Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer

INTRODUCTION — The critical role of androgens in stimulating prostate cancer growth was established in 1941 by Charles Huggins [1,2]. These findings led to the development of androgen deprivation therapy (ADT) as a treatment for patients with advanced prostate cancer. Although ADT is palliative, it can normalize serum levels of prostate-specific antigen (PSA) in over 90 percent of patients and can produce objective tumor responses in 80 to 90 percent. This antitumor activity can improve quality of life by reducing bone pain as well as the rates of complications (eg, pathologic fracture, spinal cord compression, ureteral obstruction). (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Benefits and methods for androgen deprivation therapy'.)

Some males with advanced prostate cancer have evidence of metastatic disease at presentation, while others develop metastatic disease after definitive treatment of localized disease; in some cases this may be manifested only by an elevation in the serum level of PSA, termed an isolated biochemical recurrence. The majority of males in all three groups have not been receiving long-term ADT, and serum testosterone levels are typically >50 ng/dL. These males are considered to have castration-sensitive (also termed noncastrate) prostate cancer (CSPC).

By contrast, males who relapse or recur while receiving ADT are considered to have castration-resistant prostate cancer, although they may still respond to some forms of hormone therapy. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)" and "Alternative endocrine therapies for castration-resistant prostate cancer".)

Contemporary research has led to the development of multiple combined modality approaches for males with advanced CSPC that are associated with better outcomes than can be achieved with ADT alone. The goals of systemic therapy are to prolong survival, minimize complications, and maintain quality of life. In addition to systemic therapy, there are some patients who might benefit from local therapy to the prostate or to individual metastases to prolong survival. (See 'Prostate-directed therapy' below and 'Metastasis-directed therapy for oligometastatic disease' below.)

This topic will provide an overview of the approach to CSPC using both systemic and local therapy. The options for initial systemic therapy for advanced, recurrent, and metastatic CSPC are discussed elsewhere; there are also separate discussion of the diagnostic evaluation, local salvage treatments, and the role of systemic therapy for males with a rising serum PSA after definitive local therapy.

●(See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)

●(See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification".)

●(See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management".)

●(See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)

●(See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer".)

EVALUATING DISEASE EXTENT — There is no consensus on the best imaging modality to detect distant disease. The frequency with which metastases are detected using conventional imaging studies (ie, bone scan, computed tomography [CT] of the abdomen and pelvis) is very low for males with early prostate-specific antigen (PSA)-only progression. Next generation imaging (NGI) techniques have improved sensitivity for disease recurrence. These modalities include positron emission tomography [PET] scanning using one of the newer prostate cancer-specific radiotracers and whole-body magnetic resonance imaging [MRI]. Many factors influence the type of imaging ordered including the decision about whether the patient is a candidate for treatment, availability of NGI techniques, insurance coverage, life expectancy, PSA level, and presence of symptoms.

Our general approach to imaging is as follows:

●We obtain NGI for males with a PSA that rises ≥0.2 ng/mL after radical prostatectomy or a PSA value ≥2 ng/mL above the post-radiation nadir for males treated with radiation.

●If patients are symptomatic or have a PSA above 10, we obtain conventional imaging studies initially, given the improved sensitivity in these patients. If conventional imaging is not definitive, we obtain NGI as a next step.

An accurate assessment of disease extent has implications for treatment. For instance, males who are confirmed to have only a local recurrence after definitive treatment may be candidates for local salvage therapy. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management" and "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)

Although guidelines from expert groups support the use of NGI for certain males with recurrent prostate cancer, reimbursement issues and the lack of general availability (especially for gallium-68 prostate-specific membrane antigen PET/CT) have limited widespread use. Often, insurance companies will only pay for these tests if conventional imaging is negative. However, this is an evolving area. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Guidelines from expert groups'.)

There may be a role for NGI even in males presenting with CSPC who have demonstrable metastatic disease on conventional imaging. The 2020 guidelines from the American Society of Clinical Oncology suggest a role for NGI to clarify the burden of disease and potentially shift the treatment intent from multimodality management of oligometastatic disease to palliative systemic treatment, but note that prospective data to support this benefit are limited [3]. (See 'Metastasis-directed therapy for oligometastatic disease' below.)

ISOLATED BIOCHEMICAL RECURRENCE — Monitoring prostate-specific antigen (PSA) after definitive treatment of localized prostate cancer with either radiation therapy (RT) or radical prostatectomy (RP) leads to the identification of males 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. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Definition of biochemical progression'.)

Local salvage therapy performed, if appropriate — Local salvage therapy may result in prolonged disease-free survival. Patients with a biochemical recurrence should be evaluated for local therapy such as RT or a RP. Patient-specific factors such as prior therapy, patient preference, and risk factors will determine the best treatment plan. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation" and "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".)

Choice of systemic therapy

Definition of high-risk features — We use guidelines from the American Society of Clinical Oncology (ASCO), which identify high-risk features for early metastases as:

●For those who underwent RP: A PSA doubling time <1 year or Gleason score 8 to 10; OR

●For those who underwent RT: An interval to biochemical recurrence <18 months or a Gleason score of 8 to 10 [4]

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 overall survival (OS) benefit with enzalutamide and ADT in this population [5].

High-risk features present and local therapy performed for recurrence

Androgen deprivation therapy — In males who are able to receive salvage therapy and who have high-risk features, early ADT is used. Androgen deprivation therapy (ADT) is the cornerstone of systemic therapy for advanced CSPC. ADT can be accomplished either with bilateral orchiectomy (surgical castration) or by medical castration [6-8]. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Surgical orchiectomy' and "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)

In most cases, prostate cancer that has not previously been treated with systemic therapy is dependent on androgen for its continued growth. Androgen production occurs primarily in the testes, which account for 90 to 95 percent of the total circulating testosterone; testicular production of androgen is regulated by the hypothalamic-pituitary axis. The adrenal glands produce the remainder of the circulating androgens.

These observations provide the rationale for ADT, which is a key component of initial therapy, either alone or in combination with other therapies.

●Continuous versus intermittent – Although we typically suggest continuous ADT, intermittent treatment is an appropriate alternative. Many of the acute and chronic side effects of ADT are due to continued castrate levels of testosterone. Intermittent androgen deprivation therapy (IAD) typically involves treatment for either a fixed interval of time or until a maximal response is achieved based upon serum PSA levels. It has been proposed as a less toxic alternative for those with isolated biochemical recurrence after definitive local therapy, although the effect on survival is unknown. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer".)

Although cessation of ADT results in a gradual return toward normal testosterone levels, this return is very slow, particularly for long-acting gonadotropin-releasing hormone agonists. IAD can improve quality of life while reducing side effects, especially those associated with physical and sexual function. However, when ADT is then withdrawn, patients must be followed closely for evidence of recurrence. As testosterone production resumes, the risk of disease progression also increases. The patient is followed with PSA measurements, and ADT is reinitiated based on a predefined threshold level of serum PSA (which varies with different practices but is often between 10 and 20 ng/mL) or with evidence of new metastatic disease. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Intermittent versus continuous ADT' and "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Serum testosterone level'.)

●Timing of treatment — For patients who undergo salvage therapy who have high-risk features for recurrence, we initiate early ADT.

However, ADT for those with isolated biochemical recurrence is debated. 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 and ADT is associated with toxicity. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer".)

●Side effects — ADT is associated with a wide range of side effects that can significantly impair quality of life, including loss of lean body mass, sexual dysfunction, loss of bone mineral density, hot flashes, and fatigue. These and others are discussed elsewhere. (See "Side effects of androgen deprivation therapy".)

High-risk features present and local therapy not performed for recurrence — In males with high-risk features present who are unable to have local salvage therapy, we suggest the combination of enzalutamide and ADT as this improves OS compared to ADT alone. In males who wish to avoid the toxicity of combined therapy, enzalutamide or early ADT alone are alternatives. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'High-risk features'.)

Next generation hormonal therapy — In males who are unable to receive local salvage therapy, we suggest enzalutamide and ADT instead of ADT or enzalutamide alone.

In a phase III trial in males with high-risk isolated biochemical recurrence not undergoing local therapy, the combination of enzalutamide and ADT improved five-year metastasis-free survival compared with ADT alone (87 versus 71 percent) and enzalutamide alone (87 versus 80 percent) [5]. This study defined high risk as a PSA doubling time <9 months, which is a slightly different definition than used by ASCO. The combination also improved five-year OS rates compared with ADT alone (92 versus 87 percent), with a nonsignificant trend towards improved OS compared with enzalutamide alone (92 versus 90 percent; hazard ratio [HR] 0.78, 95% CI 0.52-1.17). Enzalutamide alone is a reasonable alternative for males who wish to avoid toxicity from ADT therapy, but does not have regulatory approval as a single agent for biochemical recurrence. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'High-risk features'.)

No high-risk features present

Surveillance — For males who lack high-risk features (irrespective of whether local therapy is performed), we delay systemic treatment, with careful informed consent and periodic imaging to assess for metastatic disease (ie, active surveillance). However, for patients who prefer to initiate systemic therapy, early ADT is a reasonable alternative. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer".)

RECURRENT LOCALLY ADVANCED DISEASE — The approach to patients who present initially with locally advanced disease is discussed elsewhere. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement".)

This section discusses the approach to patients who recur with locally advanced disease.

Deciding on local therapy — Local treatments are administered depending on prior receipt of radiation therapy (RT).

●For patients who have not previously received RT – For patients without prior radiation who develop a locally advanced recurrence, we proceed with RT, followed by systemic therapy. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management" and 'Choice of systemic therapy' below.)

●For those who have previously been treated with RT – For patients with prior RT, a subset may be able to undergo repeat RT based on time from original radiation and volume treated. However, many may not be able to get additional RT due to concerns of toxicity. These patients should begin systemic therapy, as discussed below. (See 'Choice of systemic therapy' below.)

Choice of systemic therapy — For patients with recurrent locally advanced disease we suggest early initiation of androgen deprivation therapy (ADT), with or without a novel hormonal agent, given improved progression-free and prostate cancer-specific survival. We administer ADT continuously, given better outcomes than intermittent ADT (IAD) in this setting, although it may be acceptable in select patients who place a higher value on minimizing toxicity and a lower value on maximizing overall survival. (See 'Androgen deprivation therapy' above and "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Timing of treatment initiation'.)

Our approach to systemic therapy depends on whether RT is administered for recurrent disease:

●RT administered for recurrent disease – For males with locally advanced, nonmetastatic prostate cancer treated with prostate RT for recurrence we suggest ADT plus abiraterone over ADT alone.

In the phase III STAMPEDE trial, RT to the prostate was mandated for node-negative and encouraged for those with node-positive nonmetastatic high-risk disease [9]. This trial demonstrated an improvement in OS of males who received ADT and abiraterone compared with ADT alone. This trial is discussed in detail elsewhere. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus abiraterone'.)

●RT not administered for recurrent disease – Some males may not be eligible for additional radiation if they have already received it due to concerns for toxicity. There is limited data to guide therapy, but patients are offered early ADT similar to patients who do not wish to receive radiation. For males with locally advanced nonmetastatic disease who are unwilling or unable to undergo RT, early ADT may prolong overall and cause-specific survival. Deferred ADT is an acceptable alternative for asymptomatic patients who desire to avoid or at least delay potential ADT side effects. Discussions with the patient about the timing of ADT should include consideration of underlying comorbidities and the level of patient anxiety regarding their prostate cancer and the potential side effects of ADT. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Locoregional nonmetastatic disease'.)

PATIENTS WITH METASTATIC DISEASE — Treatment options for patients with advanced prostate cancer depend on individual patient characteristics such as volume of disease and risk. For those patients with higher volume and higher risk disease "triplet therapy" with androgen deprivation therapy (ADT) plus docetaxel and either darolutamide or abiraterone is preferred. For other patients, we suggest doublet therapy with ADT plus one of the following, depending on disease extent: abiraterone, docetaxel, enzalutamide, or apalutamide.

Definition of high-risk/high-volume disease — Our approach to metastatic disease depends on risk factors and volume of disease.

We define high-risk disease as ≥2 of the following:

●Presence of visceral metastases

●Gleason score ≥8 disease

●≥3 bone lesions

We define high-volume disease as the following:

●Presence of visceral metastases; and/or

●≥4 bone metastases, including at least one outside the vertebral bodies and pelvis

ADT therapy, for all patients — All males with metastatic disease are recommended to have ADT. The types of ADT available are discussed elsewhere. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)

Certain features unique to patients with metastatic disease may impact the choice of ADT. In males who receive a gonadotropin-releasing hormone (GnRH) agonist, there is a transient surge of luteinizing hormone before the luteinizing hormone levels fall. This surge can cause an increase in serum testosterone, which may rarely result in a worsening of disease in males with metastatic cancer. This "flare phenomenon" may be of particular concern in clinical settings such as impending epidural spinal cord compression or urinary tract outflow obstruction. Concurrent antiandrogens (eg, flutamide, bicalutamide) may be useful in preventing the flare phenomenon. Alternatively, GnRH antagonists avoid the flare phenomenon. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'GnRH agonists' and "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'GnRH antagonists'.)

In males who choose surgical castration there is an immediate decrease in testosterone. This may be helpful in situations such as impending spinal cord compression, urinary tract outlet obstruction, or when cost or adherence to medical therapy are an issue.

Patients with low-volume, low-risk disease

Choosing between options — For patients with low-volume, low-risk disease, we offer the combination of ADT with a novel hormonal agent (eg, enzalutamide, apalutamide, or abiraterone). There are no trials of ADT plus enzalutamide or apalutamide compared with ADT plus abiraterone in this setting. Given the lack of reliable comparative data, the choice of regimen is based on patient preferences regarding toxicities, co-morbidities, and potential of drug interactions. As an example, abiraterone is not used in patients with congestive heart failure because it can worsen lower extremity edema. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Choice of approach'.)

Abiraterone/prednisone plus ADT — Abiraterone blocks the intracellular conversion of androgen precursors in the testes, adrenal glands, and prostate tumor tissue. Combining abiraterone with ADT prolongs the benefits of treatment. In the STAMPEDE trial, benefit of ADT and abiraterone over ADT alone was shown regardless of the risk or disease volume status. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus abiraterone'.)

Enzalutamide or apalutamide plus ADT — Both enzalutamide and apalutamide bind to the androgen binding site in the androgen receptor and function as androgen receptor inhibitors. Two randomized trials (TITAN and ARCHES) showed benefit over ADT alone for metastatic CSPC, and benefits were seen regardless of the extent of disease burden. Both apalutamide and enzalutamide are now approved for use in this setting. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus second-generation antiandrogens'.)

Although triplet therapy has been evaluated in low-volume, low-risk disease we do not use it in this context given increased toxicity and limited data. A subgroup analysis in a trial of patients with metastatic CSPC showed a benefit in patients with low-risk disease treated with triplet therapy (docetaxel, ADT, and darolutamide) over doublet therapy (ADT plus docetaxel; hazard ratio [HR] 0.62, 95% CI 0.42-0.90). In the low volume subgroup there was a trend towards benefit that did not achieve statistical significance (HR 0.68, 95% CI 0.41-1.13); but there were few patients in this subgroup, which limits a definitive conclusion [10]. Grade 3 or 4 adverse events occurred in 70 percent versus 61 percent in the low-volume subgroup. Given the small numbers in this trial, and higher toxicities with triplet therapy, the addition of docetaxel is not a standard approach to patients with low-risk and/or low-volume disease.

Patients with high-risk or high-volume disease — Definition of high-risk/high-volume disease is found above. (See 'Definition of high-risk/high-volume disease' above.)

Triplet therapy (preferred) — For patients with high-risk or high-volume metastatic disease, we offer triplet therapy with ADT, docetaxel, and a novel hormonal agent such as darolutamide or abiraterone.

Although two trials showed benefit with adding either darolutamide or abiraterone to docetaxel plus ADT in metastatic CSPC, a third trial failed to demonstrate a survival benefit with the addition of enzalutamide as the third agent. As an example, in the placebo-controlled ARASENS trial, the addition of darolutamide to docetaxel plus ADT significantly improved overall survival (OS; median OS not-estimable versus 49 months; 48-month survival 63 versus 50 percent; HR for death 0.68, 95% CI 0.57-0.80), and benefits were seen in all secondary endpoints without a significant increase in toxicity [11]. Largely based on this trial, darolutamide is now approved in the United States, in combination with docetaxel, for treatment of metastatic CSPC [12]. A sub group analysis demonstrated an OS benefit compared with placebo in high-volume disease (HR 0.69, 95% CI 0.57-0.82) and high-risk disease (HR 0.71, 95% CI 0.58-0.86) [10].

As a result of these data, triplet therapy is preferred over ADT plus docetaxel alone in patients with high-risk or high-volume disease. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Patients with high-risk/high-volume disease' and "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'.)

CONTRIBUTION OF LOCAL THERAPY IN MALES WITH METASTATIC DISEASE

Prostate-directed therapy — For unselected males who have metastatic disease at initial diagnosis of prostate cancer, a benefit for local therapy directed at the prostate is not established. We prefer enrollment in a clinical trial testing the value of prostate-directed therapy in conjunction with systemic therapy, such as Southwest Oncology Group (SWOG) 1802. If protocol therapy is unavailable or declined, for males with a low burden of bone metastases (defined as four or fewer bone metastases, with none outside the vertebral bodies or pelvis) and no visceral metastases, we suggest prostate radiation therapy (RT) in conjunction with systemic therapy, rather than systemic therapy alone. For males with a high metastatic burden, we suggest systemic therapy alone.

The benefit of local therapy in conjunction with androgen deprivation therapy (ADT) for males who present with metastatic prostate cancer has been controversial. Two observational studies using propensity matching suggested that the addition of prostate-directed therapy (either RT or radical prostatectomy) improves overall survival (OS) compared with ADT alone in unselected males with metastatic prostate cancer [13,14]. In the largest of these two studies, in which 1470 of 15,501 males presenting with metastatic prostate cancer received local therapy (RT, radical prostatectomy, and brachytherapy in 77, 20, and 3 percent of cases, respectively) in conjunction with ADT, three-year OS was better in those receiving local prostate-directed therapy (63 versus 48 percent) [14].

The impact of concurrent local prostate RT in conjunction with ADT has been directly tested in two randomized trials:

●The phase III HORRAD trial randomly assigned 432 males with primary metastatic prostate cancer with bone metastases and a serum prostate-specific antigen (PSA) >20 ng/mL to ADT (bicalutamide plus a luteinizing hormone-releasing hormone agonist) with or without external beam RT (70 Gy in 35 daily 2 Gy fractions) [15]. Two-thirds of the males had more than five bone metastases. At a median follow-up of 47 months, median OS (the primary endpoint) was not improved by the addition of RT (45 versus 43 months; hazard ratio [HR] 0.90, 95% CI 0.70-1.14), although the addition of RT prolonged the median time to PSA progression (median 15 versus 12 months; HR 0.78, 95% CI 0.63-0.97). An unplanned subgroup analysis suggested that survival might be favorably impacted in the subgroup of males with fewer than five metastases, but the result was not statistically significant (HR 0.68, 95% CI 0.42-1.10).

In a later quality of life analysis, the addition of RT to ADT was associated with a clinically meaningful increase in urinary symptoms and diarrhea at month 3 but not beyond [16].

●Similarly, a survival benefit for RT to the prostate for unselected males with newly diagnosed metastatic prostate cancer could not be shown in the phase III STAMPEDE trial, in which 2061 males with newly diagnosed metastatic prostate cancer were randomly assigned to lifelong ADT with or without docetaxel and with or without prostate RT (which could be either 36 Gy in six consecutive weekly fractions of 6 Gy, or 55 Gy in 20 daily fractions of 2.75 Gy over four weeks) [17]. Metastatic burden at randomization was assessed through whole-body scintigraphy, and CT or MRI staging scans, and it was classified according to the definitions used in the CHAARTED trial [18]. High metastatic burden was defined as four or more bone metastases, with one or more outside the vertebral bodies or pelvis; visceral metastases; or both; all other assessable patients were considered to have low metastatic burden.

At a median follow-up of 37 months, OS (the primary endpoint) was not improved with prostate RT (three-year survival 65 versus 62 percent; HR for death 0.92, 95% CI 0.80-1.06), but failure-free survival (which was largely driven by a rising PSA post-treatment) was better (three-year failure-free survival 32 versus 23 percent; HR 0.76, 95% CI 0.68-0.84). In a prespecified subgroup analysis, OS was improved with RT in the males with a low metastatic burden at diagnosis (three-year survival 81 versus 73 percent; HR for death 0.68, 95% CI 0.52-0.90) but not in those with a high metastatic burden (HR 1.07, 95% CI 0.90-1.28). The survival benefit for low but not higher burden disease was maintained with long-term follow-up [19].

Adverse effects during prostate RT were modest, with 5 percent reported grade 3 or 4 bladder or bowel toxic events (versus 1 percent of the control group). However, approximately 1 percent of males receiving prostate RT had late grade 3 or 4 gastrointestinal toxicity (compared with nearly none of the control group). Late grade 3 or 4 radiation-related toxicity was reported in 37 patients receiving RT versus 1 patient in the control group (4 versus 1 percent) [17].

●On the other hand, a pooled results of both trials concluded that there was an overall improvement in biochemical progression-free survival (HR 0.74, 95% CI 0.67-0.82) and failure-free survival (HR 0.76, 95% CI 0.69-0.84) that translated into an approximately 10 percent benefit at three years for the entire cohort [20]. Although there was no significant OS benefit in the entire cohort (HR 0.92, 95% CI 0.81-1.04), there was a survival benefit for the addition of RT among males with fewer than five bone metastases (HR 0.73, 95% CI 0.58-0.92), which translated into an approximately 7 percent improvement in three-year survival.

●Additional information is available from a secondary analysis of the STAMPEDE randomized trial, as described above [21]. Of the 1932 males randomized with M1 disease, 1732 (89 percent) had bone metastases (as detected by conventional imaging), 181 (9 percent) had nonregional nodal metastases, and 171 (9 percent) had visceral/other metastases. When all patients with bone metastases (with or without nonregional nodal metastases) were considered, there was no apparent survival benefit from prostate RT (HR 0.96, 96% CI 0.82-1.13), but in unplanned subgroup analysis, an OS benefit was apparent in the group with three or fewer bone metastases (three-year OS 75 versus 85 percent; HR for death 0.64, 95% CI 0.46-0.89) but not in those with four or more bone metastases (three-year OS 53 versus 52 percent; HR 1.12, 95% CI 0.93-1.34). There was no benefit for prostate RT in those with any visceral or other metastases.

Metastasis-directed therapy for oligometastatic disease — Although promising, in our view, additional data from prospective studies are required to determine the role of metastasis-directed therapy for males with oligometastatic disease, especially how it should be integrated with ADT, before this approach can be considered standard. Decisions regarding treatment must be individualized, taking into account a wide range of patient-specific factors (eg, site of metastasis, disease-free interval, patient age, comorbidity).

After prior definitive therapy, patients will occasionally present with metachronous oligometastatic disease, which most of the time is diagnosed using positron emission tomography (PET)/CT with more sensitive prostate-specific radiotracers. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management", section on 'Impact of more sensitive diagnostic imaging' and "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'More sensitive prostate cancer-specific PET tracers'.)

There are no high-quality data on the optimal management of patients in this situation. In particular, the role of metastasis-directed therapy (eg, surgery and/or RT for isolated lymph nodes, stereotactic RT for bone metastasis) remains uncertain for any population of these patients.

The following data are available regarding the benefit of metastasis-directed therapy for males with oligometastatic prostate cancer:

●In an early phase II trial, 62 asymptomatic patients with a biochemical recurrence after primary definitive treatment, one to three metastases on conventional (not PET-based) imaging, and a serum testosterone >50 ng/mL were randomly assigned to observation alone or to metastasis-directed therapy [22]. In the latest analysis, presented at the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium, the time to initiation of ADT based on progression of symptoms, progression to more than three metastases, or progression of known lesions was significantly longer in patients who received initial metastasis-directed therapy (five-year ADT-free survival 34 versus 8 percent; HR 0.57, 95% CI 0.38-0.84), although five-year OS was similarly high in both groups (85 percent) [23].

●At least two systematic reviews are available, both of which are flawed by the inclusion of some patients who received concurrent ADT:

•One systematic review of the literature identified 20 case series that included information on 728 patients with lymph-node-only prostate cancer recurrence, as detected by conventional scanning [24]. Two-thirds of the patients were managed with lymph node dissection and one-third with RT. Approximately one-half of the patients were progression-free after short-term follow-up. Interpretation of these results is difficult since approximately two-thirds of these patients also received adjuvant ADT.

•A later systematic review of 27 studies of salvage lymph node dissection noted that complete biochemical responses occurred in 13 to 80 percent of cases (mean 44 percent), and two- and five-year biochemical progression-free survival rates ranged from 23 to 64 percent and from 6 to 31 percent, respectively [25]. However, interpretation of the results was limited by the retrospective design of all the studies; heterogeneity in terms of adjuvant treatment, definition of progression, and study population; and the absence of long-term follow-up.

●Additional information is available from two uncontrolled phase II trials, both of which used prostate-specific membrane antigen PET scan (PSMA):

•In one trial 72 patients with a rising PSA after definitive local therapy and negative conventional imaging, who all then underwent PSMA-PET/CT to detect and localize oligometastatic disease [26]. Overall, 38 were found to have a PSMA-detected oligometastatic recurrence that was thought amenable to metastasis-directed therapy, 92 percent of which were nodal only, the remainder skeletal. At a median follow-up of 15.9 months, 22 percent of the 37 patients who were treated with SBRT (n = 27) or surgery (n = 10) normalized their PSA. Median time to PSA progression (freedom from ADT) was 17.7 months.

•The OLIGOPELVIS GETUG P076 trial studied high-dose salvage RT plus short-term ADT in 67 patients with isolated oligometastatic pelvic node relapse detected by fluorocholine PET/CT after treatment for localized disease; 35 had previously received prostate RT [27]. After a median follow-up of 49.4 months, median biochemical relapse-free survival was 25.9 months, 58 percent remained progression free at three years.

Benefits of SBRT — The benefits of stereotactic body RT (SBRT) for treatment of oligometastatic disease can be illustrated by the following reports:

•The phase II Observation versus Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer trial randomly assigned 54 males with recurrent, hormone-sensitive, oligometastatic prostate cancer (three or fewer lesions as determined by conventional imaging) to observation and no further treatment for six months or to SBRT to the metastatic sites outside of the prostate that were detected by conventional imaging [28]. Six months after randomization, progression (defined as a PSA increase, radiographic progression on conventional imaging, or symptomatic decline) was observed in 19 percent of those undergoing SBRT versus 61 percent of the control group. The patients randomized to SBRT all underwent PET/CT using highly sensitive, prostate cancer-specific PSMA-based radionuclides at baseline and at six months (although clinicians were blinded as to the results during radiation treatment planning), and total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at six months (16 versus 63 percent of those who had any untreated lesions). (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Ga-68 and F-18 PSMA PET/CT'.)

•In another randomized phase II study (SABR-COMET) of 99 patients with cancer of a variety of primary tumors (16 with prostate cancer) and up to five metastatic lesions to any site (65 had bone metastases), when compared with palliative care alone (which included standard-fractionation RT with or without systemic chemotherapy), the use of SBRT for treatment of oligometastatic disease was associated with a significant improvement in five-year OS (42 versus 18 percent, p = 0.006) [29].

•A meta-analysis of 23 observational studies of SBRT for oligometastatic prostate cancer recurrence concluded that local control was excellent, with minimal severe or late toxicity, and among the five studies reporting this outcome, the average duration of ADT-free survival was approximately 20 months [30].

Several randomized trials exploring the benefit of SBRT for oligometastatic cancer, including prostate cancer, are ongoing or planned [31-34]. Eligible patients should be encouraged to enroll.

ASSESSMENT DURING TREATMENT — For males with CSPC who are undergoing systemic therapy, periodic assessment should be geared toward identifying signs and symptoms of disease progression, as well as the side effects of treatment. (See "Side effects of androgen deprivation therapy".)

Serial evaluation of serum prostate-specific antigen (PSA) is the mainstay of testing. Consensus-based guidelines from the National Comprehensive Cancer Network recommend testing PSA every three to six months during treatment for advanced prostate cancer [35]. Most clinicians make decisions about the need for radiographic evaluation based on changes in PSA values and/or the development of new symptoms. Therapeutic changes are usually not made based on a rising PSA alone.

If PSA levels do not fall in response to therapy or subsequently rise, the adequacy of testosterone suppression should be checked. We also routinely check serum testosterone levels every three months to ensure that they remain in the castrate range (<50 ng/dL), although some advocate for lower levels [36].

PSA progression alone should generally not be the sole reason to change therapy in CSPC. Conventional imaging should be used to assess radiographic progression before making changes to the treatment approach. Assessment strategies during treatment for CSPC are the same as for castration-resistant prostate cancer and are discussed in more detail separately. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Assessment during treatment'.)

MANAGEMENT OF SYMPTOMATIC BONE METASTASES — Osteoblastic metastases to the axial skeleton are the predominant site of metastases in most males with prostate cancer. Bone metastases may either be present at the time of initial diagnosis of prostate cancer or develop subsequently. Systemic therapy with androgen deprivation therapy is an important component of treatment, but external beam RT is a standard treatment for persistent bone pain from one or a few sites. This subject is discussed in detail separately. (See "Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis" and "Bone metastases in advanced prostate cancer: Management".)

PALLIATION OF PELVIC DISEASE — Advanced prostate cancer can cause pelvic symptoms that significantly impair quality of life. These include lower urinary tract symptoms, pelvic pain, hematuria, and obstructive rectal symptoms. Systemic therapy is the primary approach for the control of such symptoms, but radiation therapy to symptomatic areas may also be helpful in selected circumstances.

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.)

●Basics topics (see "Patient education: Prostate cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Treatment for advanced prostate cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Castration-sensitive prostate cancer – Males with prostate cancer who have a serum testosterone level of >50 ng/dL have castration-sensitive (noncastrate) prostate cancer (CSPC). Recurrence can manifest as an isolated biochemical recurrence with prostate-specific antigen (PSA) elevation only, locally advanced disease, or metastatic disease. (See 'Introduction' above and 'Evaluating disease extent' above.)

●Evaluating disease extent

•We obtain next generation imaging (NGI) for males with a PSA that rises ≥0.2 ng/mL after radical prostatectomy (RP) or a PSA value ≥2 ng/mL above the post-radiation nadir for males treated with radiation. (See 'Evaluating disease extent' above.)

•If patients are symptomatic or have a PSA >10, we obtain conventional imaging studies initially, given the high sensitivity in these patients. If conventional imaging is not definitive, we obtain NGI as a next step. (See 'Evaluating disease extent' above.)

●Isolated biochemical recurrence

•An increase in serum PSA that is not accompanied by signs, symptoms, or radiographic evidence of locally recurrent or disseminated disease is a biochemical recurrence. (See 'Isolated biochemical recurrence' above.)

•Patients with a biochemical recurrence should be evaluated for local salvage therapy. Patient-specific factors such as prior therapy, patient preference, and risk factors will determine the best treatment plan. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation" and "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".)

•Decisions on systemic therapy depend on whether high-risk features are present:

-High-risk biochemical recurrence after RP – A PSA doubling time <1 year or a pathologic Gleason score of 8 to 10.

-High-risk biochemical recurrence after radiation therapy (RT) – An interval to biochemical recurrence (PSA value ≥2 ng/mL above the post-radiation nadir) that occurs within 18 months of radiation, or a clinical Gleason score of 8 to 10. (See 'Definition of high-risk features' above.)

•If high-risk features are present in patients who undergo local salvage therapy for an isolated biochemical recurrence, we initiate early ADT. (See 'High-risk features present and local therapy performed for recurrence' above.)

•If high-risk features are present in patients who do not undergo local salvage therapy for an isolated biochemical recurrence, we initiate enzalutamide plus ADT. (See 'High-risk features present and local therapy not performed for recurrence' above.)

•If high-risk features are not present, irrespective of whether local salvage therapy is performed, we delay systemic treatment, with careful informed consent and periodic imaging to assess for metastatic disease (ie, active surveillance). (See 'No high-risk features present' above.)

●Recurrent locally advanced disease

•For patients without prior radiation who develop a locally advanced recurrence, we proceed with RT, followed by systemic therapy. (See 'Deciding on local therapy' above.)

•For patients with prior RT, a subset may be able to undergo repeat RT based on time from original radiation and volume treated. However, many may not be able to get additional RT due to concerns of toxicity. These patients should begin systemic therapy. (See 'Deciding on local therapy' above.)

•For males with locally advanced nonmetastatic prostate cancer treated with prostate RT for recurrence, we offer ADT plus abiraterone as systemic therapy. (See 'Choice of systemic therapy' above.)

•For males with locally advanced, nonmetastatic disease who are unwilling or unable to undergo RT we offer ADT alone. ADT may prolong overall and cause-specific survival. (See 'Choice of systemic therapy' above.)

●Patients with metastatic disease

•We offer the combination of ADT with docetaxel and darolutamide in males with either high-risk or high-volume disease; ADT, docetaxel, and abiraterone is a reasonable alternative. This combination improves overall survival compared with ADT plus docetaxel in males with high-risk/high-volume disease. (See 'Patients with high-risk or high-volume disease' above.)

•For males who are not candidates for docetaxel, or have low-risk or low-volume metastatic disease, ADT plus abiraterone, enzalutamide, or apalutamide are appropriate options. (See 'Patients with low-volume, low-risk disease' above.)

●Contribution of local therapy in males with metastatic disease

•If a clinical trial is not available, or participation is not feasible, for males with a low burden of bone metastases and no visceral metastases, we suggest prostate RT in conjunction with systemic therapy, rather than systemic therapy alone (Grade 2C). For males with a high metastatic burden, we suggest systemic therapy alone rather than systemic therapy plus prostate radiotherapy (Grade 2B). (See 'Prostate-directed therapy' above.)

•We suggest not pursuing metastasis-directed therapy for most patients with oligometastatic disease outside of the context of a clinical trial (Grade 2C). However, decision-making must be individualized, taking into account a wide range of patient-specific factors including site of metastasis, disease-free interval, patient age, and comorbidity. (See 'Metastasis-directed therapy for oligometastatic disease' above.)

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.