Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer

INTRODUCTION — Prostate-specific antigen (PSA) is a sensitive and specific serum marker for prostate tissue. Serial measurements are routinely obtained to detect early disease recurrence in males who have received definitive treatment for localized disease. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)

Monitoring PSA after definitive treatment of localized prostate cancer with either radiation therapy or radical prostatectomy leads to the identification of patients with a PSA-only (biochemical) recurrence. In this situation, increases in serum PSA are not accompanied by signs, symptoms, or radiographic evidence of locally recurrent or disseminated disease. Most of these individuals have testosterone levels that are >50 ng/mL, and their prostate cancer is described as castration-sensitive, and potentially responsive to conventional androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) agonist, GnRH antagonist, or orchiectomy. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Definition of biochemical progression'.)

For patients with biochemical recurrence in whom there is a significant likelihood that disease is confined to the prostatic bed after surgery local salvage therapy may result in prolonged disease-free survival [1,2]. (See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy" and "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management".)

Systemic treatment may be indicated for some of these patients when clinical and radiographic features suggest that disseminated disease is highly probable, and hence, salvage local therapy is not indicated. ADT may also be indicated in the setting of a biochemical recurrence when comorbidity or advanced age precludes local salvage therapy. The timing of such therapy is debated.

The role of ADT in the treatment of patients with a biochemical recurrence after definitive local therapy will be reviewed here. The management of patients with castration-sensitive disseminated or locoregionally advanced recurrent prostate cancer is discussed separately, as is the treatment of castration-resistant disease in those without disseminated metastases. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer" and "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer" and "Castration-resistant prostate cancer: Treatments targeting the androgen pathway".)

OVERVIEW OF THE GENERAL APPROACH — Monitoring prostate-specific antigen (PSA) after treatment of localized prostate cancer can lead to the identification of patients with a PSA-only (biochemical) recurrence. In this situation, increases in serum PSA over the baseline after initial treatment are not accompanied by symptoms or signs of locally recurrent or metastatic disease. Although most patients who have a rising serum PSA following definitive therapy (radiation therapy [RT] or radical prostatectomy [RP]) will not have evidence of disseminated disease (which includes pelvic nodal disease), careful evaluation is required to rule out the possibility of distant metastases prior to attempts at local salvage therapy. Imaging should be performed to evaluate for metastasis, especially in cases with initial high-risk disease and/or short PSA doubling time.

Notably, as newer more sensitive prostate-specific membrane antigen (PSMA)-based tracers for integrated positron emission tomography (PET)/computed tomography become more widely available stage-migration will occur whereby the number of patients with biochemical recurrence will shrink as a newly defined category of patients with PSA-recurrence with positive PET findings will be defined. This phenomenon will likely mean the prognosis for patients with a truly isolated biochemical recurrence will improve with time. For the purpose of this topic review distant metastasis will be defined as those that are detected using conventional, non-PET imaging. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation".)

Local salvage therapy option available — Many of these individuals are relatively young and otherwise healthy. If, after imaging evaluation, there is a significant likelihood that the clinically occult recurrent disease is confined to the prostate gland, local salvage therapy may result in prolonged disease-free survival. The following represents our general approach to integrating systemic therapy in these patients:

●For patients with a confirmed rise in serum PSA following prior RT and no suspicion for pelvic nodal or distant metastases, biopsy of the prostate is indicated to confirm the presence of residual or recurrent prostate cancer.

•For patients with a positive biopsy who are candidates for local salvage therapy, treatment options include RP, cryotherapy, and brachytherapy. (See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)

•For patients who have received definitive RT but are not candidates for salvage therapy, systemic therapy may be indicated. However, in this situation, the possibility that the rising serum PSA is due to benign prostatic hyperplasia or retained normal prostate should be considered, and a three to six month period of surveillance or trial of a 5-alpha reductase inhibitor should be considered prior to committing to systemic therapy.

●For patients who have had a RP and a confirmed serum PSA ≥0.2 ng/mL with no evidence of distant metastases, salvage RT, often combined with androgen deprivation therapy (ADT), is the primary treatment option. However, systemic therapy (ADT alone or in combination with an antiandrogen) is an alternative for those who are not candidates for or refuse salvage RT. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management".)

●Systemic therapy is also the primary therapeutic option for patients who have had local salvage therapy following their initial definitive treatment and who subsequently have an ongoing or recurrent isolated biochemical recurrence with noncastrate serum levels of testosterone (>50 ng/dL).

Local salvage therapy not feasible — Our approach to systemic therapy for castration-sensitive prostate cancer with isolated biochemical recurrence that is not amenable to salvage local therapy is consistent with updated guidelines from the American Society of Clinical Oncology (ASCO) [3] and is discussed below.

High-risk features — In males with a high-risk biochemical recurrence in whom local salvage therapy is not feasible, we suggest enzalutamide and ADT, given that these males have a higher chance of developing metastatic disease. In males with a higher risk for toxicity such as individuals with uncontrolled hypertension, seizure disorder, or have frailty ADT alone is an acceptable alternative. The use of enzalutamide alone may be an option for select patients who do not wish to receive ADT due to concerns of toxicity. (See 'Complete androgen blockade' below.)

We use ASCO guidelines, which define high-risk features as:

•For those who underwent radical prostatectomy (RP): A PSA doubling time <1 year or Gleason score 8-10; OR

•For those who underwent radiation therapy (RT): An interval to biochemical recurrence <18 months or a Gleason score of 8 to 10 [3].

However, the definition of high risk varies among trials and society guidelines. Others may reasonably define high risk to include a PSA doubling time of ≤9 months, based on a randomized trial that showed an OS benefit with enzalutamide and ADT in this population [4].

Low-risk features — In males with no high-risk features present, surveillance is preferred. ADT therapy can cause significant side effects without a clear benefit in low-risk patients. However, in those patients that value potentially maximizing survival more than the potential impact on quality of life, ADT is an option after a detailed discussion about potential toxicity and benefit.

If systemic therapy is started for an isolated biochemical recurrence with a serum testosterone level >50 ng/dL, we suggest conventional ADT monotherapy (a gonadotropin-releasing hormone [GnRH] agonist, GnRH antagonist, or orchiectomy) rather than complete androgen blockade, combined androgen blockade, antiandrogen monotherapy, or a 5-alpha reductase inhibitor. (See 'ADT monotherapy' below and 'Complete androgen blockade' below and 'Nonsteroidal antiandrogens' below and '5-alpha reductase inhibitors' below.)

EFFICACY OF AVAILABLE SYSTEMIC THERAPY OPTIONS

ADT monotherapy — Select patients with high-risk features may elect for ADT monotherapy as an alternative to enzalutamide and ADT, particularly given that it reduces side effects. Select patients with low-risk features may opt for ADT instead of surveillance, particularly if they would accept toxicities in exchange for potentially extending survival. ADT includes options using a gonadotropin-releasing hormone (GnRH) agonist, GnRH antagonist, or orchiectomy.

The rationale and efficacy of ADT for advanced disseminated prostate cancer, including the various forms of ADT, is presented elsewhere. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Benefits and methods for androgen deprivation therapy'.)

No adequate data from randomized trials have compared the role of ADT with observation in patients with biochemical recurrence, and the applicability of data from individuals with more advanced disease is unclear. Nevertheless, ADT represents an effective form of therapy, and can reduce the likelihood of disease progression. The "PSA response" to ADT following biochemical recurrence may be useful as an intermediate end point for prognosis and to predict the time to prostate cancer death in patients with biochemical recurrence following radical prostatectomy (RP) or radiation therapy (RT). (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Risk of metastases or death'.)

However, in patients with biochemical recurrence after first-line treatment, metastatic disease may not become evident for many years. ADT causes side effects that can significantly lower the quality of life. These adverse effects are particularly important in otherwise asymptomatic individuals whose only manifestation of disease is a rising serum PSA. The potential development of hot flashes, fatigue, loss of libido, decreased muscle mass, mild anemia, cognitive changes, and osteoporosis is a significant concern and needs to be considered in deciding when to initiate ADT. Furthermore, concerns about ADT-induced weight gain and an increased risk for diabetes mellitus, cardiac disease, and metabolic syndrome add credence to the use of a risk-stratified approach. (See "Side effects of androgen deprivation therapy".)

Key questions concerning the use of ADT include whether treatment should be initiated as soon as a rising PSA is detected or can be delayed, and whether initial treatment with ADT should use monotherapy (eg, a GnRH agonist, GnRH antagonist, or orchiectomy), combined androgen blockade (CAB; a GnRH agonist or orchiectomy plus an antiandrogen), ADT in combination with chemotherapy or in combination with a second-generation androgen signaling inhibitor (such as abiraterone acetate plus prednisone), or an alternative approach.

When to initiate ADT-based therapy — The optimal timing of ADT for biochemical recurrence is debated [5]. We suggest initiating ADT early rather than late in patients with life expectancy of at least 10 years, have high-risk disease, and have decided against the combination of enzalutamide and ADT. There is no consensus on what is "early" initiation of ADT, but a practical target is a PSA <5 ng/mL (or perhaps <10 ng/mL for older individuals). This approach is consistent with updated guidelines from the American Society of Clinical Oncology (ASCO) [3].

Proponents of early treatment argue that this approach can delay disease progression and may prolong survival. Others contend that treatment is best deferred until clinical metastases or symptoms develop since there is no consistent evidence for a significant survival benefit with ADT in this setting, metastatic disease may not become evident for many years [6], and treatment is associated with adverse effects. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)

Observational data have not resolved the question of optimal timing for initiation of ADT in the setting of biochemical recurrence, but they suggest that the benefit from early ADT is limited to high-risk groups:

●In a series of 2096 males with a PSA-only relapse from the Cancer of the Prostate Strategic Urologic Research Endeavor database, there was a 2 percent difference in overall survival when individuals who were treated with ADT within three months after detection of PSA increase were compared with those who were not treated until there was evidence of clinical progression [7]. The difference was not statistically significant.

●An observational cohort study analyzed 5804 males from three managed care organizations who had a biochemical recurrence after definitive therapy (RP in 44 percent and RT in 54 percent) [8]. ADT was given to 44 percent of patients, and there were no statistically significant difference in overall survival or prostate cancer-specific survival for those given immediate salvage ADT. However, salvage ADT was associated with improved overall and prostate cancer-specific survival for those with a PSA doubling time less than nine months.

●A natural history study conducted by investigators at Johns Hopkins University described risk factors for development of metastases and death for prostate cancer [9,10]. Patients with biochemical relapse after RP at most risk for development of early metastases and death from prostate cancer had a Gleason score of 8 to 10, PSA relapse less than two years after RP, and PSA doubling time <10 months.

●In the (TROG 03.06 and VCOG PR 01-03 [TOAD]) trial that included 261 males with PSA relapse after definitive treatment and 32 males with noncurable disease, patients were randomly assigned to immediate or delayed ADT [11,12]. Although the trial was originally designed to include 750 patients, it was terminated after eight years because of poor accrual. The five-year overall survival was greater with immediate ADT (91 versus 86 percent, hazard ratio [HR] 0.55, 95% CI 0.3-1.0), but only 46 deaths were observed in the entire trial cohort. Thus, the trial has too few events to date and will be underpowered to make any definitive conclusions.

●A retrospective analysis of 432 males with biochemical recurrence after first-line RT (median follow-up 95 months) showed that a PSA doubling time (PSADT) <6 months predicted distant metastasis and survival, and the need for second-line ADT [13]. The proportion of males with biochemical failure receiving second-line ADT according to their PSADT were as follows:

•PSADT <6 months: 59 percent

•PSADT 6 to 12 months: 45 percent

•PSADT 12 to 18 months: 42 percent

•PSADT 18 to 24 months:36 percent

•PSADT >24 months: 28 percent

Seven-year freedom from distant metastasis rates were 50 percent for PSADT <6 months versus 83 percent for PSADT >6 months (p = 0.0001). Seven-year cause-specific survival was 61 percent for PSADT <6 months and 85 percent for PSADT >6 months (p = 0.0001). Seven-year overall survival was 47 percent for PSADT <6 months and 53 percent for PSADT >6 months (p = 0.04).

An ongoing Canadian trial (NCT00439751) is comparing early versus delayed treatment with goserelin in patients who have a biochemical recurrence following definitive RT.

Continuous versus intermittent ADT — For patients with biochemical recurrence after first-line or second-line local therapy, intermittent rather than continuous ADT is a reasonable option as the intermittent approach appears to be associated with better physical function and quality of life, although questions remain as to whether survival is noninferior to continuous ADT. For males who place a greater value on potentially maximizing overall survival, and a lesser value on avoiding/minimizing the side effects of ADT, continuous treatment might be preferred. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Intermittent versus continuous ADT'.)

Definition and rationale — Intermittent androgen deprivation (IAD) refers to cyclic administration of ADT:

●Induction treatment until maximal response

●Temporary withdrawal of ADT

●Monitoring of PSA and testosterone while off ADT

●Re-initiation based upon predefined threshold levels of serum PSA, which vary from 2.5 to 20 ng/mL

IAD attempts to minimize the adverse effects of medical castration by withdrawing treatment in patients who have responded to ADT and then reinstituting ADT when there is evidence of recurrent or progressive disease. The biologic rationale is twofold. First, prolonged ADT theoretically may facilitate progression from androgen dependence to androgen independence. In addition, many of the acute and chronic side effects of ADT are due to castrate levels of testosterone. Off-therapy periods of time may be associated with decreases in these side effects, thereby improving quality of life.

Males managed with IAD can be expected to be off therapy approximately 35 to 50 percent of the time. Time off treatment in the first cycle ranges from 6 to 15 months and may be longer for patients with less advanced disease, such as PSA-only progression with long PSA doubling time, compared with those with overt metastatic disease. The off-treatment period is generally associated with an improvement in the sense of wellbeing, and recovery of libido and potency in those who report normal or near-normal sexual function before the start of IAD.

Evidence in patients with an isolated biochemical recurrence — Multiple randomized trials and meta-analyses have addressed the benefit of IAD in patients with an biochemical recurrence. Although intermittent approaches are associated with better physical functioning and quality of life, questions remain as to whether or not overall survival is adversely impacted.

●In an early seminal international trial, 1386 males with a rising PSA following RT were randomly assigned to either IAD or continuous ADT [14]. Patients assigned to IAD were treated for eight months; treatment was then restarted when the serum PSA reached >10 ng/mL off treatment. The primary endpoint of the trial was overall survival. The statistical design of the trial was based upon the demonstration of noninferiority, with noninferiority defined by a true difference in overall survival of less than 8 percentage points, which corresponded to an HR <1.25.

•At a median follow-up of 6.9 years, overall survival with IAD met the study criterion for noninferiority compared with continuous ADT (median 8.8 versus 9.1 years, HR 1.02, 95% CI 0.86-1.21). Notably, individuals treated with IAD had more disease- or treatment-related deaths but fewer deaths unrelated to prostate cancer compared with continuous ADT (120 versus 94 and 148 versus 162 deaths, respectively).

•Analyses of quality of life suggested that there were modest benefits with IAD, but the results may have been limited by the timing of the quality of life assessments. Differences in functional domain did not show a statistically significant benefit for IAD. Specific symptoms that did show a statistically significant benefit included hot flashes, desire for sexual activity, and urinary symptoms. Among the patients treated with IAD, serum testosterone levels returned to pretreatment levels in only 35 percent within two years after initial cycle of treatment, and only 29 percent of individuals who were potent at baseline had a return of potency.

These results suggest that there is a potential benefit for IAD compared with continuous ADT in terms of quality of life. Furthermore, overall survival did not appear to be inferior. However, only 214 out of 1386 patients (15 percent) had died when the results of the trial were analyzed.

It has been argued that all of the randomized trials addressing the benefit of intermittent as compared with continuous ADT, including this one, observed better outcomes in terms of overall and progression-free survival than were assumed at time of study design, translating into prespecified noninferiority margins or hazard ratios that reflected larger absolute differences in these survival outcomes than were initially considered appropriate [15]. These wide noninferiority margins include clinically important survival differences, not likely to be considered comparable by clinicians and patients.

●Additional information of the benefit of IAD comes from a meta-analysis that found noninferiority for IAD compared with continuous ADT for prostate cancer of any stage (HR for overall survival 1.02, 95% CI 0.87-1.19; HR for cancer-specific survival 1.02, 95% CI 0.87-1.19; HR for progression-free survival 0.94, 95% CI 0.84-1.05) although the studies all had an unclear or high risk of bias [16]. Notably, there was a minimal difference in patients’ self-reported quality of life between the two interventions, but most trials observed an improvement in physical and sexual functioning with IAD.

This conclusion is further supported by five other meta-analyses that tested whether IAD was in fact superior to continuous ADT, and all of which found no difference in overall survival between IAD and continuous ADT for both the combined population of males with non-metastatic and metastatic disease, but also separately for the non-metastatic and metastatic disease populations [17-21]. Notably, however, one of these did find a significantly higher risk of death from cancer in the IAD group (HR 1.16, 95% CI 1.02-1.31) based on somewhat weak data, but a significantly lower risk of cardiovascular death (RR 0.8, 95% CI 0.67-0.94) [17].

Combined approaches incorporating ADT — ADT can be accomplished by preventing androgen production (orchiectomy, GnRH agonists, GnRH antagonists) or by androgen receptor blockade with antiandrogens; these methods can be used either as monotherapy or in combination. Monotherapy with a nonsteroidal antiandrogen is discussed in more detail below. (See 'Nonsteroidal antiandrogens' below.)

Complete androgen blockade — The combination of a GnRH agonist or orchiectomy plus an antiandrogen is commonly referred to as CAB since it removes the influence of both testicular and adrenal androgens. For males initiating ADT for an isolated biochemical recurrence with low-risk features, we suggested ADT monotherapy rather than complete androgen blockade. However, for those with high-risk features, we suggest CAB. (See 'High-risk features' above.)

CAB can be accomplished using second-generation nonsteroidal antiandrogens (preferred) or first-generation nonsteroidal antiandrogens.

Second generation nonsteroidal antiandrogens plus ADT — The addition of enzalutamide to ADT has shown improvements in metastasis-free survival compared with ADT alone in males with a high-risk biochemical recurrence in a randomized trial [4], and is our suggested option in such patients. (See 'High-risk features' above.)

In a randomized phase III trial including 1068 males with high-risk biochemical recurrence, enzalutamide plus ADT (leuprolide) improved five-year metastasis-free survival compared with enzalutamide alone (87 versus 80 percent) or ADT alone (87 versus 71 percent) [4]. The five-year overall survival (OS) in the combination group was improved compared with ADT alone (92 versus 87 percent; HR 0.59, 95% CI 0.38-0.91). The five-year OS in the enzalutamide-alone group compared with leuprolide alone was numerically improved but did not reach statistical significance (92 versus 90 percent; HR 0.78, 95% CI 0.52-1.17).

High risk in this trial included males with a PSA doubling time of ≤9 months, which is different than the ASCO definition (see 'High-risk features' above), and a PSA level ≥2 ng/mL above nadir after radiation therapy or ≥1 ng/mL after RP. Males were excluded from this trial if they had a RP and were considered to be a candidate for salvage radiation therapy. Treatment with enzalutamide and ADT stopped at week 37 if the PSA was ≤0.2 ng/mL. Treatment was restarted if the PSA level was ≥5 ng/mL in patients with who did not have a history of a RP or ≥2 ng/mL in patients with a RP.

Treatment-related adverse events occurred in 86 percent of patients in the combination group, 88 percent in the enzalutamide-alone group, and 80 percent in the leuprolide-alone group. Hot flashes, fatigue, and arthralgias were common toxicities occurring in >20 percent of all patients. Gynecomastia was more common in the enzalutamide-alone group (45 percent) compared with 8 percent in the combination group and 9 percent in the leuprolide-alone group. Treatment was discontinued due to adverse events in 21 percent of patients in the combination group, 18 percent in the enzalutamide-alone group, and 10 percent in the leuprolide-alone group.

The efficacy of combined approaches utilizing ADT plus chemotherapy (ie, docetaxel) abiraterone, or apalutamide has not been conclusively established in patients with a rising PSA as the only evidence of advanced disease, and we suggest not pursuing this strategy outside of the context of a clinical trial. (See 'Combined approaches incorporating ADT' above and 'ADT plus abiraterone, docetaxel, or apalutamide' below.)

Less preferred combination — First-generation nonsteroidal antiandrogens include the nonsteroidal agents flutamide, bicalutamide, and nilutamide. The benefit of combined therapy using one of these agents plus ADT over ADT alone has been addressed in several randomized trials, and at least two meta-analyses, with both demonstrating significantly improved overall and progression-free survival with combined therapy in the setting of locally advanced or metastatic castration-sensitive prostate cancer [22]. However, the survival benefit was considered of marginal clinical significance and this approach is not generally supported by current ASCO or National Comprehensive Cancer Network guidelines.

There are no randomized trials comparing GnRH agonists or orchiectomy alone versus CAB using a first-generation antiandrogen in males with a PSA-only recurrence. In addition, there are no trials comparing the use of initial CAB with monotherapy followed by the addition of an antiandrogen at the time of PSA rise. Given the emergence of more effective partners for ADT (eg, the second-generation nonsteroidal antiandrogen enzalutamide, steroidal antiandrogens such as abiraterone and docetaxel), CAB using a first-generation antiandrogen has fallen out of favor. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus second-generation antiandrogens'.)

ADT plus abiraterone, docetaxel, or apalutamide — For males with locally recurrent or metastatic castration-sensitive prostate cancer, combined therapy with ADT plus docetaxel or abiraterone is a preferred approach over ADT alone. This subject is discussed in detail elsewhere. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Patients with low-risk/low-volume disease or not eligible for docetaxel'.)

However, the efficacy of these combined approaches has not been conclusively established in patients with a rising PSA as the only evidence of advanced disease, and we suggest not pursuing this strategy outside of the context of a clinical trial, an approach that is consistent with updated ASCO guidelines [3].

●ADT plus docetaxel – There are conflicting data on whether there is a survival benefit from adding docetaxel to ADT for males with an isolated rising PSA after local therapy with no documented metastases:

•The STAMPEDE trial randomly assigned 2962 males with castration-sensitive prostate cancer to ADT alone, ADT plus zoledronic acid, ADT plus docetaxel, or ADT plus docetaxel and zoledronic acid; while the majority had distant metastatic disease, 39 percent of the patients did not [23]. For the entire study population, docetaxel plus ADT significantly improved overall survival compared with ADT alone (median 81 versus 71 months, HR 0.78, 95% CI 0.66-0.93). There were no statistically significant differences between the groups with and without metastatic disease in subset analyses, but longer follow-up is needed to adequately assess results for those without metastatic disease.

•On the other hand, a benefit for adding docetaxel (70 mg/m² every three weeks for six courses) to one year of ADT in males with high-risk prostate cancer and a rising PSA level after primary local therapy could not be shown in a randomized French trial that enrolled 254 patients [24]. At a median follow-up of 30 months, PSA progression-free survival was not significantly different with the addition of docetaxel (20.3 versus 19.3 months); overall survival data were not mature.

●ADT plus abiraterone or apalutamide – There are no data to support a survival benefit from the addition of either abiraterone or apalutamide in men with isolated biochemical recurrence of prostate cancer:

•In the STAMPEDE trial comparing ADT with or without abiraterone in males with non-metastatic disease not previously treated with ADT, only 1.9 percent of the study population had an increase in serum PSA following definitive surgery or RT without metastases as the basis for inclusion in the trial, and no definitive conclusions can be drawn about the value of combined abiraterone and prednisone in this patient subset [25].

•The PRESTO trial randomly assigned patients with biochemically relapsed prostate cancer and a PSA doubling time ≤9 months to 12 months of ADT alone, ADT plus apalutamide, or ADT plus abiraterone plus prednisone [26]. In a preliminary report of an interim analysis, compared with ADT alone, two-year biochemical progression-free survival (the primary endpoint) was significant better with both ADT plus apalutamide (24.9 versus 20.3 months, HR 0.52, 95% CI 0.35-0.77) and ADT plus abiraterone (26.0 versus 20.3 months, HR 0.48, 95% CI 0.32-0.71). However, this is a weak endpoint, and data on overall survival, or metastasis-free survival were not mature. Following completion of therapy, testosterone recovery times were similar across the three treatment arms.

Noncastrating hormonal therapy — Noncastrating hormone therapy (also referred to as "peripheral androgen blockade") is a theoretically attractive approach to systemic therapy due to a differing side effect profile. However, these approaches are less effective than medical or surgical castration for advanced prostate cancer in terms of overall survival, clinical progression, treatment failure, and treatment discontinuation due to adverse events and cannot be routinely recommended.

Antiandrogens and 5-alpha-reductase inhibitors have been studied without concomitant GnRH blockage to maintain normal serum levels of testosterone. Regimens that have been studied include bicalutamide at doses ranging from 50 to 200 mg daily, finasteride plus flutamide, and enzalutamide [22,27,28]. These approaches are also associated with side effects, including gynecomastia, which can be severe; decreased libido; hypertension; and fatigue.

Nonsteroidal antiandrogens — Monotherapy with enzalutamide demonstrated an improvement in five-year metastasis-free survival when compared with leuprolide alone in males with a high-risk biochemical recurrence (80 versus 71 percent) [4]. However, the combination of enzalutamide and leuprolide had an OS benefit at five-years, but enzalutamide in comparison with leuprolide did not. There was a nonsignificant trend towards improved five-year OS in patients receiving enzalutamide alone compared with ADT (92 versus 90 percent; HR 0.78, 95% CI 0.52-1.17). However, this approach lacks regulatory approval. (See 'High-risk features' above.).

Nonsteroidal antiandrogens (ie, flutamide, bicalutamide, nilutamide, enzalutamide) has several potential advantages compared with other forms of hormone therapy, including ease of administration, a relatively favorable toxicity profile, and better quality of life. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus first-generation antiandrogens'.)

A meta-analysis of eight trials comparing flutamide or bicalutamide monotherapy versus orchiectomy, diethylstilbestrol, or a GnRH agonist in patients with advanced prostate cancer suggested that overall survival with antiandrogen monotherapy was inferior to other treatments [29]. Furthermore, some side effects of antiandrogen monotherapy can be problematic (particularly gynecomastia).

Use of enzalutamide in combination with salvage RT is being evaluated, but further data are required. This is discussed elsewhere. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management", section on 'Prostate bed RT plus androgen deprivation therapy'.)

Despite the concerns about efficacy, antiandrogen monotherapy may be a reasonable option for carefully selected patients with well-differentiated tumors and a PSA-only recurrence who wish to minimize side effects during therapy. However, antiandrogen monotherapy should not be routinely recommended.

5-alpha reductase inhibitors — The use of 5-alpha reductase inhibitors, either alone or in combination with an antiandrogen is not a standard approach to treatment of recurrent castration-sensitive prostate cancer, and we suggest not pursuing this approach.

The 5-alpha reductase inhibitors block the intraprostatic conversion of testosterone to dihydrotestosterone (DHT), the most potent androgen acting on the prostate, while the nonsteroidal antiandrogens block the cytoplasmic DHT receptor. Since testosterone conversion is blocked selectively within the prostate, serum testosterone levels are maintained during treatment. As a result, most individuals retain their pretreatment libido, potency, muscle mass, and erythropoietic capacity.

Dutasteride was evaluated as the initial treatment for biochemical failure in the ARTS trial, in which 294 patients with biochemical failure after definitive treatment for prostate cancer were randomly assigned to dutasteride or placebo for two years [30]. The incidence of PSA doubling over the treatment period, the primary endpoint of the trial, was significantly decreased with dutasteride (57 versus 28 percent). Because of the potential bias from the known effect of dutasteride on PSA, additional study, including longer follow-up, is required to assess whether this approach can delay the development of bone metastases or affect survival.

A potential role for 5-alpha reductase inhibitors in combination with antiandrogens such as flutamide or bicalutamide has also been suggested by smaller studies. However these approaches also remain experimental [27,31-35].

MANAGEMENT OF NON-METASTATIC CASTRATION-RESISTANT DISEASE — Some patients will experience an increase in serum PSA while on ADT, without clinical evidence of metastases. Randomized trials have demonstrated that treatment with an androgen receptor antagonist (enzalutamide, apalutamide, darolutamide) can significantly delay the onset of clinical evidence of metastatic disease and improve overall survival, and all three drugs have been approved for non-metastatic castration-resistant prostate cancer in the United States. Notably, standard bone scans and computed tomography, and not more sensitive imaging tests (such as fluciclovine F-18 positron emission tomography [PET] or 68-gallium-PSMA [prostate-specific membrane antigen] PET), were used to define "non-metastatic" in these trials. The results of these trials are discussed separately. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Chemotherapy-naïve'.)

SURVEILLANCE DURING TREATMENT — Surveillance strategies during systemic treatment for prostate cancer 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".)

SUMMARY AND RECOMMENDATIONS

●Definition and indications for systemic therapy

•Monitoring prostate-specific antigen (PSA) after treatment of localized prostate cancer can lead to the identification of individuals with a PSA-only (biochemical) recurrence, in which increases in serum PSA over expected remission values are not accompanied by symptoms or signs of locally recurrent or metastatic disease. Although most patients will not have evidence of disseminated disease, imaging evaluation is required to rule out the possibility of distant metastases prior to salvage therapy, especially in cases with initial high-risk disease and/or short PSA doubling time. (See 'Overview of the general approach' above.)

•Systemic therapy is the primary therapeutic option for patients who have had local salvage therapy following initial definitive treatment and who subsequently have an ongoing or recurrent isolated biochemical recurrence with noncastrate serum levels of testosterone (>50 ng/dL). Systemic therapy may also be indicated when comorbidity or advanced age precludes aggressive local salvage therapy.

●Approach to systemic therapy

•For castrate-sensitive disease – In patients with castrate-sensitive isolated biochemical recurrence in whom systemic therapy is indicated, our approach is as follows:

-For most patients with any high-risk feature for early metastases, we suggest early rather than deferred systemic therapy (Grade 2C). High-risk features are: a PSA doubling time <12 months or pathologic Gleason score 8 to 10 after radical prostatectomy, or interval to biochemical recurrence <18 months, or a clinical Gleason score 8 to 10 after radiation therapy. There is no consensus on what is "early" initiation of ADT, but a practical target is a PSA <5 to 10 ng/mL. (See 'When to initiate ADT-based therapy' above.)

For individuals who lack a high-risk feature, we delay systemic therapy, with careful informed consent and periodic imaging and monitoring of PSA to assess for progressing disease (ie, active surveillance).

-For choice of systemic therapy in patients with high-risk disease, we suggest complete androgen blockade using ADT and enzalutamide rather than ADT alone (Grade 2B). (See 'Complete androgen blockade' above and 'Nonsteroidal antiandrogens' above.)

However ADT alone is a reasonable alternative for those who are unlikely to tolerate the toxicities of the combination. For patients who are starting ADT alone for an isolated biochemical recurrence, intermittent rather than continuous ADT is a reasonable option. For individuals who place a greater value on potentially maximizing overall survival, and a lesser value on avoiding/minimizing the side effects of ADT, continuous treatment might be preferred. (See 'Continuous versus intermittent ADT' above.)

We do not offer the addition of chemotherapy or abiraterone to ADT. (See 'ADT plus abiraterone, docetaxel, or apalutamide' above.)

•For castrate-resistant disease – For patients who have an isolated biochemical recurrence while on ADT only, treatment with an androgen receptor antagonist (enzalutamide, apalutamide, darolutamide) can significantly delay the onset of metastatic disease, and all three drugs have been approved for non-metastatic castration-resistant prostate cancer in the United States. The results of these trials are discussed separately. (See 'Management of non-metastatic castration-resistant disease' above and "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Chemotherapy-naïve'.)

ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.