Overview of the treatment of castration-resistant prostate cancer (CRPC)

INTRODUCTION — Androgen deprivation therapy with or without an androgen receptor pathway inhibitor is a usual first-line option for males with advanced prostate cancer, but the vast majority eventually progress while receiving hormonal therapies, and the disease state is referred to as castration-resistant prostate cancer (CRPC). The mechanisms driving progression from androgen-dependent (hormone-sensitive or castration-sensitive) prostate cancer to CRPC are still largely unclear, although continued androgen receptor signaling, despite depletion of circulating androgens and androgen receptor blockade, is thought by many to be central to the development of CRPC.

For males with metastatic and nonmetastatic CRPC, multiple active treatment modalities have emerged. An overview of treatment options for males with CRPC is presented here. Separate topic reviews are available that focus on castration-sensitive or androgen-dependent prostate cancer, treatments targeting androgen pathways, other alternative forms of hormone therapy, chemotherapy, immunotherapy approaches, poly(ADP-ribose) polymerase inhibitors for males with CRPC and homologous recombination deficiency, investigational approaches to systemic therapy, and management of symptomatic bone metastases:

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

●(See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway".)

●(See "Alternative endocrine therapies for castration-resistant prostate cancer".)

●(See "Chemotherapy in advanced castration-resistant prostate cancer".)

●(See "Immunotherapy for castration-resistant prostate cancer".)

●(See "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency".)

●(See "Bone metastases in advanced prostate cancer: Management".)

DEFINITION OF CASTRATION RESISTANCE — Males with advanced prostate cancer who have evidence of disease progression (eg, an increase in serum prostate-specific antigen [PSA], new metastases, or progression of existing metastases) and who have castrate levels of serum testosterone (<50 ng/dL) are considered to have CRPC. Most of these males will be identified initially because of a rising serum PSA. Importantly, the presence of CRPC does not imply that the disease is totally independent of androgens and resistant to further therapies directed at blocking androgen stimulation.

These patients represent a heterogeneous group:

●PSA progression in males receiving androgen deprivation therapy (ADT) can reflect disease recurrence that is metastatic to distant sites; locoregional only, without disease in bone or visceral organs; or limited only to a PSA rise, without any demonstrable radiographic findings. Males who are diagnosed with CRPC at a time when the only manifestation of progressive disease is an increase in serum PSA level, without demonstrable radiographic disease progression involving specific organs, are considered to have nonmetastatic CRPC. (See 'Nonmetastatic CRPC' below.)

●Definitions of metastatic disease are changing in the new era of molecular imaging. In particular, the widespread availability of positron emission tomography (PET) scanning using prostate-specific radionuclides (eg, prostate-specific membrane antigen PET/computed tomography [CT]) is changing the definition of metastatic disease because of their greater sensitivity compared with conventional imaging (ie, CT, bone scan). Almost all of the trials that have demonstrated a survival benefit for various treatments for nonmetastatic as well as metastatic CRPC have been conducted in males who underwent staging using conventional imaging. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'More sensitive prostate cancer-specific PET tracers'.)

●Progression to CRPC has different treatment implications for those who have been treated with ADT plus an androgen receptor pathway inhibitor and/or docetaxel for metastatic castration-sensitive prostate cancer. (See 'Patients with metastatic CRPC' below.)

DEFINING DISEASE EXTENT

Diagnostic workup — For males who have suspected disease progression while receiving androgen deprivation therapy (ADT) for castration sensitive prostate cancer, imaging evaluation is appropriate to determine the site(s) and extent of disease spread (although imaging does not always change management). The best way to approach imaging is evolving. Newer more sensitive prostate-specific radiotracers for positron emission tomography (PET) scanning are being increasingly used. These tests are more sensitive than conventional imaging for detecting disease spread at lower prostate-specific antigen (PSA) levels, but the clinical impact of identifying and treating metastatic lesions that are not detected on conventional imaging is an area of active investigation and firm conclusion are not yet established. We individualize decision making. Next-generation imaging (ie, integrated PET/CT or PET/magnetic resonance imaging [MRI] using prostate-specific radiotracers) can be offered if a change in clinical care would be contemplated based on the findings, and if there is high clinical suspicion of subclinical metastases despite negative conventional imaging (bone scan and CT of the chest, abdomen, and pelvis). (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Evaluation for metastatic disease'.)

The conventional and most often utilized diagnostic imaging studies to define metastatic versus nonmetastatic CRPC in this scenario include technetium-99m diphosphonate scintigraphy (bone scan) for evaluation for skeletal metastases, as well as CT of the chest, abdomen, and pelvis (or MRI if CT is contraindicated). However, The sensitivity of conventional imaging to detect regional nodal or distant metastases is limited at lower PSA levels. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation".)

In particular, the role of next-generation imaging (ie, integrated PET/CT or PET/MRI using radiotracers that are more sensitive than fluorodeoxyglucose, or whole-body MRI), which is increasingly available to clinicians, is uncertain. Although next generation imaging tests such as prostate-specific membrane antigen PET/CT are more sensitive than conventional imaging for detecting disease spread at lower PSA levels, the clinical consequences of identifying and treating metastatic lesions that are not detected on conventional imaging is not established. As a result, there is no consensus from expert groups as to the utility of these novel imaging modalities in males with a rising PSA while receiving ADT:

●National Comprehensive Cancer Network (NCCN) guidelines state that workup for progression should include bone imaging, chest CT, and abdominopelvic CT or MRI with and without contrast. C-11 choline PET/CT or PET/MRI, or F-18 fluciclovine PET/CT or PET/MRI could be considered for further evaluation, but the panel was unsure what to do if distant metastatic disease was suggested by next-generation imaging but not conventional imaging [1].

●American Society of Clinical Oncology guidelines for optimum imaging strategies for advanced prostate cancer state that, for males with nonmetastatic or metastatic CRPC, next-generation imaging can be offered only if a change in clinical care is contemplated, in an individualized manner, and if there is high clinical suspicion of subclinical metastases despite negative conventional imaging [2].

●European guidelines state that new symptomatic bone lesions require a bone scan, as well as PSA progression suggesting CRPC status if a treatment modification is considered [3]. Suspicion of disease progression indicates the need for additional imaging modalities, most often initially a CT scan, but further imaging will be guided by symptoms or possible subsequent treatments. In CRPC, imaging must be individualized, with the aim of maintaining the patient's quality of life.

Definition of PSA-only progression — There are no widely accepted criteria to define the emergence of CRPC when the only evidence of disease progression while on ADT is an increase in serum prostate-specific antigen (PSA); this decision requires judgment on the part of the treating clinician.

However, practice is variable:

●Some clinicians follow the recommendations of the Prostate Cancer Working Group 3, which were primarily intended to define endpoints for clinical trial design [4]: a 25 percent increase from the nadir (considering a starting value of ≥1 ng/mL), with a minimum rise of 2 ng/mL, in the context of castrate testosterone values (<50 ng/mL).

●Guidelines from the European Association of Urology and others consider two consecutive PSA rises of >0.2 ng/mL to be suggestive of progression [3].

●The NCCN defines CRPC as prostate cancer that progresses clinically, radiographically, or biochemically despite castrate levels of serum testosterone, and it does not provide a specific definition for PSA-only progression [1].

PSA kinetics are also important in clinical decision making. Some trials conducted in males with nonmetastatic CRPC enrolled patients regardless of their absolute PSA level if their PSA doubling time was less than 10 months. This distinction is important as active treatment modalities have emerged to delay disease progression in males with nonmetastatic CRPC in which eligibility is limited to those with a PSA doubling time <10 months. (See 'Nonmetastatic CRPC' below.)

PROGNOSIS AND PROGNOSTIC FACTORS — Males with CRPC represent a heterogeneous population; at one end of the spectrum are those with a prostate-specific antigen (PSA)-only recurrence (M0 disease with a rising PSA and no demonstrable metastases), and at the other end are males with extensive, high-volume, symptomatic, metastatic disease in visceral sites (especially liver).

Clinical parameters — The most important factors influencing survival in males with CRPC are the site and extent of metastatic involvement. An individual patient data meta-analysis included information from 8820 males with CRPC who had been treated with a docetaxel-containing regimen as participants in one of nine phase III trials [5]. Overall survival (OS) was best for those with lymph-node-only disease and decreased progressively for those with bone, lung, or liver metastases (median 31.6, 21.3, 19.4, and 13.5 months, respectively).

A number of other factors can also influence survival:

●Within the group of males with only a biochemical recurrence, PSA kinetics, as assessed by PSA doubling time, are an important prognostic factor for both time to metastasis and OS [6,7].

●Two large phase III trials were used to develop and validate a model to predict OS in males with CRPC who were treated with chemotherapy [8]. Factors associated with shorter OS included a poorer performance status, the presence or absence of visceral metastases, use of opioids for pain relief, an elevated serum lactate dehydrogenase (LDH), an increasing serum PSA, an increasing serum alkaline phosphatase (ALP), a lower serum albumin, and a lower hemoglobin level.

These factors were combined into a nomogram to classify patients as being at low, intermediate, or high risk, with median OS values in the high- and low-risk groups being 14 to 17 and 26 to 30 months, respectively.

A similar model has been constructed to predict prostate cancer survival in males treated with second-line chemotherapy after docetaxel [9]. Others have developed models to predict the probability of outcomes in males with chemotherapy-naïve disease after treatment with newer androgen receptor pathway inhibitors (ARPIs) such as enzalutamide and abiraterone [10,11]. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway".)

Whether and how these factors should be used to select treatment for males with CRPC is not yet established, although at least some data suggest that males with ARPI-naïve CRPC who have high number of risk factors (liver metastases, progression to metastatic CRPC within 12 months of initiating androgen deprivation therapy [ADT], or ≥4 high-risk clinical criteria [LDH >upper limit of normal [ULN], Eastern Cooperative Oncology Group performance status 2, visceral metastatic disease, serum albumin ≤4 g/dL, ALP >ULN, or <36 months from start of ADT to study enrollment]) may derive greater benefit from cabazitaxel than from an ARPI (clinicians choice of abiraterone or enzalutamide) [12]. (See 'Prior docetaxel' below.)

Prognostic biomarkers — A variety of markers are being studied for their ability to identify subsets of patients with advanced prostate cancer who have significantly different prognoses. The most extensive data come from analyses of circulating tumor cells (CTCs) and gene expression profiles. Ultimately, these different approaches may be combined.

Circulating tumor cells — CTCs can be detected in the systemic circulation of males with prostate cancer, and the presence of an increasing number of CTCs at baseline has been associated with shorter OS in several trials [12-15]. As examples:

●In a phase III trial comparing abiraterone plus prednisone versus placebo plus prednisone in males with CRPC who had progressed on docetaxel chemotherapy, CTCs were measured in 972 of 1195 patients at baseline and/or serially thereafter [13]. Median OS was significantly longer in those with <5 CTCs per 7.5 mL compared with those with ≥5 CTCs per 7.5 mL at baseline (22.1 versus 10.9 months in those assigned to abiraterone and 19.7 versus 8.2 months in those assigned to placebo).

●In a second phase III trial, CTCs were assayed in 238 patients with metastatic CRPC who were randomly assigned to treatment with docetaxel or docetaxel plus atrasentan [14]. Median OS was significantly longer in those with <5 CTCs per 7.5 mL compared with those with ≥5 CTCs per 7.5 mL at baseline (26 versus 13 months).

●In a third phase III trial, CTCs were assayed in 208 patients with metastatic CRPC who were treated with docetaxel, prednisone, and lenalidomide as part of a larger phase III trial [15]. Median OS was significantly longer in those with <5 CTCs per 7.5 mL compared with those with ≥5 CTCs per 7.5 mL at baseline (median not reached versus 18 months, hazard ratio 3.23). In addition, OS was significantly worse in those in whom CTCs increased after three cycles of treatment from <5 to ≥5 CTCs per 7.5 mL compared with baseline, and it was best in those in whom CTCs decreased from ≥5 to <5 CTCs per 7.5 mL.

In addition, changes in the number of CTCs may be an indicator of response to treatment and subsequent improved survival. In an analysis of 6081 patients enrolled in five trials of males with CRPC, the baseline CTC count was compared with the CTC count after 12 weeks of treatment [16]. The two most effective predictors of survival were a conversion from ≥1 to 0 CTCs at week 13 and a conversion from ≥5 to ≤4 CTCs at week 13. Both were better predictors of improved survival than a decrease in serum PSA.

Commercial assays of CTCs are now available in clinical practice, but they are not in widespread use because of the lack of insurance reimbursement. The significance of circulating prostate cancer cells in males at the time of initial diagnosis is discussed separately. (See "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'Post-treatment predictive and prognostic tools'.)

Markers of bone metabolism — New bone formation and bone resorption are ongoing processes that may be disordered in the presence of bone metastases. Markers of bone metabolism provide information that may be useful either as a prognostic factor or to identify subsets of patients that may be responsive to particular agents.

The potential utility of such markers was most extensively studied in a phase III trial in patients with metastatic CRPC who were treated with docetaxel/prednisone plus either the experimental agent atrasentan or placebo [17]. Sera were collected at baseline and in follow-up from 778 patients and were assayed for two markers of bone resorption (N-telopeptide, pyridinoline) and two markers of bone formation (C-terminal collagen propeptide, bone ALP). For each of the four markers, a higher serum level at baseline (defined as greater than the median) was associated with significantly shorter OS, while increasing levels of these biomarkers after nine weeks of treatment were associated with a significantly poorer prognosis. The potential utility of this approach to identify subsets of patients who may benefit from a specific therapeutic approach was also observed. Among those patients who received the experimental agent atrasentan rather than placebo, OS was significantly increased in those who had significant elevations of all four biomarkers (median 13 versus 5 months), whereas there was no difference in OS when the remainder of the patients were analyzed.

Markers of bone metabolism are not in widespread use in clinical care.

Gene expression panels — Multiple tissue-based prognostic tests based on either molecular characteristics or cell proliferation are emerging in prostate cancer, with an aim to better risk-stratify both untreated and treated males with localized prostate cancer. However, whether these tests have any utility in stratifying prognoses for males with metastatic or nonmetastatic CRPC is not established, and they should not be used in this setting. (See "Molecular prognostic tests for prostate cancer", section on 'Clinical utility and guidelines from expert groups'.)

Neuroendocrine differentiation — Primary small cell neuroendocrine cancer of the prostate is rare at initial diagnosis but carries a poor prognosis. (See "Interpretation of prostate biopsy", section on 'Neuroendocrine neoplasms'.)

More commonly, neuroendocrine differentiation may emerge in males who have previously had ADT for prostate adenocarcinoma. These tumors, sometimes called treatment-related neuroendocrine prostate cancers are increasingly recognized in the castration-resistant phases of disease progression. These tumors can be androgen receptor negative, have a varying degree of small cell carcinoma morphology (or mixed small cell and adenocarcinoma), and can express markers of neuroendocrine differentiation (eg, chromogranin, synaptophysin). In addition, they can be associated with low PSA production, an aggressive clinical course with atypical clinical manifestations, and relative resistance to androgen signaling inhibitors. (See 'Aggressive-variant prostate cancers' below.)

OUR RECOMMENDED APPROACH TO INITIAL TREATMENT

Germline genetic testing and next-generation sequencing of tumor tissue — A substantial number of males with prostate cancer, particularly those with intraductal histology, carry germline mutations that might affect therapy decisions and screening for additional tumors. For all males with metastatic prostate cancer who have not already been referred for germline genetic testing, we suggest genetic counseling and germline testing using a panel of genes including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and postmeiotic segregation increased 2 (PMS2; for Lynch syndrome); breast cancer susceptibility gene (BRCA) 1; BRCA2; ataxia telangiectasia mutated (ATM); partner and localizer of BRCA2 (PALB2); and checkpoint kinase 2 (CHEK2). Approximately 5 to 10 percent of patients have germline mutations in DNA mismatch repair genes, and they may be eligible for poly(ADP-ribose) polymerase (PARP) inhibitors. (See "Genetic risk factors for prostate cancer", section on 'Who needs referral for genetic evaluation' and "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency".)

Next-generation sequencing can also be considered to test prostate tumor tissue for assessment of somatic genomic alterations. This may reveal potentially targetable abnormalities for which approved drugs are available regardless of tumor type (eg, a PARP inhibitor for those with homologous recombination repair deficiency, pembrolizumab for tumors associated with deficient mismatch repair [dMMR]/high levels of microsatellite instability [MSI-H] or a tropomyosin receptor kinase [TRK] inhibitor for rare neurotrophic tyrosine receptor kinase [NTRK] fusions) or for which a clinical trial is in progress testing non-approved drugs. However, in general, these treatments would be considered for disease that is refractory to taxanes and androgen signaling pathway inhibitors, and not for initial therapy. (See "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency" and "TRK fusion-positive cancers and TRK inhibitor therapy" and "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Treatment with TRK inhibitors' and "Immunotherapy for castration-resistant prostate cancer", section on 'PD-1 pathway inhibition'.)

Choice of treatment for conventional adenocarcinomas — The choice of initial systemic treatment for CRPC depends on many factors, including prior systemic treatments, the site and extent of disease involvement, the presence or absence of symptoms, and for males with nonmetastatic disease, the prostate-specific antigen (PSA) doubling time. Patients should be included in clinical trials whenever possible.

If protocol participation is not available or is not chosen, the following represents our general approach to initial treatment, which is outlined in the algorithm (algorithm 1) and is consistent with consensus-based guidelines from the National Comprehensive Cancer Network, the American Urological Association, and a combined guideline from the European Association of Urology, European Association of Nuclear Medicine, European Society for Radiotherapy and Oncology, European Society of Urogenital Radiology, and International Society of Geriatric Oncology [18-20].

Continuation of androgen deprivation therapy

For most males with CRPC, we suggest that androgen deprivation therapy (ADT) be continued while additional systemic therapy is used. Alternatively, where cost is an issue, the gonadotropin-releasing hormone (GnRH) agonist can be held, and the serum testosterone level can be monitored at two- to three-month intervals. Treatment can be resumed when testosterone levels begin to rise. Another cost-saving measure would be to consider orchiectomy.

ADT is generally continued in most males with CRPC in conjunction with secondary therapies after progression on the initial ADT regimen [21]. Androgenic steroids are growth factors for prostate cancer. When disease progresses, discontinuation of GnRH agonist therapy can result in an increase in serum testosterone and, thus, contribute to progressive disease.

There are no randomized trials that directly address the utility of continued ADT in males with CRPC. However, a multivariate analysis of 341 patients with CRPC who were treated in four clinical trials suggested that continued testicular androgen suppression was associated with a median survival benefit of two to six months [22].

Patients initially treated with an older antiandrogen — For males whose initial hormone therapy included both a GnRH agonist and an older antiandrogen (flutamide, nilutamide, or bicalutamide), withdrawing the antiandrogen should be done prior to starting a new treatment. Withdrawal may result in a clinical or biochemical response. (See "Alternative endocrine therapies for castration-resistant prostate cancer", section on 'Antiandrogens and antiandrogen withdrawal' and 'Other endocrine approaches' below.)

Patients with nonmetastatic CRPC

●Short PSA doubling time – For males with nonmetastatic CRPC and a PSA doubling time of 10 months or less progressing on ADT monotherapy, we suggest a second-generation androgen receptor blocker (enzalutamide, apalutamide, or darolutamide) plus ADT, rather than continued ADT alone or another form of therapy. At least three placebo-controlled randomized trials have documented delayed disease progression and prolonged survival using drugs that interfere with androgenic stimulation of prostate cancer growth, including enzalutamide, apalutamide, and darolutamide, in conjunction with continued ADT for the treatment of males with nonmetastatic CRPC (table 1). All three drugs are now US Food and Drug Administration (FDA) approved for nonmetastatic CRPC, all given in conjunction with continued ADT. Abiraterone is an alternative, but does not have FDA approval for this indication. These trials were all conducted in males with short PSA doubling times (≤10 months), and the control arm was placebo plus ongoing ADT. (See 'Enzalutamide, apalutamide, and darolutamide' below.)

An important point is that all three trials enrolled males who were categorized as nonmetastatic based on conventional imaging (CT, bone scan). Newer molecular imaging studies with integrated positron emission tomography/CT (PET/CT) using prostate-specific membrane antigen (PSMA)-specific radiotracers clearly demonstrate that PET-positive lesions are identified in 98 percent of males with nonmetastatic CRPC and a PSA doubling time of <10 months (including 55 percent with M1 disease despite negative conventional imaging) [23]. The optimal way to manage these patients is uncertain. While radiotherapy of the PSMA PET positive lesions in this disease state can result in PSA declines [24], further studies are required to understand the clinical risk/benefits of this approach. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'More sensitive prostate cancer-specific PET tracers'.)

●Longer PSA doubling times – The optimal approach for patients with nonmetastatic CRPC and longer PSA doubling times is not established. Observation or treatment with an androgen receptor pathway inhibitor (ARPI) such as enzalutamide (if it was not previously used) are options. (See 'Other endocrine approaches' below.)

Some clinicians use abiraterone in this setting, based upon results from the uncontrolled phase II IMAAGEN trial [25], and a network meta-analysis comparing different treatments for nonmetastatic CRPC [26]. One major advantage of abiraterone is that it is less expensive than enzalutamide as it is available in generic form. However, given the lack of phase III trials, this is a controversial area.

Patients with metastatic CRPC — For patients with metastatic CRPC, multiple agents have been shown to improve overall survival in phase III trials (table 2), all given in conjunction with continued ADT. However, these patients are a heterogeneous group, particularly with regard to prior therapies. Given advances in management of metastatic castration-sensitive prostate cancer, they may have already received docetaxel and/or an ARPI. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer".)

The choice of treatment is dependent on prior therapy, as illustrated in the algorithm (algorithm 1), and outlined in the sections below:

●Patients previously not exposed to an ARPI or a taxane

•For this group of patients, adding an androgen receptor pathway inhibitor (ARPI) to ADT is the preferred approach. Options include:

-Interference with androgenic stimulation of prostate cancer growth using an androgen signaling inhibitor such as enzalutamide. (See 'Enzalutamide, apalutamide, and darolutamide' below.)

-Inhibition of androgen biosynthesis (abiraterone). (See 'Abiraterone' below.)

•Cytotoxic chemotherapy using docetaxel is generally reserved for patients with relatively rapidly progressing symptomatic disease for which less toxic approaches (eg, abiraterone, enzalutamide) may not be appropriate options. (See 'Docetaxel' below.)

•Sipuleucel-T is an option for minimally symptomatic males who have slowly progressive disease not requiring a rapid response. (See 'Sipuleucel-T' below.)

•The bone-targeted radiopharmaceutical radium-223 (Ra-223) is an option for males with symptomatic bone metastases and no visceral disease. (See 'Radium-223' below.)

●Patients previously exposed to an ARPI but not docetaxel

•Treatment with a taxane is an option, for those who are appropriate candidates for a cytotoxic agent.

Many clinicians choose docetaxel over cabazitaxel as the initial chemotherapy regimen for chemotherapy-naïve patients. Cabazitaxel may be preferred in older or frail patients and those at high risk for neutropenia, based on its lower toxicity and similar efficacy, despite its higher cost. However, cabazitaxel is not US Food and Drug Administration (FDA) approved for chemotherapy-naïve patients and reimbursement challenges may occur. If neutropenia is a concern with docetaxel, the addition of a granulocyte colony-stimulating factor to docetaxel is another option. (See 'Docetaxel' below and 'Cabazitaxel' below.)

•The role of Sipuleucel-T in patients with post-ARPI progression is not clear, and we would not pursue it in this setting. (See 'Sipuleucel-T' below.)

•The bone-targeted radiopharmaceutical Ra-223 is an option for males with symptomatic bone metastases and no visceral disease. (See 'Radium-223' below.)

•Selected patients may be eligible for a poly(ADP-ribose) polymerase (PARP) inhibitor (ie, those with homologous recombination repair deficiency) or an immune checkpoint inhibitor (ie, deficient mismatch repair, high levels of tumor mutational burden), but the optimal timing of these treatments (ie, pre-taxane or after progression on both an ARPI and a taxane) is debated. (See 'PARP inhibitors for patients with deficiency in homologous recombination repair' below and 'Pembrolizumab for deficient mismatch repair' below.)

●Patients previously exposed to both an ARPI and docetaxel

•For patients with progression despite prior ADT plus an ARPI and docetaxel, lutetium Lu-177 vipivotide tetraxetan is a preferred option for those with PSMA-positive disease. (See 'Radioligand therapy for PSMA-positive tumors' below.)

•Cabazitaxel is another option for those who are appropriate candidates for cytotoxic therapy. (See 'Cabazitaxel' below.)

•The role of Sipuleucel-T in those with post-ARPI progression is not clear, and we would not pursue it in this setting. (See 'Sipuleucel-T' below.)

•The bone-targeted radiopharmaceutical Ra-223 is an option for males with symptomatic bone metastases and no visceral disease. (See 'Radium-223' below.)

•Selected patients may be eligible for a PARP inhibitor (homologous recombination repair deficiency) or an immune checkpoint inhibitor (eg, deficient mismatch repair, high levels of tumor mutational burden).

Aggressive-variant prostate cancer — The best regimen for CRPC tumors that have features of an aggressive variant but who are not pure small cell cancers (eg, aggressive-variant prostate cancer) is not established. Some patients may benefit from a taxane/platinum combination. Aggressive variants are variously defined but may include liver metastases, lytic bone, lesions, rapid progression on ADT, etc [27]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Aggressive prostate cancer variants'.)

EFFICACY OF DIFFERENT SYSTEMIC THERAPY OPTIONS

Conventional adenocarcinomas — The therapeutic landscape of advanced typical CRPC is continuously changing because of new therapeutic options and improved understanding of the molecular characteristics of these tumors. The rapid evolution of treatment and the lack of high-quality randomized trials that compare available treatments and explore optimal sequencing have led to a variety of differing clinical guidelines in this area [28].

The following sections will provide an overview of the available data supporting the efficacy of various systemic treatment options for the initial treatment of usual castration-resistant prostate adenocarcinomas. Options for aggressive-variant prostate cancers (ie, aggressive clinical course with low prostate-specific antigen [PSA]) are discussed below, as are therapeutic options for refractory disease. (See 'Aggressive-variant prostate cancers' below.)

Interference with androgenic stimulation — An improved understanding of the role of androgens in stimulating the growth of prostate cancer has led to the development of abiraterone and agents that block signaling at the androgen receptor, including enzalutamide, apalutamide, and darolutamide. These agents have all significantly improved metastasis-free survival compared with placebo in phase III trials in patients with CRPC, including males previously treated with docetaxel-based chemotherapy and those who were chemotherapy naïve. Either enzalutamide or the combination of abiraterone plus prednisone is the preferred systemic approach for initial use when hormone therapy is indicated after progression on androgen deprivation therapy (ADT) [21]. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Abiraterone' and "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Enzalutamide'.)

The choice of agent is largely based on potential side effects and availability (table 2):

●Abiraterone plus prednisone and enzalutamide were directly compared with each other in one randomized trial, the HEAT trial, in which the primary endpoint was the difference in fatigue scores, and secondary outcomes included changes in health-related quality of life (QOL), body composition, weight, glucose control, lipid profile, and blood pressure [29]. Abiraterone resulted in less fatigue than enzalutamide, but abiraterone had a higher increase in glycated hemoglobin (HbA1C) and a higher risk for diabetes mellitus (8 of 85 versus none of 84 with enzalutamide). Group differences in health-related QOL were not statistically significant.

●Beyond these issues, abiraterone cannot be used in patients with severe liver dysfunction. Enzalutamide is associated with an increased risk of falls and can interfere with therapeutic anticoagulation by decreasing exposure to warfarin. There is a very low risk of seizures with enzalutamide and apalutamide.

●Drug-drug interactions may also influence the choice of one agent over another. As an example, enzalutamide is a CYP450 3A4 inducer and it can interfere with therapeutic anticoagulation by decreasing the plasma concentrations of warfarin, apixaban, and rivaroxaban. These are major drug-drug interactions and concomitant use is not recommended. On the other hand, abiraterone is a CYP450 3A4 inhibitor leading to increased plasma concentration of apixaban. Coadministration leads to only a moderate interaction requiring no dose adjustment but close monitoring.

There appears to be no benefit to combining abiraterone with enzalutamide. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Combining abiraterone and an AR antagonist'.)

There are only limited data on the activity of enzalutamide in patients who have previously been treated with abiraterone and on the activity of abiraterone after treatment with enzalutamide, but the available data suggest that the clinical value of a switch is limited. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Prior enzalutamide therapy' and "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Prior abiraterone therapy'.)

Abiraterone — Androgens produced in the testes, adrenals, and tumor cells themselves can cause "autocrine/paracrine" signaling, which results in tumor progression. Abiraterone is an orally administered small molecule that irreversibly inhibits the products of the cytochrome P450 family 17 (CYP17) gene (including both 17,20-lyase and 17-alpha-hydroxylase). In doing so, abiraterone blocks the synthesis of androgens in the tumor as well as in the testes and adrenal glands. However, inhibition of 17-alpha-hydroxylase also decreases cortisol, and there is a compensatory rise in adrenocorticotropic hormone (ACTH), which is mediated by a hypothalamic response to partial adrenal inhibition.

The increased ACTH release can cause increased adrenal mineralocorticoid production, which can lead to hypertension and hypokalemia. When abiraterone is given without concomitant glucocorticoids, patients typically do not experience clinical adrenal insufficiency since cortisol production is preserved. The effects of mineralocorticoid excess can be attenuated with coadministration of prednisone, which reduces ACTH-mediated stimulation of the adrenal glands. However, long-term combined treatment is associated with muscle wasting and weakness. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Abiraterone'.)

In two phase III trials, abiraterone plus prednisone prolonged overall survival (OS) compared with prednisone alone in males who had previously been treated with docetaxel [30] and in those who were chemotherapy naïve [31]. Abiraterone is generally well tolerated, although fluid retention, hypokalemia, and hypertension may require treatment.

Abiraterone plus prednisone has limited activity in males with CRPC who have previously been treated with both docetaxel and enzalutamide [32,33]. As an example, 10 to 20 percent of such patients in a retrospective case series had a decrease in serum PSA during treatment with abiraterone [32]. Median progression-free survival (PFS) was 2.7 months.

Enzalutamide, apalutamide, and darolutamide — Enzalutamide, apalutamide, and darolutamide are orally administered agents that act at multiple sites in the androgen receptor signaling pathway, including blocking the binding of androgen to the androgen receptor, inhibition of nuclear translocation of the androgen receptor, and inhibition of the association of the androgen receptor with nuclear DNA. The mechanism of action and efficacy profile with apalutamide are very similar to those with enzalutamide; however, it has fewer central nervous system toxicities (although it is still associated with seizures). Darolutamide (ODM-221) is an androgen receptor antagonist with a distinct structure that offers the potential for fewer and less severe toxic effects than with either enzalutamide or apalutamide because of its low penetration of the blood-brain barrier and low binding affinity for gamma-aminobutyric acid type A receptors (which are thought to be responsible for the tendency of other androgen receptor antagonists to induce seizures).

Unlike with abiraterone, concurrent treatment with steroids is not required when these agents are used. These drugs have been explored both in males with metastatic (enzalutamide only) and nonmetastatic (enzalutamide, apalutamide, darolutamide) CRPC.

Metastatic CRPC — Enzalutamide has been shown to improve OS in at least two placebo-controlled phase III trials, one in males who had previously been treated with docetaxel [34] and the other in those who were chemotherapy naïve [35]. Enzalutamide is approved for males with metastatic CRPC. Treatment with enzalutamide has been associated with seizures in approximately 1 to 2 percent of cases [36], but a pre-existing seizure disorder is not a contraindication to its use. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Enzalutamide'.)

Enzalutamide has limited activity in males with CRPC who have previously been treated with both docetaxel and abiraterone [37,38]. As an example, in a retrospective case series, approximately 10 percent of such patients had a ≥50 percent decrease in serum PSA during treatment with enzalutamide [37].

Use of the poly(ADP-ribose) polymerase (PARP) talazoparib concurrently with enzalutamide has shown PFS benefit relative to enzalutamide alone, as discussed elsewhere. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Combining enzalutamide with a PARP inhibitor'.)

There are no phase III trials and only limited data comparing abiraterone with enzalutamide in the initial management of patients with metastatic CRPC [39], and the choice of one agent over another should be based on toxicity profiles and patient-specific factors, including reimbursement from third-party payers. Many insurers are requiring abiraterone first because it is available as a generic drug and is somewhat less expensive. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Abiraterone versus enzalutamide'.)

Nonmetastatic CRPC — At least three placebo-controlled randomized trials provide support for enzalutamide [40,41], apalutamide [42,43], and darolutamide [44,45] in the treatment of males with nonmetastatic CRPC (table 1). All three trials limited enrollment to males with a short PSA doubling time (<10 months), and none had an active comparator arm All three drugs are now US Food and Drug Administration approved for nonmetastatic CRPC. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Enzalutamide'.)

In this setting, the efficacies of these three agents have not been compared directly, but they appear to be similar [46]. Differences in the safety profiles may drive treatment decisions. Darolutamide has been reported to induce fewer central nervous system side effects compared with enzalutamide and, to a lesser extent, apalutamide, although the data are less than definitive. All three agents carry a risk of drug-drug interactions, which should be examined closely prior to choosing one agent over another. As an examples, enzalutamide is a CYP450 3A4 inducer, and it can interfere with therapeutic anticoagulation by decreasing the plasma concentrations of warfarin, apixaban and rivaroxaban. These are major drug-drug interactions and concomitant use is not recommended. On the other hand, abiraterone is a CYP450 3A4 inhibitor leading to increased plasma concentration of apixaban. Coadministration leads to only a moderate interaction requiring no dose adjustment but close monitoring. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Is any one drug superior to the others in nonmetastatic CRPC?'.)

The optimal approach to males with longer PSA doubling times is not established. We consider that observation alone is a reasonable alternative to hormone therapy. If hormone therapy is chosen, options include enzalutamide, a first-generation antiandrogen, a glucocorticoid, ketoconazole, estrogen (including diethylstilbestrol), or progesterones. (See 'Other endocrine approaches' below.)

Chemotherapy — Taxanes are the only cytotoxic chemotherapy agents that have significantly prolonged OS in clinical trials in males with metastatic CRPC and no prior chemotherapy. Cytotoxic chemotherapy with a taxane is generally reserved for males with relatively rapidly progressing symptomatic disease, for which less toxic approaches (eg, abiraterone, enzalutamide) are not an appropriate option. Either docetaxel or cabazitaxel is an appropriate choice for chemotherapy-naïve patients but there is no FDA approval for cabazitaxel for those without prior docetaxel chemotherapy. In a large trial, cabazitaxel was equivalent to docetaxel in efficacy, with less neuropathy and alopecia. We prefer cabazitaxel rather than docetaxel rechallenge for patients who have progressed after treatment with docetaxel, as it has been shown to prolong survival in this setting [47]. Notably, the use of prednisone in conjunction with docetaxel or cabazitaxel was based on the original trials establishing the efficacy of these agents compared with mitoxantrone plus prednisone. However, the benefit of adding prednisone to docetaxel or cabazitaxel has never been tested.

Docetaxel — Docetaxel (75 mg/m²) given every three weeks in combination with daily prednisone (5 mg twice a day) significantly prolonged OS compared with mitoxantrone plus prednisone in the TAX 327 phase III trial [48]. Based on those results, docetaxel plus prednisone has become a standard initial regimen when chemotherapy is indicated for CRPC. A randomized trial comparing 50 mg/m² docetaxel every two weeks versus 75 mg/m² every three weeks found that the lower dose was associated with a longer time to treatment failure and less febrile neutropenia [49]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Chemotherapy-naïve patients'.)

Docetaxel causes significant myelosuppression and requires premedication to minimize the risk of infusion reactions. Contraindications include underlying hepatic dysfunction or compromised bone marrow function.

Cabazitaxel — Cabazitaxel is a synthetic taxane derivative with activity in patients with and without prior exposure to docetaxel.

No prior docetaxel — Many clinicians choose docetaxel over cabazitaxel as the initial chemotherapy regimen for chemotherapy-naïve patients. Cabazitaxel (20 mg/m²) may be preferred in older or frail patients and those at high risk for neutropenia, based on its lower toxicity and similar efficacy, despite its higher cost; however, but this approach is not FDA approved and reimbursement challenges may occur. If neutropenia is a concern with docetaxel, the addition of a granulocyte colony-stimulating factor (G-CSF) to docetaxel is another option.

Comparable activity for cabazitaxel versus docetaxel in the first-line setting was demonstrated in the FIRSTANA trial, in which cabazitaxel (20 or 25 mg/m²) was directly compared with docetaxel (75 mg/m²); all three arms also received daily oral prednisone [50]. OS was not inferior with cabazitaxel, and there was no significant difference in PFS. The incidence of febrile neutropenia was lower with cabazitaxel 20 mg/m² compared with either docetaxel or higher dose cabazitaxel. Hematuria was more frequent with cabazitaxel, while peripheral neuropathy, edema, alopecia, and nail disorders were more frequent with docetaxel. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Docetaxel versus cabazitaxel'.)

Prior docetaxel — For males who develop CRPC after a prior course of docetaxel and who are being considered for chemotherapy, we suggest cabazitaxel rather than a docetaxel rechallenge or treatments targeting the androgen receptor. One potential exception is patients with androgen receptor pathway inhibitor-refractory prostate-specific membrane antigen-positive metastatic CRPC treated previously with docetaxel, in whom we suggest lutetium Lu-177 vipivotide tetraxetan over cabazitaxel based on results from the ANZUP 1603 trial. (See 'Radioligand therapy for PSMA-positive tumors' below.)

Cabazitaxel requires premedication to minimize the risk of infusion reactions. Contraindications include underlying hepatic dysfunction or compromised bone marrow function. Primary prophylaxis with recombinant human G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) should be considered, especially for patients older than 65 years and those with extensive prior radiation therapy (RT), as well as other high-risk groups. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Indications, benefits, and guidelines'.)

Increasingly, males with high-risk, high-volume metastatic castration-sensitive disease are being offered ADT plus concurrent systemic therapy, often an 18-week course of docetaxel, based on the results of the CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trials. The addition of a third agent (darolutamide or abiraterone) to docetaxel and ADT is generally recommended due to the survival benefits seen in the ARASENS and PEACE-1 trials. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Patients with high-risk/high-volume disease'.)

●Cabazitaxel versus other chemotherapy regimens – In a phase III trial, cabazitaxel plus prednisone significantly increased survival compared with mitoxantrone plus prednisone in males whose disease had progressed on docetaxel [47]. Another phase III trial found that a dose of 20 mg/m² was as effective and less toxic than the approved dose of 25 mg/m² [51]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Men who have received prior docetaxel'.)

●Cabazitaxel versus androgen receptor therapy – Whether cabazitaxel is a better choice than approaches that interfere with androgenic stimulation after failure of docetaxel has been addressed in the following trials, all of which suggest benefit for cabazitaxel:

•Cabazitaxel was compared with abiraterone or enzalutamide (by investigator choice) in a randomized phase II trial of 95 males with poor-prognosis advanced CRPC (liver metastases, early CRPC <12 months from the start of ADT, and/or more than three of six poor prognostic criteria [52]), with crossover at progression [53]. Approximately one-half had received prior docetaxel. Accrual to the trial was discontinued before the target (n = 120) was reached because of slow accrual and shifts in treatment practices towards earlier use of androgen receptor therapy in the setting of castration sensitive disease.

In the latest analysis, the clinical benefit rate (defined as PSA decline ≥50 percent, objective response, or stable disease ≥12 weeks) was significantly but modestly greater with cabazitaxel (80 versus 62 percent), although the main difference between the two groups was in the percentage of patients achieving stable disease for longer than 12 weeks (75 versus 56 percent) [12]. There were no significant differences in radiographic response, PSA decline, time to radiographic or PSA progression or PFS, and median OS was not significantly different (37 versus 15.5 months, hazard ratio 0.58, p = 0.073). This modest benefit was counterbalanced by a significantly worse toxicity profile for cabazitaxel (grade 3 or worse adverse effects in 50 versus 10 percent), most commonly neutropenia, diarrhea, infection, and fatigue.

•The safety and efficacy of cabazitaxel as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) in males with metastatic CRPC who were previously treated with docetaxel and who had progressed within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) were addressed in the randomized CARD trial [54]. At a median follow-up of 9.2 months, third-line cabazitaxel was superior in terms of imaging-based progression or death (74 versus 80 percent), median OS (13.6 versus 11 months), PSA response (36 versus 14 percent), and objective tumor response (37 versus 12 percent). Grade ≥3 adverse events occurred in a similar percentage of patients in both groups (56 versus 52 percent), although those that occurred more frequently with cabazitaxel were asthenia/fatigue (4 versus 2.4 percent), and diarrhea, peripheral neuropathy, and febrile neutropenia (for all categories 3.2 percent versus none). (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Third-line cabazitaxel versus androgen signaling therapy'.)

In a later preliminary analysis presented at the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium, in a subset of 172 males who had moderate to severe pain at randomization, those who received third-line cabazitaxel rather than enzalutamide or abiraterone also had better pain response rates as judged by patient-reported outcomes [55].

Mitoxantrone — Mitoxantrone was the first chemotherapy agent approved for use in males with CRPC based on improvement in symptoms and not prolongation of survival. Its use now is generally limited to patients requiring chemotherapy who have progressed on or are not candidates for taxane chemotherapy, although there are limited data in these populations. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Mitoxantrone'.)

Radium-223 — Radium-223 (Ra-223) is an alpha-particle-emitting radiopharmaceutical. Radium is a bone-seeking element, and its radioactive decay allows for the deposition of high-energy radiation over a much shorter distance than that with beta-particle-emitting radioisotopes, thus minimizing toxicity to normal bone marrow and other organs. (See "Bone metastases in advanced prostate cancer: Management", section on 'Radium-223'.)

In a phase III trial conducted in males with CRPC and symptomatic bone metastases, treatment with Ra-223 was well tolerated and increased both OS and time to first symptomatic skeletal-related event (ie, external beam RT to relieve skeletal symptoms, new symptomatic pathologic fracture, spinal cord compression, or tumor-related orthopedic surgical intervention) [56]. Because of its mechanism of action, use of Ra-223 is limited to males who have symptomatic bone metastases without other clinically significant sites of disease (including visceral metastases).

Ra-223 is being studied in combination with other agents for the treatment of metastatic CRPC. However, a beneficial role for such combinations has not been established, and at least some data suggest higher fracture rates when Ra-223 is combined with abiraterone, although this risk appears to be completely abolished by the continuous use of a bone protecting agent (osteoclast inhibitor). For most males, Ra-223 and abiraterone should only be initiated at the same time with a concomitant osteoclast inhibitor. Specific recommendations for use of this agent are presented elsewhere. (See "Bone metastases in advanced prostate cancer: Management", section on 'Radium-223-based combinations'.)

Sipuleucel-T — For males with slowly progressive disease, where a relatively rapid response to treatment is not required, and who are not receiving opioids or glucocorticoids for pain, sipuleucel-T is an option. Treatment is contraindicated in patients who are receiving steroids or opioids for cancer-related pain, and sipuleucel-T should be used with caution in patients with liver metastases.

Sipuleucel-T is a dendritic cell vaccine that is prepared from peripheral blood mononuclear cells obtained by leukapheresis. These cells are exposed ex vivo to a novel recombinant protein immunogen that consists of prostatic acid phosphatase fused to human GM-CSF. These activated cells are then infused back into the patient approximately three days after the original harvesting.

In randomized trials in males with minimally symptomatic metastatic CRPC, sipuleucel-T prolonged OS compared with placebo [57]. However, sipuleucel-T did not significantly increase PFS or affect serum PSA. Thus, assessing the impact of therapy on an individual patient can be difficult or impossible. Sipuleucel-T is approved for asymptomatic or minimally symptomatic males with metastatic CRPC. Since its approval was based on trials done prior to the approval of androgen receptor pathway inhibitors (ARPIs), its efficacy post ARPI progression is untested/unknown. Specific recommendations for use of this agent are provided elsewhere. (See "Immunotherapy for castration-resistant prostate cancer", section on 'Therapeutic vaccination with Sipuleucel-T'.)

Aggressive-variant prostate cancers — Aggressive prostate cancer variants with low PSA levels and either neuroendocrine features or a poorly differentiated histology may be relatively insensitive to additional hormone therapy maneuvers after initial treatment with ADT. Some patients may benefit from a taxane/platinum combination rather than a taxane alone.

Pure small cell or neuroendocrine carcinomas of the prostate are rare at initial diagnosis (≤2 percent of cases [58]), and they have a dismal prognosis, with most patients dying within one year, despite their sensitivity to the same platinum-based cytotoxic chemotherapy regimens that are used for small cell lung cancer. (See "Interpretation of prostate biopsy", section on 'Neuroendocrine neoplasms' and "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'High-grade, low-PSA prostate cancer' and "Limited-stage small cell lung cancer: Initial management", section on 'Chemotherapy'.)

More commonly, neuroendocrine differentiation may also emerge in males who have previously had ADT for prostate adenocarcinoma. These tumors, sometimes called treatment-related neuroendocrine prostate cancers or aggressive-variant prostate cancers, are increasingly recognized in the castration-resistant phases of disease progression. These tumors can be androgen receptor negative, have a varying degree of small cell carcinoma morphology (or mixed small cell and adenocarcinoma), and can express markers of neuroendocrine differentiation (eg, chromogranin, synaptophysin). In addition, they can be associated with low PSA production and with an aggressive clinical course with atypical clinical manifestations, and they are relatively resistant to androgen signaling inhibitors.

These issues and the role of chemotherapy in these patients is discussed in detail elsewhere. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Aggressive prostate cancer variants'.)

ALTERNATIVES FOR REFRACTORY DISEASE — Several options are available for patients who are refractory to taxanes and androgen signaling pathway inhibitors.

PARP inhibitors for patients with deficiency in homologous recombination repair — All males with a germline or somatic mutation in a gene associated with homologous recombination repair (HRR; including breast cancer susceptibility gene [BRCA] 1, BRCA2, checkpoint kinase 2 [CHEK2], ataxia telangiectasia mutated [ATM], partner and localizer of BRCA2 [PALB2], FANCA, RAD51B, among others), particularly those with a BRCA2 mutation, should be considered for treatment with a poly(ADP-ribose) polymerase (PARP) inhibitor at some point in their treatment. Many clinicians would reserve this treatment for use after failure of an ARPI and a taxane, although the US Food and Drug Administration (FDA) approval of olaparib for CRPC does not require prior treatment with a taxane. Other clinicians would use a PARP inhibitor pre-taxane, if they were appropriate candidates.

PARP inhibitors block the repair of DNA single-strand breaks, and for tumors associated with HRR deficiency they result in cell death due to inefficiencies in cell repair mechanisms. Several PARP inhibitors have been studied in males with metastatic CRPC and DNA repair mutations, and two (olaparib, rucaparib) are now approved for use in CRPC with HRR deficiency. Rucaparib received an accelerated approval for patients with BRCA1/2 germline or somatic defects after failure of an androgen receptor pathway inhibitor (ARPI) and a taxane. Olaparib is FDA approved for those after an ARPI alone or an APRI plus a taxane for those with a broad spectrum of HRR deficiency mutations. Of all the HRR deficiencies involving DNA damage response pathways, males with BRCA2 mutations appear to benefit the most. Data supporting the benefit of and indications for a PARP inhibitor in males with metastatic CRPC and HRR deficiency are discussed in detail elsewhere. (See "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency", section on 'Benefit of PARP inhibitors'.)

Pembrolizumab for deficient mismatch repair — Pembrolizumab is an option for patients whose tumors are deficient in mismatch repair (dMMR) for whom there are no satisfactory alternatives or for those who cannot tolerate other forms of treatment.

Tumor and germline sequencing may reveal dMMR/high levels of microsatellite instability (MSI-H) and overexpression of programmed cell death ligand 1, which may indicate potential benefit from therapies that target programmed cell death receptor 1. The FDA has approved pembrolizumab for the treatment of a variety of advanced solid tumors (including prostate cancers) that have MSI-H or dMMR, that progressed following prior treatment, and for which there are no satisfactory alternative treatment options, the first such approval of a tissue-agnostic anticancer treatment. (See "Immunotherapy for castration-resistant prostate cancer", section on 'PD-1 pathway inhibition' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Other tumors with MSI-H/dMMR'.)

Radioligand therapy for PSMA-positive tumors — For individuals with taxane and ARPI-refractory prostate-specific membrane antigen (PSMA)-positive metastatic CRPC, lutetium Lu-177 vipivotide tetraxetan, where available is an FDA approved option. For patients with docetaxel-refractory and ARPI-refractory metastatic CRPC, we suggest lutetium Lu-177 vipivotide tetraxetan rather than cabazitaxel, given the similar long-term outcomes, more favorable side effect profile, and better patient-reported outcomes in the ANZUP 1603 trial. This recommendation is consistent with a systemic therapy update for CRPC from the American Society of Clinical Oncology (ASCO), which recommends the use of Lu-177 vipivotide tetraxetan as a treatment option for patients with PSMA PET/CT-positive CRPC who have progressed on one prior line of ARPI and at least one line of prior chemotherapy [59].

PSMA, also known as folate hydrolase I and glutamate carboxypeptidase II, is a cell membrane protein that is highly expressed on the surface of prostate cancer cells [60]. PSMA is expressed to a lesser extent on other cells, including in particular the salivary glands and kidney. Multiple ligands of PSMA have been developed that are linked to radioisotopes, including lutetium-177 (177-Lu), a beta particle emitter.

Multiple retrospective and prospective studies have been conducted with lutetium Lu-177 vipivotide tetraxetan (previously referred to as 177-Lu-PSMA-617) in patients with PSMA-positive metastatic CRPC, although few have directly compared this with other active forms of treatment:

●A systematic review and meta-analysis of 22 retrospective/prospective reports and a single uncontrolled phase II trial [61] (totaling 744 patients treated with lutetium Lu-177 vipivotide tetraxetan) concluded that 75 percent of treated patients experienced any level of PSA decline, with 46 percent having a >50 percent decline [62]. A radiographic partial remission was seen in 37 percent, median overall survival (OS) was 13.8 months, and median progression-free survival (PFS) was 11 months. The most common treatment-related side effects were myelosuppression, nephrotoxicity, and salivary gland toxicity (pain, swelling, and dry mouth).

●In the only randomized phase II trial, the Australian randomized phase II ANZUP 1603 trial, lutetium Lu-177 vipivotide tetraxetan (every six weeks for up to 6 cycles) was directly compared with cabazitaxel (20 mg/m² IV every three weeks for up to 10 cycles) in 200 males with PSMA-positive metastatic CRPC who had previously received androgen receptor-directed treatment and docetaxel [63]. Males who received radioligand therapy had a higher likelihood of a ≥50 percent PSA decline (the primary endpoint, 66 versus 37 percent), and fewer grade 3 or 4 adverse events (33 versus 53 percent). Pain response was more frequent with lutetium Lu-177 vipivotide tetraxetan (60 versus 43 percent) and there were also clinically meaningful improvements in health-related quality of life in the domains of diarrhea, fatigue, social functioning, and insomnia compared with the cabazitaxel group. In the latest analysis presented at the 2022 annual ASCO meeting, after a median follow-up of 36 months, overall survival was similar to that in the cabazitaxel group (the restricted mean survival time to 36 months was 19.1 versus 19.6 months, respectively [difference -0.5, 95% CI -3.7 to 2.7]), although post-protocol crossover limits this analysis [64].

●An overall survival benefit was first shown in the phase III VISION trial that compared lutetium Lu-177 vipivotide tetraxetan (four cycles every six weeks; responding patients could have an extra two cycles) plus standard of care versus standard of care alone in 831 patients with PSMA-avid metastatic CRPC who were previously treated with one to two taxane-containing regimens and an androgen receptor signaling inhibitor [65]. The standard of care was investigator-determined (mainly corticosteroids and androgen receptor targeted agents, even though 60 percent had already received an androgen receptor-targeted agent), but excluded taxane-based chemotherapy or radium-223, therapies of proven benefit in selected subsets of males [66].

At a median follow-up of 20.9 months, lutetium Lu-177 vipivotide tetraxetan significantly improved median radiographic PFS (8.7 versus 3.4 months, hazard ratio [HR] for progression 0.40, 95% CI 0.29-0.57) and median OS (15.3 versus 11.3 months, HR for death 0.62, 95% CI 0.52-0.74), and was associated with a higher objective response rate (30 versus 2 percent), and median time to first symptomatic skeletal event (11.5 versus 6.8 months, HR 0.50). There was a higher rate of serious (grade 3 or 4) treatment emergent adverse effects in the radioligand group (53 versus 38 percent), which included high-grade bone marrow suppression in approximately 25 percent and dry mouth (not high grade) in 39 percent; however, therapy was generally well tolerated, with a delayed time to worsening in health-related quality of life and time to skeletal events compared with standard of care alone [67].

As a result of these data from the VISION trial, lutetium Lu-177 vipivotide tetraxetan has been approved by the US FDA for treatment of patients with PSMA–positive metastatic CRPC (as determined by an approved PSMA-11 diagnostic assay) who have previously been treated with androgen-receptor pathway inhibitors and taxane-based chemotherapy [68,69]. Lutetium Lu-177 vipivotide tetraxetan also has limited availability (Germany) in Europe and Australia.

In a later analysis of the VISION trial results, presented at the 2022 annual ASCO meeting [70], clinical efficacy of lutetium Lu-177 vipivotide tetraxetan was observed regardless of prior treatment, including Ra-223 and a second prior taxane. (See 'Patients previously treated with Ra-223' below.)

Although emerging data suggest that the higher levels of uptake on PSMA-PET appear to predict a higher likelihood of favorable response [71], studies are ongoing to predict which patients might benefit the most from lutetium Lu-177 vipivotide tetraxetan therapy [72,73].

Patients previously treated with Ra-223 — Many clinicians avoid radium-223 (Ra-223) if the patient might be eligible for future radioligand therapy, given the dearth of data on safety of lutetium Lu-177 vipivotide tetraxetan in the setting of prior Ra-223, although data on safety and efficacy are emerging [70,74-77]:

●Although the VISION trial excluded such patients from enrollment [65], 62 of the enrolled 831 patients had received prior Ra-223 (43 of the experimental group and 19 of the standard of care group). In a preliminary report presented at ASCO [70], clinical efficacy of lutetium Lu-177 vipivotide tetraxetan was observed regardless of prior treatment, including Ra-223, but safety was not addressed in this population.

●In a retrospective analysis of a subgroup of 16 patients who received lutetium Lu-177 vipivotide tetraxetan after Ra-223 in the ongoing REASSURE study, treatment-emergent grade 3 hematologic events occurred in nine (56 percent); time course of recovery was not stated [76]. The median survival from the start of lutetium Lu-177 vipivotide tetraxetan was 13.2 months, which compares favorably with other populations.

●Additional information is available from a retrospective analysis of 49 patients who were enrolled in the observational RALU study, and received lutetium Lu-177 vipivotide tetraxetan after Ra-223 [77]. In a preliminary report presented at the 2022 annual ASCO meeting, the median time from the last Ra-223 dose to the first dose of lutetium Lu-177 vipivotide tetraxetan was 9.3 (range 0.9 to 41.9) months. Any grade treatment-emergent adverse events to 30 days of follow-up occurred in 92 percent of patients, and they were serious (ie, grade ≥3) in 20 percent. Of the grade 3 to 4 hematologic laboratory abnormalities that occurred up to 90 days post-treatment with lutetium Lu-177 vipivotide tetraxetan, most were anemia (35 percent), followed by thrombocytopenia (13 percent) and neutropenia (2 percent). No grade 5 toxicities occurred. The time course of recovery was not stated. Overall, 39 percent of patients had a ≥30 percent decline in PSA during lutetium Lu-177 vipivotide tetraxetan and the median overall survival was 12.6 months.

Other endocrine approaches — For patients who are ineligible for immunotherapy, PARP inhibitors, or radioligand therapy, who have already received treatment with an ARPI such as abiraterone or enzalutamide, who have no other therapeutic options, and for those with a poor performance status who are not candidates for other systemic therapies, second-line endocrine therapy is an option. Specific recommendations are provided separately. (See "Alternative endocrine therapies for castration-resistant prostate cancer" and "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Enzalutamide'.)

ASSESSMENT DURING TREATMENT — For males with CRPC 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. Serial evaluation of serum prostate-specific antigen (PSA) is the mainstay of testing. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend testing PSA every three to six months. Most clinicians make decisions about the need for further 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.

Prostate-specific antigen — Serial evaluation of serum PSA is the mainstay of testing in males with CRPC. A rising PSA is an indication of treatment failure and the need to consider alternative therapies. Serial PSA testing can also provide reassurance to patients of a continuing response to treatment. The optimal frequency of testing is not established. Consensus-based guidelines from the NCCN recommend testing PSA every three to six months [19].

Not all prostate cancers make significant amounts of PSA. Some of these are neuroendocrine tumors, which may respond to cisplatin-based chemotherapy rather than hormonal manipulation. Others lack neuroendocrine features but represent poorly differentiated prostatic adenocarcinomas, which just make less PSA than do more well-differentiated tumors. Objective responses in such patients are difficult to measure, but their response duration and median survival tend to be shorter after initial androgen deprivation therapy compared with males with PSA-producing prostate adenocarcinoma [78-81]. Management of these patients is discussed below. (See 'Aggressive-variant prostate cancers' above.)

Diagnostic imaging — The onset of new symptoms during therapy (eg, back pain with neurologic abnormalities due to spinal cord compression, bone pain due to pathologic fracture) may suggest the need for further diagnostic evaluation or specific site-directed therapy (eg, radiation therapy to a painful bone metastasis). (See "Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.)

There is no clear consensus as to the optimal surveillance imaging strategy for males with metastatic CRPC in the absence of new symptoms. Cross-sectional imaging is appropriate as a restaging study to evaluate males with visceral metastases who have a rising PSA. However, many males have disease that is limited to bone. Although radionuclide bone scan is the most commonly used imaging study to detect bone metastases, bone scans may normalize after highly effective systemic therapy for metastatic disease. Furthermore, reliably evaluating the extent of metastatic burden in bone as an objective endpoint of therapy is challenging, as most radiographic assessments (including bone scan) are neither objective nor quantitative. Quantitation of bone metastases using newer techniques, such as the Automated Bone Scan Index, has been shown to correlate with prognosis in males with metastatic CRPC [82], and if validated, it may provide an objective imaging biomarker for response assessment. However, this test is not yet clinically available.

The Radiographic Assessments for Detection of Advanced Recurrence (RADAR) III group made new recommendations around serial imaging in males with metastatic (M1) prostate cancer who are undergoing treatment, suggesting that repeat imaging using traditional scans (ie, bone scan or CT) is indicated when at least one of the following occurs [83]:

●Every doubling of PSA since the previous image was taken

●Every six to nine months in the absence of a PSA rise

●Change in symptomatology

●Change in performance status

There is not widespread consensus on these recommendations (particularly the recommendation to repeat imaging every six to nine months in the absence of a PSA rise) and on whether to image less frequently in asymptomatic males with limited metastatic disease burden. Many clinicians, including some of the authors and editors associated with this topic, review the PSA curves and results of prior imaging with patients and pursue shared decision making in assessing the need for and timing of imaging studies.

The Prostate Cancer Working Group 3 uses a threshold for progression of two or more new bone lesions on the first post-treatment bone scan and requires confirmation in a subsequent scan [4]. At least some data suggest that, at least among patients treated with enzalutamide, one or more new unconfirmed bone lesions seen on the first or second post-treatment scan in patients who seem to be otherwise responding to treatment are common (occurring in approximately one in five males treated in one of two studies of enzalutamide for metastatic CRPC) and are indicative of a favorable treatment response to enzalutamide (ie, pseudoprogression) [84]. However, this finding was limited to males who had not received prior docetaxel. The detection of new unconfirmed bone lesions in males treated with enzalutamide after previously receiving docetaxel was associated with worse overall survival and was felt to likely represent true progression.

Compared with conventional imaging (bone scan, CT), both local recurrences and distant metastases can be better confirmed with next-generation imaging (ie, positron emission tomography [PET]/CT using prostate cancer-specific tracers, such as F-18 fluciclovine). Given their greater sensitivity, use of these imaging techniques has the potential to improve outcomes by leading to earlier therapeutic intervention for castration-resistant disease (eg, the use of enzalutamide or apalutamide in males with nonmetastatic CRPC). However, accessibility and cost may be significant issues. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Enzalutamide' and "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Apalutamide'.)

The RADAR III guidelines suggest next-generation imaging (ie, PET/CT using a prostate cancer-specific tracer, such as F-18 fluciclovine) only if traditional scans are negative and the clinician still suspects disease progression based on a rising PSA and/or a change in symptomatology [83]. A similar recommendation has been made by American Society of Clinical Oncology [2]. We agree with these guidelines. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Next-generation imaging'.)

BIPOLAR ANDROGEN THERAPY — While early studies are promising, additional study is needed to determine the optimal clinical integration of bipolar androgen therapy (BAT) into conventional treatment algorithms for CRPC, and this approach remains investigational.

Preclinical experiments showed that prostate cancer cells become resistant to chronic castration via an adaptive increase in androgen receptor expression, a liability that can be exploited therapeutically. Experimental data suggested that rapid cycling between supraphysiologic (>1500 ng/dL) and castrate (<50 ng/dL) testosterone levels may resensitize CRPC to further androgen-directed therapies [85]. This approach, which involves cyclical high-dose testosterone therapy, is referred to as BAT.

The following data are available:

●In a randomized multicenter phase II trial comparing BAT versus enzalutamide alone in 195 asymptomatic males with CRPC was undertaken (NCT02286921) [86]. The clinical/radiographic progression-free survival (PFS) was 5.7 months in both arms, and rates of 50 percent decline in PSA were not substantially higher with BAT (28 versus 25 percent). However, the duration of biochemical PFS was longer with BAT (10.9 versus 3.8 months). Overall survival endpoints were complicated by the crossover design of the trial.

●A phase II single center, open label study of BAT included several cohorts of males with both metastatic and nonmetastatic CRPC (the RESTORE study, NCT02090114). Two cohorts evaluated whether BAT may restore sensitivity to abiraterone and/or enzalutamide in males with metastatic CRPC who have previously failed one or both of these therapies by treating such patients with BAT followed by subsequent retreatment with abiraterone or enzalutamide, and one evaluated BAT in males with CRPC and no prior exposure to second-generation androgen receptor targeting therapies. The following results are available:

•In a report of one cohort from this study, 30 males with metastatic CRPC who had progressed on enzalutamide were treated with BAT [87]. A 50 percent decrease in PSA was observed in nine cases (30 percent). Among 21 patients who were retreated with enzalutamide after progression on BAT, a PSA response was observed in 15 (52 percent of those eligible who had completed BAT treatment).

In a later analysis of the cohort of 29 males receiving BAT after progression on abiraterone, a 50 percent decrease in PSA was only observed in 17 percent of cases, and among the 19 males who were rechallenged with abiraterone, a PSA response was only noted in 3 (16 percent) [88]. Thus, BAT may be more effective at resensitizing to enzalutamide as compared with abiraterone.

•In a report of the cohort examining BAT as first-line hormonal treatment for males with metastatic CRPC not exposed to AR-targeted therapies, BAT was well tolerated and resulted in prolonged disease stabilization, with favorable responses to subsequent second-generation AR-targeted therapies [89].

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 topic (see "Patient education: Prostate cancer (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

●Definition and initial workup – Castration-resistant prostate cancer (CRPC) is advanced prostate cancer with evidence of disease progression despite castrate levels of serum testosterone (<50 ng/dL) after medical or surgical orchiectomy. (See 'Definition of castration resistance' above.)

Conventional imaging (bone scan and CT of the chest, abdomen, and pelvis) is used to determine the site(s) and extent of disease spread. We reserve more sensitive next-generation imaging using prostate-specific positron emission tomography radiotracers for patients with a high suspicion of subclinical metastases despite negative conventional imaging if results might impact clinical care. Prostate-specific membrane antigen (PSMA) positron emission tomography/CT assessment is required prior to lutetium Lu-177 vipivotide tetraxetan. (See 'Defining disease extent' above.)

●Genomic testing – All males with metastatic prostate cancer should undergo genomic testing as findings may influence the choice of therapy. (See 'Germline genetic testing and next-generation sequencing of tumor tissue' above.)

●Initial systemic therapy for conventional adenocarcinoma – CRPC prognosis and treatment is heavily dependent on prior therapies including the use of docetaxel and/or androgen receptor pathway inhibitors (ARPIs) which are now commonly used for metastatic castration-sensitive prostate cancer, prior to the onset of CRPC.

Our approach, which is stratified by prior therapy, and outlined in the algorithm (algorithm 1), is summarized below:

•For most patients treated with androgen deprivation therapy (ADT) monotherapy, we suggest continued ADT while additional systemic agents are added (Grade 2C). (See 'Continuation of androgen deprivation therapy' above.)

•If initial therapy included an older antiandrogen (bicalutamide, flutamide, nilutamide), we suggest antiandrogen withdrawal (Grade 2C). Alternative systemic therapy is reserved for subsequent progression. (See "Alternative endocrine therapies for castration-resistant prostate cancer", section on 'Antiandrogens and antiandrogen withdrawal'.)

Selection of additional systemic therapy to be added to continued ADT for typical CRPC is guided by clinical stage, prior treatment, and expected toxicity. (See 'Efficacy of different systemic therapy options' above.):

•Nonmetastatic disease

-For males with nonmetastatic CRPC and a prostate-specific antigen (PSA) doubling time ≤10 months, we suggest an androgen receptor pathway inhibitor (ARPI; ie, enzalutamide, apalutamide, or darolutamide) plus ADT, rather than continued ADT alone or another form of hormone therapy (Grade 2B). (See 'Patients with nonmetastatic CRPC' above.)

-For patients with longer PSA doubling times, acceptable options include observation alone or an ARPI. (See 'Other endocrine approaches' above.)

•Metastatic disease

-No prior ARPI – For most patients who were not previously exposed to an ARPI, we suggest adding abiraterone or enzalutamide rather than taxane-based chemotherapy to ADT (Grade 2C). We base the choice on toxicity profiles and reimbursement from third-party payers. (See 'Interference with androgenic stimulation' above.)

We reserve cytotoxic chemotherapy for patients with rapidly progressing symptomatic disease. Either docetaxel or cabazitaxel are appropriate for chemotherapy-naïve patients; efficacy appears similar, but side effect profiles differ. For patients who developed CRPC after a prior course of docetaxel, cabazitaxel is an option, although an ARPI may also be appropriate if the patient has not previously received an ARPI, particularly if they are poor candidates for cytotoxic chemotherapy. (See 'Docetaxel' above and 'Cabazitaxel' above.)

Sipuleucel-T is an alternative for males with slowly progressive minimally symptomatic metastases and no liver metastases who are not using opioids or glucocorticoids for pain. (See 'Sipuleucel-T' above.)

Radium-223 is an alternative for patients with symptomatic bone metastases and no visceral metastases. (See 'Radium-223' above.)

-Prior ARPI – For patients who have previously received an ARPI, we suggest taxane chemotherapy rather than an alternative ARPI (Grade 2C). Cabazitaxel may be preferred over docetaxel, if available, but it is not approved for metastatic CRPC in those not previously treated with docetaxel. (See 'Cabazitaxel' above.)

One potential exception is patients with ARPI-refractory PSMA-positive metastatic CRPC treated previously with docetaxel, in whom we suggest lutetium Lu-177 vipivotide tetraxetan (where available) rather than cabazitaxel (Grade 2C). (See 'Radioligand therapy for PSMA-positive tumors' above.)

Radium-223 is an alternative for patients with symptomatic bone metastases and no visceral metastases. (See 'Radium-223' above.)

●Aggressive prostate cancer variants – Aggressive prostate cancer variants with low PSA levels and either neuroendocrine features or a poorly differentiated histology may be insensitive to hormone therapy maneuvers after ADT. Such patients may benefit from a taxane/platinum combination rather than a taxane alone. Specific recommendations are provided separately. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Aggressive prostate cancer variants'.)

●Alternative options in conjunction with continued ADT for selected patients with refractory disease

•Pembrolizumab is an option for patients whose tumors are deficient in mismatch repair or a high tumor mutational burden for whom there are no satisfactory alternatives or for those who cannot tolerate other forms of treatment. (See 'Pembrolizumab for deficient mismatch repair' above.)

•For patients with germline or somatic alterations in a homologous recombination repair gene, treatment with a poly(ADP-ribose) polymerase (PARP) inhibitor is another option. (See 'PARP inhibitors for patients with deficiency in homologous recombination repair' above and "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency", section on 'Benefit of PARP inhibitors'.)

•For patients who are ineligible for immunotherapy, PARP inhibitors, or radioligand therapy, and for those with a poor performance status who are not candidates for other systemic therapies, other forms of second-line endocrine therapy are alternative options. (See 'Other endocrine approaches' above.)

●Assessment during treatment – Disease activity is monitored with serum PSA. Radiographic reevaluation is guided by PSA changes and symptoms. (See 'Assessment during treatment' 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.