disease) treated with RT for prostate cancer who were enrolled in six randomized trials testing the optimal duration of ADT, lifelong ADT improved overall survival in those with Gleason grade group 5 disease (HR for death 0.48, 95% CI 0.31-0.76), whereas neither short-term nor long-term ADT did [113]. By contrast, among males with Gleason grade group 4 disease, both long-term and short-term ADT improved overall survival over RT alone, but lifelong ADT did not.

Intermediate-risk disease — For most males with UIR disease, we suggest combined RT plus ADT rather than RT alone. Consistent with guidelines from the NCCN and AUA/ASTRO, our approach is to combine RT with a four- to six-month course of ADT [37,53]. For males with FIR disease who choose RT, we treat with RT alone. For most males we initiate ADT prior to rather than concurrent with RT. There is no consensus as to the optimal duration of neoadjuvant ADT, and practice varies.

A role for ADT in males choosing RT is less well established for intermediate-risk than high-risk disease. The following data are available:

●Randomized trials – Three large randomized trials provide some evidence in support of the addition of ADT to RT in males with intermediate-risk disease, especially for UIR [114-118]. The two largest are described below:

•In the EORTC 22991 trial, 819 patients were randomly assigned to RT with or without six months of ADT; 75 percent had intermediate-risk disease and 25 percent had high-risk disease [115]. The dose of RT was 70, 74, or 78 Gy and was standardized by treatment center.

At a median follow-up of 7.2 years, biochemical disease-free survival was significantly improved with the use of ADT (five-year rate 83 versus 70 percent, HR 0.52, 95% CI 0.41-0.66). Similarly, the clinical PFS was significantly improved with the use of a six-month course of ADT (five-year rate 88.7 versus 80.8 percent, HR 0.63, 95% CI 0.48-0.84). These results were maintained in a later analysis at a median follow-up of over 12 years, and 10-year overall survival also favored the addition of ADT, although the difference was not statistically significant (80 versus 74 percent, HR 0.74, 95% CI 0.53-1.04) [116].

•Additional information is available from a secondary analysis [117] of the RTOG 9408 trial, in which males with intermediate-risk disease were randomly assigned to RT with or without four months of ADT [118]. A total of 890 males could be characterized as having FIR (n = 377) or UIR (n = 513). Compared with those with FIR, patients with UIR had a higher risk of distant metastases, prostate cancer-specific mortality, and all-cause mortality, and the addition of ADT to RT in this group improved distant metastases and prostate cancer-specific mortality. By contrast, for the males with FIR, the addition of ADT to RT did not improve distant metastases, prostate cancer-specific mortality, or all-cause mortality.

●Meta-analysis – Further support for the benefit of ADT in conjunction with RT for intermediate-risk disease is provided by the individual patient data meta-analysis described above [85]. The addition of ADT to RT significantly prolonged metastasis-free survival (HR 0.83, 95% CI 0.77-0.89), and the benefits were seen regardless of risk group. In subset analysis, metastasis-free survival favored the addition of ADT to RT for both high-risk (HR 0.72, 95% CI 0.64-0.82) and intermediate-risk disease (HR 0.84, 95% CI 0.75-0.93), and the p test for interaction was significant (p = 0.0014). (See 'Benefits' above.)

For males considering the addition of ADT to RT for UIR, the additional prognostic value derived from tissue-based molecular assays may also help inform the decision [119,120]. (See "Molecular prognostic tests for prostate cancer", section on 'Clinical utility and guidelines from expert groups'.)

Sequencing and duration — For most males with high- or intermediate-risk disease who are beginning treatment with RT, we suggest initiating ADT prior to rather than initiating in the adjuvant setting. Some data suggest initiating androgen deprivation concurrently may be an appropriate alternative.

There is no consensus as to the optimal duration of neoadjuvant ADT, and practice varies. For most individuals with high-risk disease, we suggest two to eight months of neoadjuvant ADT before commencing RT, while for those with intermediate-risk disease, we suggest two to three months of neoadjuvant ADT rather than a longer duration.

Longer durations of neoadjuvant therapy (ie, seven to eight months versus two to three months) may maximize cytoreduction prior to EBRT or brachytherapy, and achieve a greater prostate volume reduction [121,122]. However, clinical practice varies, and the issue of neoadjuvant versus concurrent plus adjuvant ADT is not addressed in guidelines from the NCCN [37] or in published guidelines from ASCO or AUA/ASTRO [3,53].

While some of the data are inconsistent with respect to identifying whether there is an optimal sequencing [123,124] and duration of neoadjuvant ADT in patients receiving EBRT for localized prostate cancer [75,125], the majority of the studies and most common clinical practice support the use of two to eight months of neoadjuvant ADT prior to and concurrent with RT.

The following studies have addressed optimal sequencing and duration of ADT during RT:

●Is there benefit for neoadjuvant versus adjuvant ADT during RT? – Randomized trials have demonstrated conflicting results in regards to initiating ADT in the neoadjuvant setting versus during or after RT. Meta-analyses suggest some benefits with adjuvant administration in patients receiving PORT (rather than WPRT), but have methodologic issues.

As an example, in an analysis of patient level data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT with RT for localized disease, the following was observed [124]:

•In 3049 patients receiving WPRT, ADT sequenced either before or after RT was associated with similar progression-free and overall survival; however, adjuvant/concurrent therapy was associated with higher rates of distant metastases (HR 1.6, 95% CI 1.2-2.1).

•In 4355 patients receiving PORT, concurrent/adjuvant ADT was associated with improved overall survival (HR 0.69, 95% CI 0.57-0.83), as well as metastasis-free survival (10-year benefit 8 percent, HR 0.65), distant metastases (HR 0.52), and prostate cancer–specific mortality (HR 0.30).

By contrast, although a previous meta-analysis of two randomized trials in males receiving PORT showed improved PFS with adjuvant versus neoadjuvant/concurrent ADT (15-year survival of 36 versus 29 percent), metastasis-free and overall survival were similar [126].

Overall, we do not consider these data sufficient to justify initiating ADT in the adjuvant setting. The interpretation of the data on the sequencing of ADT and EBRT continues to evolve. Based on available evidence, the most common practice is to give ADT prior to EBRT or concomitantly.

●Duration – The most important trials examining the optimal duration of neoadjuvant ADT are as follows:

•Two versus seven months – The benefit of delaying the start of RT was studied in 1489 evaluable males with prostate cancer in the RTOG trial 9910; 84 percent of the males had intermediate-risk disease, and 16 percent had high-risk disease [127]. Patients were randomly assigned to either two or seven months of ADT initially, which was followed in both groups by an additional two months of androgen suppression given in combination with RT. Androgen suppression consisted of a GnRH plus an antiandrogen (bicalutamide or flutamide) throughout the treatment course. RT dose was 70.2 Gy in 39 fractions.

At a median follow-up of 9.4 years, there were no statistically significant differences for the two- versus seven-month groups in any of the efficacy outcomes: 10-year disease-specific survival (95 and 96 percent), 10-year overall survival (66 and 67 percent), 10-year cumulative incidence of distant metastasis (6 and 6 percent), or 10-year biochemical recurrence rate (27 and 27 percent).

•Three versus eight months – On the other hand, better prostate cancer-specific outcomes with a longer duration of therapy were noted in a Canadian trial of 378 males with low-, intermediate-, or high-risk localized prostate cancer who were randomly assigned to three versus eight months of neoadjuvant ADT prior to conventionally dosed RT (66 Gy) [128]. A longer period of hormone therapy prior to RT did not alter the patterns of failure, although males with high-risk disease who received longer duration therapy had a significant improvement in five-year disease-free survival (71 versus 42 percent).

•Meta-analysis – The issue of neoadjuvant ADT duration in males undergoing RT for high-risk or intermediate-risk prostate cancer was addressed in the individual patient data meta-analysis described above [85]. Across three randomized trials (2213 patients, median follow-up 10.3 years), the addition of prolonged neoadjuvant ADT (ie, five to eight versus two to three months) to RT did not significantly prolong metastasis-free survival (HR 0.95, 95% CI 0.83-1.09). Prolonged neoadjuvant ADT also did not improve overall survival (HR 0.95, 95% CI 0.82-1.10). In subset analysis, benefit for prolonged therapy could not be shown for either the high-risk or intermediate risk subgroups.

GnRH agonist alone versus combined androgen blockade — Whether ADT should consist of a GnRH agonist alone or with the addition of an antiandrogen during treatment initiation has not been addressed in a randomized trial. Data from an observational study support the addition of an antiandrogen, but they were derived from a series in which ADT was given for a median duration of only four months [129]. Current protocols from the NRG/RTOG use an antiandrogen in combination with a GnRH agonist during the first four months of therapy. We agree with this approach.

Brachytherapy plus androgen deprivation therapy — There are no results from randomized trials that have evaluated the role of ADT in patients with intermediate-risk prostate cancer who are treated with brachytherapy, whether given alone or in conjunction with EBRT, and we do not pursue this approach. Information to guide clinical practice is expected from the ongoing RTOG 0815 trial includes patients who are treated with brachytherapy with or without short-term ADT.

The most extensive observational data come from a multicenter study of 1342 males who were treated with brachytherapy either alone, with ADT, with EBRT, or with ADT plus EBRT [130]. All patients had high-risk or locally advanced disease, defined by a serum PSA >20 ng/mL, clinical T3 or T4 disease, and/or a Gleason score of 8 to 10. ADT was given for an average of four months and was completed prior to brachytherapy. Median follow-up was five years.

Factors associated with a poorer prognosis and increased cancer-specific mortality included a clinical stage T2 or T3 primary tumor, a Gleason score of 8 to 10, and a higher serum PSA. A combined modality approach was used more frequently in patients with multiple negative prognostic factors, and these patients had a higher mortality. However, multivariate analysis incorporating all of these factors found that prostate cancer-specific mortality was significantly lower in patients treated with brachytherapy plus both EBRT and ADT compared with brachytherapy alone (adjusted HR 0.32, 95% CI 0.14-0.73).

The differences in prostate cancer-specific mortality with brachytherapy alone versus either brachytherapy plus EBRT without ADT or brachytherapy plus ADT without EBRT were not statistically significant.

Intensification of systemic therapy

Addition of abiraterone plus prednisone — For most patients with high-risk disease (either involved lymph nodes or at least two of the following: tumor stage T3 or T4, International Society of Urological Pathology grade group 4 to 5, PSA ≥40 ng/mL) who are being managed with RT, we discuss the risks and benefits of adding abiraterone plus prednisone to ADT, and individualize decision making based on patient preference. While combined treatment may improve oncologic outcomes compared with ADT alone, treatment-related toxicity is also clearly worse.

The STAMPEDE platform trials were conducted predominantly in the UK and Switzerland; they recruited patients with advanced prostate cancer who were starting ADT, stratified by the presence or absence of distant metastases at presentation, and tested the benefit of adding docetaxel, abiraterone, or abiraterone plus enzalutamide to ADT. Outcomes analyses for populations who were enrolled with metastatic disease are presented elsewhere [131,132]. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus docetaxel' and "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus abiraterone'.)

Two separate STAMPEDE trials conducted between 2011 and 2016 had overlapping eligibility criteria, enrolled both metastatic and nonmetastatic patients, and were designed to evaluate the efficacy of adding abiraterone plus prednisone or abiraterone plus prednisone and enzalutamide to ADT:

●The first trial (the abiraterone trial) included 914 males with high-risk nonmetastatic prostate cancer who were randomized to ADT alone (three years) or ADT plus abiraterone (1000 mg daily plus a low-dose glucocorticoid) for two years.

●The second trial (the abiraterone plus enzalutamide trial) included 1060 males with high-risk nonmetastatic disease who were allocated to ADT alone or abiraterone (1000 mg daily plus an oral low-dose glucocorticoid) plus enzalutamide (160 mg daily orally for two years).

Local RT was administered as a standard of care to 85 percent of the participants in both trials; it was mandated for those with clinically node-negative disease, and encouraged for those with node-positive disease. The primary outcome measure for both trials in the nonmetastatic population was metastasis-free survival.

Outcomes for patients with high-risk nonmetastatic disease were addressed in a pooled analysis of both trials [133]. Because of similar eligibility, the control groups from both groups were combined for the analysis. In addition, both experimental groups (ADT plus abiraterone with or without enzalutamide) were also pooled for the analysis, given that two other contemporary trials combining abiraterone with either enzalutamide or a related agent, apalutamide, had failed to show any advantage to combined therapy. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Combining abiraterone and an AR antagonist'.)

At a median follow-up of 72 months, compared with ADT alone, combination therapy (abiraterone plus prednisone with or without enzalutamide) was associated with a significantly better metastasis-free survival (HR 0.53, 95% CI 0.44-0.64; six-year metastasis-free survival 82 versus 69 percent), but there was no evidence of a metastasis-free survival benefit when enzalutamide plus abiraterone was compared with abiraterone alone (interaction HR 1.02, 95% CI 0.70-1.5). Combination therapy provided other benefits over ADT alone as well, including better overall survival (HR 0.6, 95% CI 0.48-0.73), prostate cancer-specific survival (HR 0.49, 95% CI 0.37-0.65), biochemical failure-free survival (HR 0.39, 95% CI 0.33-0.47), and median PFS (HR 0.44, 95% CI 0.36-0.54). Treatment-related toxicity was clearly worse with combined abiraterone plus enzalutamide (grade 3 or worse adverse events in 57 percent versus 37 percent with ADT plus abiraterone and 29 to 32 percent for both control groups).

Role of chemotherapy — Chemotherapy in conjunction with RT does not yet have an established role as part of a combined modality approach for high-risk or locally advanced prostate cancer, but this is an evolving, active area.

Several trials have explored the benefit of adding docetaxel-based chemotherapy to ADT and RT, but the results are conflicting.

Several reports suggest potential benefit for this approach:

●In the GETUG 12 trial, 413 patients with high-risk localized prostate cancer were randomly assigned to the combination of docetaxel, prednisone, and estramustine in conjunction with ADT for three years or to ADT alone [134]. Definitive local therapy (RT in 87 percent of cases) was given three months after initiation of ADT with or without chemotherapy. With a median follow-up of 8.8 years, there was a trend toward improvement in the eight-year RFS rate with chemotherapy plus ADT versus ADT alone (62 versus 50 percent, HR 0.71, 95% CI 0.54-0.94).

●In RTOG 0521, 563 evaluable patients were treated with ADT for two years beginning two months prior to RT (72 to 75 Gy) [135]. Those randomly assigned to chemotherapy also received docetaxel (75 mg/m²) plus prednisone for six cycles beginning one month after the completion of RT. All patients had high-risk disease: median serum PSA was 15 ng/mL, 53 percent had Gleason 9 or 10 disease, and 27 percent had clinical T3 or T4 disease. At a median follow-up of 5.7 years, overall survival was improved with adjuvant chemotherapy (four-year overall survival rate 93 versus 89 percent, HR 0.69, 95% CI 0.49-0.97). Disease-free survival was improved with the addition of chemotherapy compared with ADT alone (six-year disease-free survival rate 65 versus 55 percent, HR 0.76, 95% CI 0.58-0.99).

●Additional evidence supporting a potential role for chemotherapy in high-risk patients comes from the STAMPEDE trial, which included males with both metastatic disease and high-risk nonmetastatic disease [131]. In that trial, 22 percent of patients had no evidence of lymph node or distant metastases (N0M0), and 14 percent had lymph node but not distant metastases (N1M0). The results of that trial are discussed separately. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'ADT plus abiraterone, docetaxel, or apalutamide'.)

On the other hand, three trials do not support any benefit from the addition of docetaxel to RT and ADT [136-138]. In the largest of these, 376 patients were randomized to six cycles of adjuvant docetaxel or surveillance following RT for intermediate- or high-risk prostate cancer. Treatment also included neoadjuvant/adjuvant ADT [136]. With a median follow-up of 59 months, there was no difference in the biochemical disease-free survival comparing docetaxel with surveillance (HR 1.14, 95% CI 0.79-1.64).

CLINICAL EVIDENCE OF LYMPH NODE INVOLVEMENT — Lymph node involvement may be diagnosed clinically based on imaging studies prior to definitive treatment.

For most males who are candidates for definitive therapy, radiation therapy (RT) including the whole pelvis in conjunction with androgen deprivation therapy (ADT) given before, concurrently (two months before and during), and postradiation is the preferred option. Extrapolating from the experience with patients with regionally localized high-risk prostate cancer, ADT should be continued for a total of 18 to 24 months after RT.

Although radical prostatectomy (RP) is not included in guideline statements (including those of the National Comprehensive Cancer Network), increasing numbers of retrospective series suggest a benefit for carefully selected patients. We reserve this approach for healthy patients with grade group 4 and 5 disease and minimal suspected regional lymphatic spread. There is no consensus on this definition, but one that we utilize is regional nodes that are positron emission tomography scan positive only or less than 2 cm on cross-sectional imaging. If surgery is chosen, we employ a combination strategy that includes postoperative ADT and/or RT.

Males with clinical evidence of lymph node involvement are classified as having stage IV disease (table 1A and table 1B), regardless of the extent of their primary tumor, and thus, are not officially categorized as having either intermediate- or high-risk prostate cancer. However, clinical evidence of lymph node involvement (stage IVA disease) in the absence of distant metastases does not preclude definitive therapy. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'Evaluation of the regional lymph nodes'.)

While there are no randomized trials establishing the role of definitive therapy in males with clinically evident lymph nodes, observational data from large and comprehensive population-based studies suggest that initial radical therapy in males at high risk of disseminated prostate cancer may provide selected patients with survival benefits [139-143]. The selection criteria remain undefined and at the discretion of a well-communicated discussion between the patient and clinician.

The benefits of local therapy can be illustrated by an analysis from the National Cancer Database that identified 2967 males with clinically node-positive prostate cancer without distant metastases (stage IVA (table 1A-B)) at presentation [139]. Overall, 1987 males were treated with definitive local therapy (either RT, with or without ADT, or RP, with or without ADT), and 980 received ADT alone. Definitive local therapy was associated with a significantly better overall mortality-free survival at five years compared with ADT alone (78.8 versus 49.2 percent, hazard ratio [HR] 0.31, 95% CI 0.13-0.74). There was no statistically significant difference between those treated with RT and those managed with RP. Although there were important baseline differences between males treated with definitive local therapy and those managed with ADT alone, the difference in overall mortality-free survival remained significant on multivariate analysis.

Another propensity-score-adjusted analysis of outcomes for males with locally advanced (T3-4N0) or regionally advanced (T3-4N1) prostate cancer derived from the Surveillance, Epidemiology, and End Results database of the National Cancer Institute concluded that males treated with RP plus RT had a lower risk of prostate cancer-specific mortality than did those undergoing RT plus ADT, albeit with higher rates of erectile dysfunction and urinary incontinence [144]. However, retrospective analyses such as these are limited because of unmeasured confounding bias and selection bias that may have accounted for at least a portion of the observed survival difference.

Other population-based observational series also support a survival benefit for definitive treatment in males with clinically node-positive prostate cancer [140].

Role of ADT with or without abiraterone — For most patients with involved lymph nodes who are being managed with RT, we discuss the risks and benefits of adding abiraterone plus prednisone to ADT, and individualize decision making based on patient preference. While combined treatment may improve oncologic outcomes compared with ADT alone, treatment-related toxicity is also clearly worse.

While there are no randomized trials comparing RT alone with RT plus ADT that were conducted exclusively in males with clinical evidence of lymph node involvement, the available data in males with high-risk localized disease and trials that included some patients with pathologic lymph node involvement demonstrate that the addition of ADT to RT improves local control and decreases the incidence of distant metastases. We generally suggest both neoadjuvant and concurrent ADT (two months before and during RT), based on results from Radiation Therapy Oncology Group (RTOG) 9413 [75]. (See 'High-risk disease' above.)

In this setting, the addition of abiraterone to ADT should be strongly considered. This issue is addressed above [133]. (See 'Addition of abiraterone plus prednisone' above.)

Management of males with pathologic node involvement after RP for prostate cancer is discussed in more detail elsewhere. (See "Prostate cancer: Postoperative management of pathologic stage T3 disease, positive surgical margins, and lymph node involvement following radical prostatectomy", section on 'Lymph node involvement'.)

SURVEILLANCE AFTER TREATMENT — Surveillance strategies following initial definitive treatment are discussed separately. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of prostate cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic

SUMMARY AND RECOMMENDATIONS

●Risk stratification – Newly diagnosed prostate cancer is risk stratified based on digital rectal examination, serum prostate-specific antigen (PSA), prostate biopsy, and imaging studies (table 3). Intermediate-risk disease is further subdivided into favorable and unfavorable subsets, although definitions vary (table 7). (See 'Risk stratification and staging' above.)

●Candidates for definitive local therapy: selection of treatment strategy

•Intermediate-risk

-For patients with favorable intermediate-risk (FIR) disease, we suggest definitive local therapy rather than active surveillance (AS) (Grade 2C). However, for selected patients who do not have of areas of cribriform or intraductal histology, are willing to accept a potentially higher risk of developing metastases, are comfortable with the psychosocial burden of living with an indolent cancer without active treatment, and willing to undergo monitoring for disease progression, AS is an alternative to definitive local therapy, especially for those with a shorter life expectancy (ie, <10 years). (See 'Options for intermediate-risk disease' above and 'Active surveillance' above.)

-For patients with unfavorable intermediate-risk (UIR) disease, we suggest definitive local therapy rather than AS (Grade 2B).

•High- or very high-risk – For patients with high- or very high-risk disease, we recommend definitive local therapy rather than AS (Grade 1B). We do not offer AS to males with high-risk prostate cancer. (See 'Males who are not candidates for definitive local therapy' above.)

•Selecting a definitive local therapy – The choice between radiation therapy (RT) versus radical prostatectomy (RP) is individualized based on the advantages and disadvantages associated with each approach, contraindications, and personal preferences (table 4 and table 5 and table 6). For males with intractable non-cancer-related lower urinary tract obstructive symptoms, RP may be preferred over RT. Tumor fixation to adjacent structures is a contraindication to RP. (See 'Radiation therapy versus prostatectomy' above.)

•RP is selected – For most males undergoing RP, we suggest not using neoadjuvant androgen deprivation therapy (ADT) prior to RP (Grade 2C). Randomized trials proving benefit are lacking, but some clinicians, including some of the authors and editors associated with this topic review, inform patients of promising data from newer phase II trials and individualize decision making. (See 'Neoadjuvant ADT approaches' above.)

Pelvic lymphadenectomy is recommended during RP for those with high- or UIR disease. (See "Radical prostatectomy for localized prostate cancer".)

The use of adjuvant ADT is discussed separately. (See "Prostate cancer: Postoperative management of pathologic stage T3 disease, positive surgical margins, and lymph node involvement following radical prostatectomy".)

•Radiation therapy is selected – Options for RT include external beam RT (EBRT) to the prostate alone with or without a brachytherapy boost, brachytherapy alone, or whole pelvis RT. (See 'Radiation therapy' above.)

-Choice of technique

For most males with intermediate-risk disease, we suggest EBRT with or without brachytherapy rather than brachytherapy alone (Grade 2C). However, brachytherapy alone can be used to treat selected patients with FIR disease. (See 'EBRT with brachytherapy boost' above.)

For most patients, the choice between EBRT plus brachytherapy versus EBRT alone is individualized based on individual values and preferences. Combined treatment may improve clinical outcomes but increase toxicity. However, for males with grade group 5 disease (table 2) we suggest EBRT plus brachytherapy over EBRT alone (Grade 2C). Prior transurethral resection of the prostate or significant lower urinary tract symptoms are relative contraindications for brachytherapy. (See 'EBRT with brachytherapy boost' above.)

At some institutions, males without clinical evidence of pelvic lymphadenopathy who have an estimated risk of nodal involvement >15 percent are offered elective whole-pelvis radiation therapy. In our view, this is acceptable but not mandatory. (See 'Whole-pelvis versus prostate-only radiation therapy' above.)

-Role and duration of ADT – For males with high- or very high-risk disease, we recommend ADT plus EBRT rather than EBRT alone (Grade 1A).

For most males with UIR, we suggest neoadjuvant ADT rather than RT alone (Grade 2B). We start two to three months prior to RT, and continue during and afterward to complete a total of four to six months of ADT. (See 'Intermediate-risk disease' above.)

For patients receiving ADT and RT, we suggest initiating ADT two to eight months prior to RT rather than adjuvant RT (Grade 2C), although some data suggest initiating androgen deprivation concurrently may be an appropriate alternative. We typically continue ADT for 24 months, although individuals who place a greater value on quality of life during treatment might reasonably choose to limit ADT to 12 to 18 months. (See 'High-risk disease' above.)

For males with FIR who choose RT, we suggest RT alone rather than with neoadjuvant or adjuvant ADT (Grade 2C).

-Role of other agents – For most patients with high-risk disease (either involved lymph nodes or at least two of the following: tumor stage T3 or T4, International Society of Urological Pathology grade group 4 to 5, PSA ≥40 ng/mL) who are being managed with RT, we discuss the risks and benefits of adding abiraterone plus prednisone to ADT, and individualize decision making based on patient preference. While combined treatment may improve oncologic outcomes compared with ADT alone, treatment-related toxicity is also clearly worse. (See 'Addition of abiraterone plus prednisone' above.)

•Clinical lymph node involvement

-For most patients with clinical lymph node involvement, we suggest local definitive therapy rather than ADT alone, given the potential benefits for prostate cancer-related mortality (Grade 2C). (See 'Clinical evidence of lymph node involvement' above.)

-If definitive therapy is chosen, for most males, we suggest prostate plus whole pelvis RT rather than RP (Grade 2C). Extrapolating from the experience with patients with regionally localized high-risk prostate cancer, we initiate ADT prior to RT and continue ADT for a total of 24 months after RT.

-For most patients with involved lymph nodes who are being managed with RT, we discuss the risks and benefits of adding abiraterone plus prednisone to ADT, and individualize decision making based on patient preference. While combined treatment may improve oncologic outcomes compared with ADT alone, treatment-related toxicity is also clearly worse. (See 'Addition of abiraterone plus prednisone' above.)

-RP is a reasonable alternative for healthy patients with grade group 4 and 5 disease (table 2) and minimal suspected regional lymphatic spread. If surgery is chosen, we employ a combination strategy that includes postoperative ADT and/or RT. (See "Prostate cancer: Postoperative management of pathologic stage T3 disease, positive surgical margins, and lymph node involvement following radical prostatectomy".)

●Age or comorbidity precludes definitive therapy – For such patients, systemic therapy with ADT is useful to delay progression of disease and as a palliative approach. (See 'Males who are not candidates for definitive local therapy' above.)

ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate acknowledges Dr. Vogelzang's past work as an author for this topic.