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 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 other 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 prostate-specific antigen (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 noncastrate (also termed castration-sensitive) prostate cancer.
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 noncastrate prostate cancer 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 noncastrate (castration-sensitive) prostate cancer (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 "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)
DISEASE EXTENT AND THE APPROACH TO THERAPY
Evaluating disease extent — In many cases, the only manifestation of disseminated disease is an elevated or rising serum prostate-specific antigen (PSA) following definitive local radiation therapy or radical prostatectomy (termed an isolated biochemical recurrence). In other cases, overt metastatic disease may be present when the patient is first diagnosed or at some time after definitive treatment for locoregional disease.
Males with locally recurrent disease after definitive local treatment may be candidates for local salvage therapy, particularly if they were previously treated with prostatectomy. In such cases, diagnostic imaging is needed to establish the sites and extent of disease. Osteoblastic axial skeleton metastases are the primary manifestation of widely disseminated disease, while the pelvis is the most common site of locoregional recurrence. (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".)
The frequency with which unsuspected 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 PSA-only progression. Because of this, conventional imaging studies have often been restricted to those at highest risk for recurrence (eg, PSA levels >10 ng/mL). However, newer next-generation imaging (NGI) techniques (especially positron emission tomography [PET] scanning using one of the newer prostate cancer-specific radiotracers and whole-body magnetic resonance imaging [MRI]) have improved sensitivity for disease recurrence at lower PSA levels. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Next-generation imaging'.)
Although guidelines from expert groups support the use of NGI for certain males with recurrent prostate cancer after initial definitive local therapy, reimbursement issues (insurance companies frequently will only pay for these tests if conventional imaging is negative) and the lack of general availability of some of these tests (especially gallium-68 prostate-specific membrane antigen PET/CT) have limited their more widespread use. 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 also be a role for NGI in males presenting with CSPC who have demonstrable metastatic disease on conventional imaging. Year 2020 guidelines from the American Society of Clinical Oncology (ASCO) suggest a role for NGI to clarify the burden of disease and potentially shift the treatment intent from multimodality management of oligometastatic disease to systemic anticancer treatment, alone or in combination with targeted therapy for palliative purposes, but note that prospective data to support this benefit are limited [3]. (See 'Metastasis-directed therapy for oligometastatic disease' below.)
The approach to initial systemic treatment, stratified according to disease extent, and outlined below is consistent with updated guidelines for managing noncastrate prostate cancer from the ASCO [4], which are outlined in the algorithm (algorithm 1). The ASCO guidelines provide recommendations for initial systemic therapy in the following scenarios:
●What are the standard initial treatment options for males with metastatic disease?
●Are combination therapies such as androgen deprivation therapy (ADT) plus a nonsteroidal antiandrogen better than ADT alone for males with locally advanced nonmetastatic disease?
●Does early rather than deferred ADT improve outcomes for males with locally advanced nonmetastatic disease?
●Is intermittent better than continuous ADT for males with isolated biochemical recurrence after definitive local therapy?
General approach to therapy
Isolated biochemical recurrence — Monitoring PSA after definitive treatment of localized prostate cancer with either radiation therapy (RT) or radical prostatectomy 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'.)
●For males in whom there is a significant likelihood that disease is confined to the prostatic bed, local salvage therapy may result in prolonged disease-free survival. However, early initiation of systemic treatment may be indicated when clinical or radiographic features suggest that disseminated disease is highly probable, and hence, salvage local therapy is not indicated.
Early ADT may also be recommended for those with an apparently isolated biochemical recurrence who have high-risk features for early metastases, including a PSA doubling time <1 year or a pathologic Gleason score 8 to 10 after radical prostatectomy, a clinical Gleason score 8 to 10 after radiation therapy, or an interval to biochemical recurrence <10 months. For males who lack these high-risk features, initiation of ADT can be delayed, with careful informed consent and periodic imaging to assess for metastatic disease (ie, active surveillance). (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'When to initiate ADT-based therapy'.)
●For males initiating ADT for an isolated biochemical recurrence after local therapy, intermittent rather than continuous ADT is a reasonable option as the intermittent approach appears to be associated with better physical and sexual function and quality of life, although questions remain as to whether survival is noninferior to continuous ADT. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'When to initiate ADT-based therapy'.)
●The optimal approach to males with a biochemical recurrence after local therapy, including the role of systemic therapy, is addressed in detail elsewhere. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification" and "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" and "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy" and "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer".)
Locally advanced and metastatic disease
ADT — ADT (ie, lowering the serum testosterone level to castrate levels) is an integral component of the initial treatment of males with advanced castration-sensitive locally advanced nonmetastatic and metastatic prostate cancer. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Historical evolution'.)
For males with asymptomatic metastatic disease, early rather than delayed treatment is generally preferred. Although early treatment may not improve overall survival, this approach is associated with improved progression-free survival. For patients with symptomatic metastases, ADT should be initiated promptly, both to palliate symptoms and to prevent severe complications (eg, pathologic fractures, spinal cord compression). (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Timing of treatment initiation'.)
Continuous therapy rather than intermittent androgen deprivation therapy is preferred because of better oncologic outcomes. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Intermittent versus continuous ADT'.)
Combined approaches — More recently, the development of additional effective systemic therapies has led to their use in combination with ADT for initial therapy of males with advanced disease, and these combined approaches have now become a preferred approach for males with locally advanced nonmetastatic and metastatic CSPC:
●Abiraterone/prednisone plus ADT – Abiraterone acts by blocking the intracellular conversion of androgen precursors in the testes, adrenal glands, and prostate tumor tissue. Randomized trials showed that combining ADT with abiraterone plus prednisone in patients with very high-risk localized nonmetastatic or metastatic castration-sensitive disease prolongs overall survival compared with ADT alone. One of these trials also showed benefit for combined therapy in males with recurrent locally advanced nonmetastatic disease, in conjunction with prostate radiation. (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. Three randomized trials (ENZAMET [Australian and New Zealand Urogenital and Prostate Cancer Trials Group 1304], TITAN, and ARCHES) showed benefit over ADT alone for metastatic CSPC. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus second-generation antiandrogens'.)
●Docetaxel plus ADT and triplet therapy – Randomized trials have demonstrated that combining docetaxel with ADT offers a clinically meaningful survival advantage for patients with high-volume castration-sensitive metastatic disease (ie, visceral metastases or four or more bone metastases, at least one outside of vertebral bodies and pelvis), albeit with greater treatment-related toxicity. More recently, at least two trials have shown a survival benefit for ADT plus docetaxel and a second systemic agent (darolutamide, abiraterone) over ADT plus docetaxel alone, and this is now a preferred approach for high-risk/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'.)
Particularly for individuals without high-risk/high-volume disease, the choice of the specific regimen is usually based on disease extent as well as a discussion with the patient about potential toxicities associated with abiraterone, apalutamide, and enzalutamide, as well as the expected duration and cost of treatment. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Choice of approach'.)
An example of an approach that is based upon disease extent at the time of presentation is presented in the algorithm (algorithm 1).
Issues specific to locally advanced nonmetastatic disease — For males with locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo RT, early ADT may prolong overall and cause-specific survival. However, for males with locally advanced nonmetastatic prostate cancer who are willing and able to undergo prostate RT, ADT plus abiraterone is a preferred approach over ADT alone, based on results from the phase III STAMPEDE trial. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus abiraterone'.)
For males with locally recurrent disease after local treatment, the best approach is not clear. Deferred ADT is often preferred by patients who desire to avoid or at least delay potential ADT side effects. However, many clinicians restrict this practice to asymptomatic individuals. 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.
OVERVIEW OF AVAILABLE SYSTEMIC THERAPIES
Androgen deprivation therapy — 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.
●Rationale – 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 chemotherapy, and is also used in conjunction with other therapies for castration-resistant disease. ADT can be accomplished with either bilateral orchiectomy (surgical castration) or medical orchiectomy [5-7].
Options
●Surgical orchiectomy – Bilateral orchiectomy (surgical castration) is a simple, cost-effective procedure. Following surgery, serum testosterone levels rapidly decrease to castrate levels. In many countries, bilateral orchiectomy remains the standard of care for initial hormone therapy of metastatic prostate cancer. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Surgical orchiectomy'.)
Surgical castration may be particularly useful when an immediate decrease in testosterone is necessary (eg, impending spinal cord compression, urinary tract outlet obstruction) or when cost or adherence to medical therapy are an issue.
●Medical orchiectomy – Medical orchiectomy decreases testicular production of testosterone through its effects on the hypothalamic-pituitary axis.
The most widely used approach is continuous treatment with a gonadotropin-releasing hormone (GnRH) agonist, which suppresses luteinizing hormone production and, therefore, the synthesis of testicular androgens. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'GnRH agonists'.)
A number of GnRH agonists are available (leuprolide, goserelin, buserelin, triptorelin). Depot formulations are frequently used to permit less-frequent treatment administration. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Formulations'.)
With the initiation of treatment with GnRH agonists, 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. Antiandrogens (eg, flutamide, bicalutamide) may be useful in preventing the flare phenomenon. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'GnRH agonists'.)
GnRH antagonists are an alternative to a GnRH agonist for initial ADT, and may be preferred when an immediate rapid decrease in testosterone levels is required:
•The GnRH antagonist degarelix binds to the GnRH receptors on pituitary gonadotropin-producing cells but does not cause an initial release of luteinizing hormone. Degarelix suppresses testosterone production and avoids the flare phenomenon observed with GnRH agonists. It is administered subcutaneously once monthly. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Degarelix'.)
•An oral GnRH antagonist, relugolix, has been shown to suppress testosterone levels faster than leuprolide, with a more favorable side effect profile [8]. This agent was approved by the US FDA for treatment of advanced prostate cancer in December 2020. Cost may be prohibitive for some patients. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Relugolix'.)
Continuous versus intermittent ADT — Many of the side effects of ADT are due to castrate levels of serum testosterone. When medical castration is withdrawn, serum testosterone levels gradually return toward normal; however, discontinuation of a long-acting GnRH agonist may be associated with a very slow testosterone recovery. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Serum testosterone level'.)
Intermittent ADT (IAD) has been proposed as an alternative to continuous ADT for treatment of advanced CSPC.
Many of the acute and chronic side effects of ADT are due to castrate levels of testosterone. Periods of time when males are off therapy may be associated with decreases in these side effects, especially those associated with physical and sexual function, thereby improving quality of life. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Intermittent versus continuous ADT'.)
IAD typically involves treatment for either a fixed interval of time or until a maximal response is achieved based upon serum prostate-specific antigen (PSA) levels. ADT is then withdrawn, and patients are followed for evidence of recurrence. As testosterone production resumes, the side effects of ADT are mitigated, but 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.
●Metastatic disease – IAD is probably inferior to continuous ADT in males with metastatic prostate cancer, and the intermittent approach is not generally used in patients with metastatic prostate cancer unless a patient places a greater value on avoiding/minimizing the side effects of ADT and maintaining quality of life, and a lesser value on maximizing overall survival. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Intermittent versus continuous ADT'.)
●Isolated biochemical recurrence – In contrast, IAD is a more accepted option for males with an isolated biochemical recurrence after definitive local therapy, although questions remain as to whether survival is adversely impacted as compared with continuous ADT. This subject is addressed in detail elsewhere. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'Continuous versus intermittent ADT'.)
Timing of treatment — The optimal time to initiate systemic therapy is uncertain. Systemic therapy for disseminated prostate cancer is not curative, and immediate therapy has not been shown to prolong overall survival compared with delayed therapy. Furthermore, treatment-related side effects can adversely affect quality of life.
●Locoregional nonmetastatic and metastatic disease – For males with locoregional nonmetastatic and asymptomatic metastatic disease, early rather than delayed treatment is generally preferred. Although early treatment may not improve overall survival, this approach is associated with improved progression-free and prostate cancer-specific survival. For patients with symptomatic metastases, ADT should be initiated promptly, both to palliate symptoms and to prevent severe complications (eg, pathologic fractures, spinal cord compression). (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Timing of treatment initiation'.)
●Isolated biochemical recurrence – The optimal timing for the initiation of ADT for patients with an 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 in this setting, and ADT is associated with bothersome side effects. Guidelines from American Society of Clinical Oncology (ASCO) suggest early ADT may also be recommended for those with an apparently isolated biochemical recurrence who have high-risk features for early metastases, including a PSA doubling time <1 year or a pathologic Gleason score 8 to 10 after radical prostatectomy, and interval to biochemical recurrence <18 months, or a clinical Gleason score 8 to 10 after radiation therapy [4]. For males who lack these high-risk features, initiation of ADT can be delayed, with careful informed consent and periodic imaging to assess for metastatic disease (ie, active surveillance) [4]. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'When to initiate ADT-based therapy'.)
Side effects — ADT is associated with a wide range of side effects that can significantly impair quality of life. (See "Side effects of androgen deprivation therapy".)
Important and/or frequent side effects include:
●Loss of lean body mass, increased body fat, and decreased muscle strength.
●Sexual dysfunction – Loss of libido in males receiving GnRH agonists usually develops within the first several months and is followed by erectile dysfunction.
●Loss of bone mineral density, which can result in bone fracture due to osteoporosis. This effect may be compounded by the presence of bone metastases.
●Vasomotor instability, which is manifested by hot flashes.
●Gynecomastia, decreased body hair, and smaller penile and/or testicular size.
●Fatigue or lack of energy.
●Behavioral and neurologic effects.
●Cardiovascular and metabolic abnormalities.
Although these side effects are potentially significant, they should not preclude the use of ADT in appropriate clinical settings.
Indications for combining ADT plus docetaxel, abiraterone, enzalutamide or apalutamide — More recently, the development of additional effective systemic therapies has led to their use in combination with ADT for initial therapy of males with advanced disease. The options are doublet therapy with ADT plus abiraterone, docetaxel, enzalutamide, or apalutamide, and, for those with high-risk/high-volume disease, "triplet therapy" with ADT plus docetaxel and either darolutamide or abiraterone.
Patients with high-risk/high-volume disease
Docetaxel plus ADT — Docetaxel prolongs survival in males with metastatic castration-resistant prostate cancer. Subsequently, the results of three randomized clinical trials suggest that ADT combined with docetaxel-based chemotherapy improves progression-free and overall survival in males with metastatic CSPC compared with ADT alone. Benefit has been most convincingly shown in males with high-risk/high-volume metastatic disease (defined by conventional scanning as the presence of visceral metastases and at least one bone lesion, or at least four bone lesions with at least one outside the axial skeleton, Gleason score 8 disease, or de novo metastatic disease). Data from these three trials established the preference for combined docetaxel plus ADT over ADT alone for males with metastatic high-risk/high-volume CSPC. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus docetaxel'.)
However, most recently, the combination of ADT plus docetaxel and a second systemic agent (darolutamide or abiraterone, "triplet therapy") is now preferred over ADT plus docetaxel ("doublet therapy") in this population given the survival benefits seen in two randomized trials, described below.
Triplet therapy — Two trials (ARASENS and PEACE-1) have demonstrated the superiority of adding a second systemic agent (darolutamide, abiraterone) to docetaxel plus ADT in metastatic CSPC, while a survival benefit from the addition of enzalutamide could not be shown in a third trial. As an example, in the placebo-controlled ARASENS trial, the addition of darolutamide to docetaxel plus ADT significantly improved overall survival (HR for death 0.68, 95% CI 0.57-0.80, median overall survival not-estimable versus 48.9 months; 48-month survival 62.7 versus 50.4 percent), and benefits were seen in all secondary endpoints without a significant increase in toxicity [9]. Largely based on this trial, darolutamide is now approved, in combination with docetaxel, for treatment of metastatic CSPC in the United States [10].
As a result of these data, triplet therapy is preferred over ADT plus docetaxel alone in patients with high-risk/high-volume disease who are candidates for docetaxel. For patients who are not candidates for docetaxel, doublet therapy (ADT plus abiraterone, enzalutamide, or apalutamide) is a reasonable alternative. (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'.)
Patients with low-volume disease, or not candidates for docetaxel
Abiraterone/prednisone plus ADT — Abiraterone acts by blocking the intracellular conversion of androgen precursors in the testes, adrenal glands, and prostate tumor tissue. It initially was shown to prolong overall survival in castration-resistant disease. More recently, at least two randomized trials showed that combining ADT with abiraterone plus prednisone in patients with very high-risk localized nonmetastatic or metastatic castration-sensitive disease prolongs overall survival compared with ADT alone.
In one of these trials, the STAMPEDE trial, benefit from the addition of abiraterone to ADT was seen in both metastatic and nonmetastatic locoregionally advanced disease. Notably, radiation therapy (RT) to the prostate was mandated in this trial for those with no prior local therapy and either node-negative or node-positive nonmetastatic high-risk disease. Because of this, updated guidelines from ASCO suggest early ADT alone for males with locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo RT, and ADT plus abiraterone rather than ADT alone for males who have not had prior definitive local therapy and who are willing and able to undergo prostate RT, based upon results from the STAMPEDE trial (algorithm 1) [4]. (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. Both drugs have significant activity in males with castration-resistant prostate cancer. More recently, two randomized trials (TITAN and ARCHES) showed benefit over ADT alone for metastatic castration-sensitive prostate cancer, 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'.)
Choice of approach — 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 supporting one approach over any other, the choice of the specific regimen if combined therapy is chosen is usually based on a discussion with the patient about disease extent, potential toxicities associated with abiraterone, docetaxel, apalutamide, and enzalutamide, as well as the expected duration and cost of treatment. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Choice of approach'.)
ASSESSMENT DURING TREATMENT — For males with castration-sensitive prostate cancer 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 [11]. 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 [12].
PSA progression alone should generally not be the sole reason to change therapy in castration-sensitive prostate cancer. Conventional imaging should be used to assess radiographic progression before making changes to the treatment approach. Assessment strategies during treatment for castration-sensitive prostate cancer 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'.)
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 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 overall survival 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 overall survival (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, overall survival (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, overall survival 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 overall survival 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 overall survival benefit was apparent in the group with three or fewer bone metastases (three-year overall survival 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 overall survival 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 (ASCO) 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 overall survival 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 PET scanning:
•In one trial 72 patients with a rising PSA after definitive local therapy and negative conventional imaging, who all then underwent prostate-specific membrane antigen (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 overall survival (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.
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 ADT 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.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment versus harm from COVID-19, ways to minimize immune suppression during cancer treatment (eg, using abiraterone, apalutamide, or enzalutamide rather than the more myelosuppressive agent docetaxel in combination with androgen deprivation therapy [ADT] in the setting of advanced CSPC), ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources.
These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with 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 5th to 6th 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 10th to 12th 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: Prostate cancer treatment; stage I to III cancer (Beyond the Basics)" and "Patient education: Treatment for advanced prostate cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Indications and timing of systemic therapy
•Some males with advanced prostate cancer have evidence of metastatic disease at presentation (de novo). Others develop metastases after definitive treatment of localized disease; if manifested only by an elevation in serum prostate-specific antigen (PSA), this is termed an isolated biochemical recurrence. The vast majority of males in all three groups have not been receiving long-term hormone therapy, and serum testosterone levels are typically >50 ng/dL. These males are considered to have noncastrate (or castration-sensitive) advanced prostate cancer. (See 'Introduction' above.)
•Males with locally recurrent disease after definitive local treatment may be candidates for local salvage therapy, particularly if they were previously treated with prostatectomy. In such cases, diagnostic imaging serves to localize the sites and extent of recurrent disease. (See 'Evaluating disease extent' above.)
•Androgen deprivation therapy (ADT) with either medical or surgical orchiectomy is the cornerstone of initial treatment to suppress serum testosterone levels for all patients requiring systemic therapy for advanced castration-sensitive prostate cancer (CSPC). (See 'Androgen deprivation therapy' above.).
●Approach to systemic therapy – The approach to ADT varies depending on disease extent. Our approach is outlined in the algorithm and summarized below:
•Timing – For an isolated biochemical recurrence following definitive locoregional therapy, early initiation of systemic treatment may be indicated when clinical or radiographic features suggest that disseminated disease is highly probable, and hence, salvage local therapy is not indicated. Early ADT may also be recommended if there are high-risk features for early metastases (eg, PSA doubling time <1 year or a pathologic Gleason score 8 to 10 after radical prostatectomy, a clinical Gleason score 8 to 10 after radiation therapy, or an interval to biochemical recurrence <18 months). For males who lack high-risk features, initiation of ADT can be delayed, with careful informed consent and periodic imaging to assess for metastatic disease (ie, active surveillance). (See 'Isolated biochemical recurrence' above.)
For males with locoregionally recurrent nonmetastatic and for those with metastatic disease, immediate rather than delayed ADT is preferred, and continuous rather than intermittent therapy is the standard approach. (See 'Locally advanced and metastatic disease' above.)
•Indications for combined therapy – For males with metastatic disease, combined ADT plus abiraterone, docetaxel, enzalutamide or apalutamide significantly prolongs overall survival compared with ADT alone. Benefit for docetaxel plus ADT has been most convincingly shown for individuals with high-risk/high-volume metastatic disease (ie, visceral metastases or four or more bone metastases, at least one located outside of the vertebral bodies and pelvis, Gleason score 8 disease, or de novo metastatic disease). More recently, the combination of ADT with docetaxel and either darolutamide or abiraterone significantly improves overall survival compared with ADT plus docetaxel alone in males with high-risk/high-volume disease, and this is a preferred approach. (See 'Patients with high-risk/high-volume disease' above.)
For males who are not candidates for docetaxel, or have low-risk/low-volume metastatic disease, ADT plus abiraterone, enzalutamide, or apalutamide is a reasonable alternative. (See 'Patients with low-volume disease, or not candidates for docetaxel' above.)
●Prostate-directed therapy
•The role of prostate-directed therapy in males with metastatic CSPC is evolving. For unselected males who have metastatic disease at initial diagnosis of prostate cancer, 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 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 radiation therapy 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.)
●Metastasis-directed therapy
•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.
