Immunotherapy for castration-resistant prostate cancer

INTRODUCTION — Immunotherapy has emerged over the last decade as an important treatment option for many advanced malignancies, providing rapid, deep, and durable decreases in tumor burden and prolonged survival in a subset of patients over a wide range of tumor types. In particular the development of checkpoint inhibitors has dramatically changed how many cancers are treated, although questions still remain as to the biomarkers that best predict benefit from these agents. (See "Principles of cancer immunotherapy", section on 'Predictors of response to immune-based therapy'.)

The benefits of immunotherapy have been difficult to demonstrate in conventional prostate adenocarcinoma, which is generally considered to have an immunologically "cold" microenvironment. Nevertheless, in 2010, the therapeutic vaccine sipuleucel-T was approved for males with metastatic castration-resistant prostate cancer (CRPC), becoming the first (and still only) autologous cellular therapeutic vaccine to be approved for any solid tumor. However, the modest benefits and substantial cost of this treatment have hampered widespread uptake. (See 'Efficacy' below.)

There are no other approved immunotherapies specifically for advanced CRPC. Results from immune checkpoint inhibitor immunotherapy, which has been so successful in other solid tumors, have been disappointing in prostate cancer, with limited response rates in unselected patients. The sole exception is those few patients whose tumors are characterized as having a high mutational load because of deficient deoxyribonucleic acid (DNA) mismatch repair. (See 'Deficient mismatch repair' below.)

This topic will review the rationale for immunotherapy in the context of advanced prostate cancer, discuss approved agents and indications, discuss what is known about individuals who are most likely to benefit from immunotherapy, and briefly explore clinical trial data of investigational therapies that offer clinical insights for future approaches A general discussion of the principles of immunotherapy is presented separately. (See "Principles of cancer immunotherapy".)

IMMUNOBIOLOGY OF PROSTATE CANCER AND RATIONALE FOR IMMUNOTHERAPY — Immunotherapeutic approaches to cancer therapy are based on the premise that the body's own immune system plays a key role in the surveillance and eradication of malignancy, that tumors evolve ways to elude the immune system so that they can continue to grow and metastasize, and that the mechanisms that underlie this immune tolerance can be circumvented for therapeutic benefit. Cancer progression is often fueled by a preponderance of genetic aberrations, including mutations, that can lead to newly expressed peptides (sometimes called "neoantigens") that are entirely absent from normal noncancer human tissues, or to peptides that are expressed at a higher level in tumors but may be present at a lower level in normal cells (eg, tumor associated antigens such as prostatic acid phosphatase). Tumor cells that contain antigens such as these may be seen by the body's immune system as not normal or "non-self", and as such, they can be recognized by the immune system and killed.

Chen and Mellman's concept of the cancer immunity cycle is useful in understanding the immunobiology of prostate cancer (figure 1) [1]. The generation of immunity to cancer is a cyclical process that can be self-propagating, leading to an accumulation of immune-stimulatory factors that, in principle, should amplify and broaden the in vivo immune response. There are two key cells in this immune process: the antigen-presenting cell (APC; eg, macrophage or dendritic cell) and the T cell.

Briefly, tumor cells that die get taken up by APCs. These cells fill the role of both clearing garbage and raising the alarm to other cells in the immune system if there are antigens present (eg, multiple mutations, functioning as "neoantigens") that should not be present (ie, they are "non-self"). To do this, these APCs travel to the draining lymph nodes and interact with T cells, where the tumor antigens are processed by chopping them into 7 to 15 amino acid residues that are then bound to major histocompatibility complex (MHC) molecules, and this complex is then transported to the cell surface where it can signal other T cells. The appropriately presented MHC-peptide complex on the APC binds to a T cell receptor, leading to activation of that T cell. Once activated, the T cell can undergo division, making additional copies of itself, all of which can bind the specific target that was presented to the T cell, and these cells can travel to any site in the body. Once they reach the area of the tumor, they can identify the tumor using the same MHC-peptide recognition method. Most cells in the body have MHC molecules, allowing T cells to interact with them. Upon recognition, and in the presence of costimulatory signals, the T cell can kill the cell by releasing granzymes or perforin that can puncture the tumor cell membrane, causing the tumor cell to die. The T cell then can move on searching for more tumor cells.

This costimulatory process is tightly regulated by both "agonist" molecules which stimulate the immune response, and inhibitory signals on both the APC and T cells, often collectively referred to as "immune checkpoint" molecules, which function as a physiologic brake on unrestrained cytotoxic T effector function. Examples of co-inhibitory or "immune checkpoint" molecules include cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death-1 (PD-1). These immune checkpoints exist to dampen the immune response in order to protect against detrimental inflammation and autoimmunity, and in the setting of malignancy, such immune checkpoints can result in immune tolerance to the tumor allowing evasion of the immune response and progression of the malignancy. (See "Principles of cancer immunotherapy", section on 'The "immune synapse"'.)

Inhibition of these checkpoints using immune checkpoint inhibitors (ICIs, (table 1)), which "releases the brake," on the immune response to the non-self antigens, restoring cytotoxic T effector function, might be expected to halt tumor progression. Although use of these agents has dramatically changed how many cancers such as melanoma, renal cell cancer, lung cancer, and advanced esophagogastric cancer are treated, not all patients benefit, and questions still remain as to the biomarkers that best predict benefit. In many tumors, benefit is independent of biomarker status, while in some (eg, esophagogastric, non-small cell lung, head and neck squamous cell cancers), benefit seems most pronounced among those with high levels of expression of the programmed cell death ligand 1 (PD-L1). (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic therapy of advanced clear cell renal carcinoma" and "Initial management of advanced non-small cell lung cancer lacking a driver mutation" and "Extensive-stage small cell lung cancer: Initial management", section on 'Rationale for addition of immune checkpoint inhibitors to chemotherapy' and "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Immunotherapy-based regimens'.)

Immunotherapies such as ICIs have been less successful for treatment of advanced prostate cancer. Although prostate cancer cells express a number of tumor-associated antigens that can serve as targets for immunotherapy, prostate cancer is generally considered as having a "cold" immune microenvironment, characterized by T cell exclusion (especially CD8+ T cells), a relatively low neoantigen load, and a relatively high immunosuppressive microenvironment, which includes a high proportion of myeloid-derived suppressor cells [2-7]. The limited presence of tumor infiltrating lymphocytes suggests a scant adaptive immune response against tumor cells. Moreover, prostate cancer tumor cells (particularly those that are castration-resistant) frequently present with phosphatase and tensin homolog (PTEN) loss, which may interact with the interferon-1 pathway, a pivotal step in the immune process, leading to its dysfunction, and immunosuppression [8]. These many factors can thwart a tumor-directed immune response, leading to a state of immune tolerance, or anergy. The poor in vivo immune response to prostate cancer has been attributed to decreased immunogenicity of the tumor-associated antigens and/or blunted effectiveness of the immune response mounted against them. (See "Principles of cancer immunotherapy", section on 'Tumor evasion of immune surveillance'.)

CURRENT STATUS OF IMMUNOTHERAPY FOR PROSTATE CANCER — Given the limited immune response to prostate cancer in vivo, it is not surprising that immunotherapeutic approaches that have been so successfully applied to other solid tumors and hematologic malignancies (eg, immune checkpoint inhibitors [ICIs], chimeric antigen receptor [CAR]-T cells) have not shown comparable clinical efficacy in unselected prostate cancers, although clinical studies of many of these therapies are ongoing. (See 'Other patients' below and 'CAR-T cells' below.)

There are some notable exceptions, and at least three approved immunotherapy treatments for metastatic CRPC (ie, advanced prostate cancer that has become resistant to first-line hormone therapy, typically androgen deprivation therapy [ADT]):

●Therapeutic vaccines use varying types of antigens, and accompanying immune adjuvants to influence an adaptive in vivo immune response. (See "Principles of cancer immunotherapy", section on 'Vaccines'.)

Sipuleucel-T was the first autologous cellular therapeutic vaccine approved for any cancer in 2010. This approval for males with metastatic CRPC was based upon a four-month improvement in median overall survival (OS) in randomized trials conducted in males with asymptomatic or minimally symptomatic metastatic disease, albeit with little evidence of objective antitumor activity. Notably, other therapeutic vaccines have not been successful at improving outcomes in advanced metastatic CRPC. (See 'Therapeutic vaccination with Sipuleucel-T' below and 'Other vaccines' below.)

●A subset of particularly aggressive prostate cancers, including those with deficient mismatch repair (dMMR) genes, or defective homologous recombination DNA repair genes (eg, alterations in cyclin-dependent kinase [CDK]-12) have been variably associated with higher tumor mutational burden (TMB) and neoantigen load, and an increase in T-cell related transcripts within the tumor, which may reflect enhanced antitumor immunity, and potential benefit from ICIs [9-11].

Two ICIs, pembrolizumab and dostarlimab, have received a "tissue agnostic" or "pan-cancer" approval by the US Food and Drug Administration (FDA) for treatment of refractory solid tumors (including prostate cancer) with no other satisfactory treatment alternatives that have dMMR (or, in the case of pembrolizumab, a high level of TMB). Unfortunately, dMMR/high levels of microsatellite instability (MSI-H) and high TMB are relatively uncommon in prostate cancer. Furthermore, the available data supporting efficacy in metastatic CRPC are very limited. (See 'Efficacy' below.)

In contrast to dMMR and high TMB, whether ICIs targeting the PD-1 pathway are clinically useful for treatment of other advanced prostate cancers (ie, unselected patients or those with high levels of PD-L1 expression) is unclear. In the KEYNOTE-199 study, response rates for pembrolizumab in patients with metastatic CRPC were <5 percent, regardless of PD-L1 expression status. (See 'Deficient mismatch repair' below and 'Other biomarkers' below.)

Integration into the treatment sequence for prostate cancer

●Castration-sensitive disease – Standard initial therapy for advanced metastatic hormone-naïve (castration-sensitive) prostate cancer (CSPC) is medical or surgical ADT, either alone or in combination with other systemic agents. The vast majority eventually progress to CRPC and require other treatments. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)

There have been few trials of ICIs in individuals with CSPC [12], and there is insufficient evidence to suggest benefit in this setting although several clinical trials are ongoing (reviewed in [5]).

●Castration-resistant disease – There is no consensus on how best to integrate immunotherapy approaches into the treatment schema for advanced metastatic CRPC. The treatment landscape for metastatic CRPC has expanded significantly over the past decade with multiple agents, all given in conjunction with continued ADT, demonstrating improved OS in phase III trials (table 2). One of these options is sipuleucel-T. However, there are no trials comparing sipuleucel-T with other systemic approaches which include cytotoxic chemotherapy, androgen receptor targeted therapies, radium-223 (which is typically reserved for those with symptomatic bone metastases without visceral metastases), radioligand therapy (which is typically reserved for those with prostate-specific membrane antigen-positive tumors), or poly ADP-ribose phosphate (PARP) inhibitors (for those with a deficiency in a gene associated with DNA homologous recombination repair). The choice is dependent on prior treatments, disease status, and anticipated treatment-related toxicity. In general, sipuleucel-T is reserved for patients with asymptomatic or minimally symptomatic slowly progressive metastatic CRPC who do not have visceral (especially hepatic) metastasis or cancer pain requiring opioids, but even in this population, other treatments may also be appropriate. (See 'Indications' below.)

The optimal way to integrate ICI therapy for patients with dMMR/high TMB CRPC is also not clear. The FDA "tissue agnostic" approval covered a variety of advanced solid tumors other than colorectal cancer that had MSI-H or dMMR, that had progressed following prior treatment, and for which there were no satisfactory alternative treatment options. This position is interpreted variably by clinicians caring for patients with advanced metastatic CRPC. Some clinicians, including the author and some of the editors associated with this topic review, reserve immunotherapy for those progressing on abiraterone or enzalutamide, while others consider that patients should have no other available therapeutic options, including Ra-223, cabazitaxel, or sipuleucel-T.

An overview of the available systemic therapies for initial treatment of CRPC, which includes an algorithmic approach to selecting therapy (algorithm 1), is presented separately. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)

IMPORTANCE OF GENOMIC TESTING — Germline genomic testing and next generation sequencing of tumor tissue should be carried out in all males with advanced prostate cancer because they might influence treatment decisions.

Because immune checkpoint inhibitors targeting the programmed death receptor 1 (PD-1) pathway have good activity in only selected subpopulations of patients with metastatic CRPC, it is important to use appropriate testing to determine if a patient is an appropriate candidate. Although most of the mismatch repair (MMR) defects identified in metastatic CRPC are somatic mutations (tumoral) and not inherited (germline), the standard should be combined tumor (somatic) and germline genomic testing to maximize the detection of potentially actionable mutations. (See 'Mechanism of benefit and prevalence of actionable findings' below and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Approach to testing dMMR as a predictive marker' and "Genetic risk factors for prostate cancer", section on 'Who needs referral for genetic evaluation'.)

THERAPEUTIC VACCINATION WITH SIPULEUCEL-T

Definition, mechanism of benefit — Sipuleucel-T is a therapeutic vaccine that is prepared from autologous peripheral blood mononuclear cells obtained by leukapheresis, and pulsed ex vivo with a unique fusion protein of granulocyte-macrophage colony stimulating factor (GM-CSF) and prostatic acid phosphatase (PAP), termed PA2024. Theoretically, GM-CSF fosters maturation of dendritic cells and other antigen-presenting cells (APCs) to present PAP to the patient's T cells, which then recognize the PAP, and this results in PAP-specific T-cell proliferation which then targets the PAP-expressing prostate cancer cells for killing. Both antibody (humoral) and cellular responses are reported, and the peripheral immune responses to PAP correlate with overall survival (OS), as do measures of APC activation [13,14]. However, the mechanism of benefit is not completely understood. In the pivotal phase III study, the degree of PAP-specific T cell proliferation at week 6 did not correlate with survival, raising the possibility that additional immunologic mechanisms might explain this survival benefit. (See 'Monotherapy' below.)

One possibility is a direct local immune effect of systemically administered sipuleucel-T on prostatic tissue. This was suggested in a clinical trial in which 42 patients with untreated localized prostate cancer who received sipuleucel-T prior to prostatectomy, in whom there was a more than threefold increase in T cells that travelled to the tumor microenvironment (comparing pre-biopsies with prostatectomy specimens) [15]. Interestingly, this was observed at the tumor normal interface and not within the tumor itself. Furthermore, the magnitude of the circulating immune response did not directly correlate with T cell infiltration within the prostate.

Preparation, dosing, and administration — The individual leukapheresis product is sent to a central manufacturing facility where the APCs are enriched and pulsed with the GM-CSF/PAP fusion protein. This product is then sent back to the treating clinician, and infused into the patient. The entire process takes three to four days from apheresis to infusion. This procedure is repeated twice more at two week intervals to complete the treatment course (three infusions over approximately four weeks). Clinicians lacking access to apheresis in their center can work with the American Red Cross or other centers that perform apheresis.

Each dose of sipuleucel-T contains a minimum of 50 million autologous CD54+ cells activated with PAP/GM-CSF, suspended in 250 mL of Lactated Ringers. Patients should be premedicated with acetaminophen and an antihistamine prior to each infusion, and the infusion should be administered over approximately 60 minutes without the use of a cell filter. Infusions can be interrupted or slowed for evidence of infusion reactions. Notably, the vaccine product is not routinely tested for transmissible infectious diseases, and health care professionals should employ universal precautions when handling the vaccine.

Indications — Sipuleucel-T is an option for patients with asymptomatic or minimally symptomatic slowly progressive metastatic CRPC who lack visceral (especially hepatic) metastasis or cancer pain requiring opioids. Significant declines in prostate-specific antigen (PSA) or radiographically detectable objective antitumor responses are unlikely to occur, and as a result, this treatment is not appropriate for those with high-burden, highly symptomatic disease. For most patients, we use this agent earlier rather than later as this may optimize outcomes. (See 'Efficacy' below.)

Until further information is available, we suggest sequential rather than concurrent use of sipuleucel-T with other agents, such as enzalutamide or abiraterone, or radium-223 (Ra-223). (See 'Plus androgen receptor targeted therapy' below.)

Efficacy

Monotherapy — Sipuleucel-T was approved by the US Food and Drug Administration (FDA) in 2010 based on the consistent results of three randomized trials, all of which enrolled a similar patient population (metastatic CRPC, testosterone <50 ng/dL, Eastern Cooperative Oncology Group performance status of 0 or 1, and exclusion of patients with visceral metastasis or requiring opioid analgesics) [16-18]. In all three trials, patients were randomized in a 2:1 ratio to receive sipuleucel-T or placebo (apheresis product not pulsed with the GM-CSF/PAP fusion protein), and those who progressed on placebo could cross over to sipuleucel-T. The results are as follows:

●The initial two randomized studies had progression-free survival (PFS) as the primary endpoint [16,17]. A combined analysis of both trials showed a trend towards better time to tumor progression that favored sipuleucel-T (median 11.1 versus 9.7 months, hazard ratio [HR] 1.26, 95% CI 0.95-1.689). However, OS, which was a secondary endpoint of the study, was significantly different between the arms (median 23.2 versus 18.9 months, HR 1.5, 95% CI 1.10-2.05) [17]. This was despite 72 percent of the placebo arm crossing over to vaccine-based immunotherapy after disease progression. At three years, twice as many patients treated with sipuleucel-T were still alive (33 versus 15 percent). The overall PSA response rate with sipuleucel-T was 5 percent.

●Subsequently, a larger placebo-controlled trial (n = 512) with OS as the primary endpoint was conducted [18]. While there was no difference in PFS and there were few objective or PSA responses, the OS was again improved by a clinically meaningful 4.1 months (median 25.8 versus 21.7 months), reflecting a 22 percent reduction in the risk of death. The differences in OS could not be accounted for by subsequent treatment or by time to subsequent treatment between the arms. Although sipuleucel-T significantly prolonged OS, it rarely induced disease regression and did not have a perceptible effect on radiographic PFS. Furthermore, it did not induce consistent changes in serum PSA level. Whether this is due to a delayed effect of immunotherapy or whether some other mechanism is involved is unclear [19,20].

Nevertheless, largely based on this study, sipuleucel-T received FDA approval for treatment of asymptomatic or minimally symptomatic metastatic CRPC.

Factors predicting benefit — There is some evidence that clinical factors can be used to define benefit from sipuleucel-T:

●PSA is an indicator of disease burden in individuals with prostate cancer. In a retrospective analysis of the phase III study used to approve sipuleucel-T, baseline PSA was found to be a strong predictor of outcome [21]. Patients who had baseline PSA in the lowest quartile (<22.1 ng/mL) had the best outcomes relative to placebo (49 percent reduction in the risk of death and a 13-month improvement in median OS), while those in the highest PSA quartile had the least benefit (16 percent reduction in the risk of death and 2.8-month improvement in median OS). This was despite the fact that more control patients in the lowest PSA quartile received salvage sipuleucel-T (73 versus 43 percent of those in the highest quartile).

Some of this effect may in part be attributable to a delayed benefit of the drug, which has been noted in other immunotherapies. As an example, the Kaplan-Meier curves for time to disease-related pain and time to first opioid analgesic use with sipuleucel-T versus placebo both begin to separate after approximately six months [19].

A similar relationship between lower baseline PSA quartile and longest median OS after sipuleucel-T was also noted in an analysis of the PROCEED prospective registry of 1976 patients treated with sipuleucel-T [22].

Largely based on these data, for most patients, we suggest earlier rather than later use of this agent as this may optimize outcomes.

●There are interesting, hypothesis-generating data suggesting that Black individuals may benefit more from sipuleucel-T than White patients do. A prospective registry study of individuals who received sipuleucel-T as part of their prostate cancer care between 2011 and 2017, included 219 Black patients who were compared with 438 PSA-matched White patients [23]. The survival difference between these two groups suggested as much as a 30 percent reduction in the risk of death for Black patients compared with the White patients (median OS 35.3 months versus 25.8 months), and differences were larger in those who had lower baseline PSA levels. We view these data as hypothesis generating, and not definitive.

Assessing treatment response — The absence of objective parameters to judge whether or not an individual patient is benefiting from vaccine therapy poses a major difficulty in determining when to consider sipuleucel-T ineffective and initiate alternative treatment, especially given the short treatment course (approximately four weeks) [24]. In the randomized studies of sipuleucel-T, described above, subsequent treatment was typically not offered until approximately one year after initiation of sipuleucel-T. However, this was in the setting where PFS was also being closely followed according to protocol requirements. We individualize treatment decisions based on tumor growth characteristics (ie, evidence of rising PSA and/or radiographic progression) and patient preference.

Combination therapies

Plus androgen receptor targeted therapy — For patients with metastatic CRPC, individual therapies (ie, androgen signaling inhibitors, cytotoxic chemotherapy, sipuleucel-T, bone-targeted radiopharmaceuticals) are usually introduced sequentially rather than concurrently. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Patients with metastatic CRPC'.)

At least two studies have explored the benefit of concurrent versus sequential use of an androgen signaling inhibitor with sipuleucel-T, and neither provides a definitive answer as to whether there is meaningful benefit to concurrent therapy:

●In a phase II trial, in which 69 patients with metastatic CRPC were randomly assigned to three infusions of sipuleucel-T, with abiraterone plus prednisone started within one day of, or 10 weeks after, the initial vaccine infusion concluded that concurrent therapy was safe [25]. The vaccine could be successfully manufactured during concurrent administration of prednisone without blunting cellular responses to priming of the autologous blood mononuclear cells with the GM-CSF/PAP fusion protein, or altering in vivo immune parameters that correlated with vaccine clinical benefit. The percentage of patients with a ≥50 percent PSA decrease was not significantly different for concurrent versus sequential treatment (66 versus 59 percent), but other oncologic disease control parameters were not reported. Adverse events were similar across treatment arms.

●In the STRIDE trial, 52 individuals with CRPC were randomly assigned to three infusions of sipuleucel-T, with enzalutamide started 2 weeks before or 10 weeks after the initial vaccine infusion [26]. In a preliminary report presented at the 2018 American Society of Clinical Oncology genitourinary cancers symposium, concurrent treatment was well tolerated, and there were no concerning safety signals, but there was also no suggestion that concurrent therapy improved OS or disease progression.

Plus RA-223 — A preliminary report suggests that combining sipuleucel-T with radiation (using the bone targeted radioisotope radium-223 [Ra-223]) may improve the likelihood of objective disease regression without enhancing toxicity [27]. In this randomized phase II study in which 32 males with asymptomatic bone predominant metastatic CRPC without visceral metastases >1 cm were randomly assigned to sipuleucel-T alone, or with six doses of Ra-223, median radiographic PFS was longer with combined therapy (39 versus 12 weeks, HR 0.32, 95% CI 0.14-0.76), as were PSA responses (50 percent decline in PSA in 33 versus 0 percent). To put this in context, only 7.7 percent of males in the phase 3 ALSYMPCA trial of Ra-223 alone had a 50 percent decrease in PSA [28].

Despite these early favorable results, in our view, the available data are not yet sufficient to recommend use of this combination.

Plus docetaxel — Although there are no trials of docetaxel with or without sipuleucel-T in metastatic CRPC, a randomized trial of a related dendritic vaccine generated using the LNCAP cell line (stapuldencel-T, [DCVAC/PCa]) failed to demonstrate a survival benefit for adding vaccine therapy to docetaxel versus docetaxel plus placebo in the VIABLE phase III trial. (See 'Other vaccines' below.)

Safety — Based on a combined analysis set from the three randomized studies (601 treated with sipuleucel-T and 303 treated with "placebo" control [non-activated peripheral blood mononuclear cells]), the most common adverse events (>15 percent) with sipuleucel-T were chills, fatigue, fever, back pain, nausea, joint ache, and headache. However, these were typically mild, and ≥grade 3 events were 3 percent or less for all adverse events [29]. In addition, only the chills, fever, and headache were appreciably more in the sipuleucel-T arm than in the control arm. Typically, adverse events are transient and resolve within one to two days. Serious adverse events in the vaccine group included infusion reactions, cerebrovascular events, and single case reports of rhabdomyolysis, myasthenia gravis, myosotis, and tumor flare. Cerebrovascular events (mainly transient ischemic attacks) were reported in 3.5 percent of patients treated with sipuleucel-T compared with 2.6 percent of the control group.

The clinical significance and causal relationship of cerebrovascular events with sipuleucel-T are uncertain. Additional information on cerebrovascular toxicity is available from a real-world follow-up study (PROCEED) of 1976 males receiving treatment with sipuleucel-T, in whom the incidence of cerebrovascular events was 2.8 percent, and the rate per 100 person-years was 1.2 (95% CI 0.9-1.6) [22]. These results were comparable with the cerebrovascular event incidence among 11,972 males with metastatic CRPC from the Surveillance, Epidemiology, and End Results-Medicare database (2.8 percent); the rate per 100 person-years was 1.5 (95% CI 1.4-1.7).

PD-1 PATHWAY INHIBITION — Tumors that have an underlying immune recognition, including those with a high mutational burden, often respond to agents that block immune checkpoints that function as a "brake" on T-cell mediated immune system recognition and targeting of tumor cells in vivo. One well-characterized checkpoint being targeted in several tumor types is programmed cell death 1 (PD-1). PD-1 is upregulated on activated T cells, and upon recognition of tumor via the T cell receptor, PD-1 engagement by programmed cell death ligand 1 (PD-L1) expressed by tumor or other immune cells infiltrating the tumor tissue can lead to T cell inactivation and a "brake" on immune-mediated tumor eradication. (See 'Immunobiology of prostate cancer and rationale for immunotherapy' above.)

The development of several inhibitors of this pathway has led to marked progress in immuno-oncology over the last decade although the optimal selection of patients for this immune checkpoint inhibitor immunotherapy, and especially the role of predictive biomarkers, is in evolution. Among these, the most studied in different tumor types are high expression of PD-L1, deficient mismatch repair (dMMR), the biologic footprint of which is high levels of microsatellite instability (MSI-H), high tumor mutational burden (TMB), and DNA homologous recombination repair (HRR) defects. (See "Principles of cancer immunotherapy", section on 'Checkpoint inhibitor immunotherapy' and "Principles of cancer immunotherapy", section on 'Predictors of response to immune-based therapy'.)

Mechanism of benefit and prevalence of actionable findings

Deficient mismatch repair — Mutations in one of the DNA MMR genes are found in the germline of individuals with Lynch syndrome (hereditary nonpolyposis colorectal cancer) and in tumor tissue from cancers that have dMMR. There are four relevant mismatch repair genes: mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and postmeiotic segregation increased 2 (PMS2). (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genetics'.)

MMR is one of a cell's mechanisms for repairing damage to DNA that primarily results from single base pair insertions or deletions (called indels) when slippage occurs during DNA replication by DNA polymerases. This type of DNA polymerase error tends to occur at areas of short, repetitive DNA sequences, termed microsatellites. When a high rate of variation in microsatellite length exists across the genome a tumor is said to have MSI-H, which reflects underlying deficiency in MMR capability. As expected, an inability to repair DNA damage results in the accumulation of mutations. These mutations code for mutant proteins, and mutation-derived antigens ("neoantigens") can be recognized by CD8+ T cells, and targeted by the immune system in vivo. At least some data support the view that in advanced prostate cancer, dMMR mutational signatures overexpress a variety of immune transcripts, including those associated with T cells [3]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Biology of mismatch repair and tumor mutational burden'.)

As noted above, several immune checkpoints exist to dampen the immune response in order to protect against detrimental inflammation and autoimmunity, and in the setting of malignancy, such immune checkpoints can result in immune tolerance to the tumor allowing evasion of the immune response and progression of the malignancy. Inhibition of these checkpoints might be expected to halt/reverse disease progression. (See 'Immunobiology of prostate cancer and rationale for immunotherapy' above.)

Proof of principle that cancers with dMMR might be particularly susceptible to inhibition of the PD-L1/PD-1 interaction was initially provided by a study of pembrolizumab in dMMR colorectal cancer, and subsequently shown in a variety of tumor types. These data are described in detail elsewhere. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Clinical efficacy of anti-PD-1 therapy'.)

Unfortunately, dMMR/MSI-H is relatively uncommon in prostate cancer (ranging from <1 to 8 percent) [3,30-37]. As examples:

●One database study of 741 patients with metastatic CRPC, all of whom underwent comprehensive genomic profiling revealed 2 with MSI-H/low TMB disease (<1 percent) and 20 (2.7 percent) with MSI-H and TMB ≥10 mutations per megabase (Mut/Mb); an additional 24 (3.2 percent) had microsatellite stable tumors but a TMB ≥10 Mut/Mb [35].

●Another study that sequenced (paired germline and tumor) 1033 patients with prostate cancer found 32 (3.1 percent) had dMMR/MSI-H tumors, of whom 7 (21.9 percent) had a germline mutation in a Lynch syndrome-associated gene [30]. In this study, 2.4 percent of non-CRPC patients were MSI-H or dMMR, whereas 4.5 percent of patients with CRPC (and 5.4 percent of patients who had prior abiraterone or enzalutamide) were MSI-H or dMMR.

●At least one analysis that used whole exome sequencing suggest higher levels of dMMR in advanced prostate cancer; in this series, 10 of 124 patients with metastatic CRPC (8.1 percent) had at least one biopsy with dMMR [3].

●There have been several other reports [30,31,36,37], with one [37] showing only 12 of 722 (1.7 percent) patients with prostate cancer having MSI-H disease.

The available evidence supporting benefit for PD-1 targeted therapy in the small subset of patients who have dMMR CRPC is described below. (See 'dMMR/MSI-H, and high levels of TMB' below.)

High TMB — Tumors with high mutational burden (TMB; particularly those arising in the setting of dMMR) are thought to be more immunogenic and responsive to immune checkpoint inhibitor immunotherapy. The vast majority of dMMR tumors have very high TMB, with the median number of mutations often in the thousands. However, not all TMB-high tumors have dMMR (figure 2), and in these cases, the number of mutations is much lower, approximately 10 Mut/Mb on the FoundationOne CDx platform. Given these issues, TMB has been of increasing interest as a potential biomarker of benefit from immune checkpoint inhibitor immunotherapy beyond dMMR.

As noted above, prostate cancers are generally characterized by low TMB [9,38-40]. A small subset have high levels of TMB, but at least half of these are MSI-H [9]. (See 'Deficient mismatch repair' above.)

The available evidence supporting benefit for PD-1 targeted therapy in patients with CRPC who have high TMB is discussed below. (See 'Efficacy' below.)

DNA HRR gene alterations — Homologous recombination repair (HRR) gene alterations have been observed in up to 23 percent of metastatic CRPCs; the most frequent are found on breast cancer susceptibility gene (BRCA)2, ataxia-telangiectasia mutated (ATM), checkpoint kinase 2 (CHEK2), and BRCA1 genes. These tumors may be uniquely susceptible to poly ADP-ribose phosphate (PARP) inhibitors. (See "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency", section on 'Benefit of PARP inhibitors'.)

However, the presence of these gene alterations might also increase the DNA mutational load, and genomic instability, resulting in an enhanced antitumor response [41]. Among the HRR gene alterations, CDK12 deserves specific mention as CDK12-mutated prostate cancers are typically linked to poor prognosis, insensitivity to PARP inhibitors, but an increased neoantigen load and tumoral lymphocyte infiltration [42]. While there are emerging data that patients with CDK12-altered prostate cancer may have responses to PD-1 targeted therapy, the data are preliminary and additional data is needed. (See 'Other patients' below.)

Other biomarkers — There are no other biomarkers (including PD-L1 expression) that can be reliably used to select patients with CRPC for a trial of an immune checkpoint inhibitor. (See 'Other patients' below.)

PD-L1 expression is utilized as a predictive biomarker of response to immune checkpoint inhibitors (ICIs) in multiple tumor histologies, such as head and neck, non-small cell lung, and advanced esophagogastric cancer [43]. Notably, the PD-L1 positivity cutoff value and evaluation method vary among the tumor types. In other tumor types, PD-L1 expression is prognostic but not predictive of responsiveness to ICI immunotherapy (see "Treatment of metastatic and recurrent head and neck cancer", section on 'Pembrolizumab with or without platinum and fluorouracil' and "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'PD-L1-high tumors (at least 50 percent)' and "Initial systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'PD-L1 expression status in upper GI tract cancers'). In prostate cancer, rates of PD-L1 expression are highly variable [44,45], but expression does not seem to independently predict responsiveness to ICIs. (See 'Other patients' below.)

Indications and dosing — Pembrolizumab is an option for treatment of patients with metastatic CRPC who have tumors with dMMR or high levels of TMB (≥10 Mut/Mb) that has progressed following prior treatment and for whom there are no satisfactory alternative treatment options. Dostarlimab is an alternative to pembrolizumab for patients with dMMR metastatic CRPC that has progressed following prior treatment for whom there are no satisfactory alternative treatment options.

Ideally, patients offered therapy with an ICI should not have underlying clinically significant, active autoimmune issues that cannot easily be handled with replacement hormones (eg, levothyroxine).

Pembrolizumab is administered intravenously either as 200 mg every three weeks or 400 mg every six weeks. It is diluted in either normal saline or D5W to a final concentration between 1 to 10 mg/mL and infused over 30 minutes [46]. Dostarlimab is administered as 500 mg every three weeks through four cycles then 1000 mg every six weeks [47].

Patients with metastatic small cell undifferentiated prostate cancer are also appropriate candidates for an ICI (typically atezolizumab), administered as a component of a small cell lung-cancer-type chemotherapy regimen. (See 'Small cell neuroendocrine prostate cancer' below.)

Efficacy

dMMR/MSI-H, and high levels of TMB — The available data for ICIs targeting the PD-1 pathway in deficient DNA mismatch repair (dMMR) metastatic CRPC and in tumors with high levels of tumor mutational burden (TMB) are limited and somewhat conflicting.

●Two PD-1 targeted monoclonal antibodies (pembrolizumab, dostarlimab) have received tissue-agnostic approval by the US Food and Drug Administration (FDA) for refractory dMMR tumors without satisfactory treatment alternatives but the trials used to support the FDA approval had very few numbers of prostate cancer patients enrolled. As an example, the pembrolizumab approval was significantly influenced by two studies, KEYNOTE-016 (which only enrolled two patients with prostate cancer with one partial response and one stable disease) [48] and KEYNOTE-158 (which did not include any patients with prostate cancer) [49]. (See 'Mechanism of benefit and prevalence of actionable findings' above and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

●One case series included 11 patients with metastatic CRPC who were treated with PD-1 inhibition. Six of these patients had a greater than 50 percent decline in PSA, and of those six, four of the five patients with measurable disease had a partial response [30].

●A retrospective analysis of 741 males with metastatic CRPC who had genomic profiling prior to therapy and were treated with immune checkpoint inhibitor or taxane therapy demonstrated that for those patients with a TMB of ≥10 Mut/Mb, ICIs were associated with better outcomes [35]. Immunotherapy-treated patients had longer time to next therapy (median 8 versus 2.4 months, hazard ratio [HR] 0.37, 95% CI 0.15-0.87) and longer survival (median 19.9 versus 4.2 months, HR 0.23, 95% CI 0.10-0.57). In this study 5.9 percent of the patients tested had a TMB ≥10 Mut/Mb. (See 'High TMB' above.)

●Additional data are available from a retrospective analysis of 27 patients with dMMR/MSI-H advanced prostate cancer, 17 of whom received pembrolizumab [33]. Eight (53 percent) had at least a 50 percent reduction in PSA, seven of whom were still receiving treatment without evidence of progression at a median follow-up of 12 months (range 3 to 20).

●On the other hand, another report of over 10,000 tumors from the Cancer Genome Atlas showed that, in prostate cancer (as well as breast cancer and glioma), there was no correlation between CD8+ T cell expression and neoantigen load, and TMB was not predictive of response to ICI [50]. This analysis is limited given the lack of information on the number of patients with prostate cancer, and their disease stage.

It remains uncertain whether this is the appropriate threshold to define high TMB in prostate cancer, as validation studies were conducted mainly in lung and urothelial cancers and thresholds for TMB are likely to vary across tumor types, and across platforms (ie, FoundationOne versus others such as Tempus or Caris). However, best currently available data discussed above [35] suggest that 10 Mut/Mb is a reasonable cutoff to define benefit from immune checkpoint inhibitor immunotherapy in CRPC. This subject is discussed in detail elsewhere. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Approach to testing for high levels of TMB'.)

Small cell neuroendocrine prostate cancer — Immune checkpoint inhibitor immunotherapy is an appropriate component of treatment for metastatic pure small cell undifferentiated (neuroendocrine) tumors arising in the prostate, which are treated as extrapulmonary small cell lung cancers with platinum-based chemotherapy plus a PD-1 pathway inhibitor.

Pure small cell neuroendocrine carcinoma arising in the prostate is a rare disorder that is distinct from the far more common prostatic adenocarcinoma, and from prostate adenocarcinomas with focal neuroendocrine differentiation that emerge after prior androgen deprivation therapy (the so-called "aggressive variant prostate cancers"). These patients are considered to have extrapulmonary small cell lung cancer, and are usually approached with regimens that are used for extensive stage pulmonary small cell lung cancer. One of these regimens is carboplatin, etoposide, and atezolizumab (a PD-L1 inhibitor), approved by the FDA for small cell lung cancer and associated with approximately a 30 percent reduction in the risk of death in small cell lung cancer compared with chemotherapy alone. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Aggressive prostate cancer variants' and "Extrapulmonary small cell cancer", section on 'Prostate ESCC' and "Extensive-stage small cell lung cancer: Initial management", section on 'Preferred option: Immunotherapy plus platinum-etoposide'.)

Other patients

●Biomarker unselected or PD-L1-expressing – A clear role for PD-1 targeted ICI immunotherapy in patients with metastatic CRPC who are either unselected for biomarkers, or those with expression of programmed cell death ligand 1 (PD-L1) ≥1 percent has not been established. The available data are conflicting:

•Published results for the prostate adenocarcinoma cohort (n = 23) of the nonrandomized phase Ib KEYNOTE-028 trial suggest that pembrolizumab can result in durable responses for some individuals with CRPC whose tumors have PD-L1 expression in ≥1 percent of tumor or stromal cells [51]. There were four confirmed partial responses (objective response rate 17 percent), and an additional eight (35 percent) had stable disease. The median duration of response was 13.5 months.

•Others report lower rates of objective response despite PD-L1 expression. In the KEYNOTE-199 phase II study of pembrolizumab in 258 males with docetaxel-refractory metastatic prostate cancer, the objective (radiographic) response rate by central review in the 133 who had measurable disease expressing PD-L1 was only 5 percent; the response rate in the 67 males with low PD-L1 expression was 3 percent [52]. Notably, there were two radiographic complete responses, both in males with PD-L1 overexpression. The disease control rate (defined as the percentage of patients with a confirmed radiographic objective response of any duration or stable disease, or a noncomplete response or nonprogressive disease for six months or longer) in both groups was only approximately 10 percent at six months. Responses did appear to be durable (median duration of response was 16.8 months in a combined analysis of both cohorts).

•In a third trial, atezolizumab monotherapy was associated with a 50 percent PSA response rate of only 8.6 percent, although more than half of enrolled patients were still alive at 12 months [53].

•A phase III, open label trial in biomarker unselected patients with metastatic castration-resistant prostate cancer randomly assigned patients to pembrolizumab plus olaparib or a next-generation hormonal agent. Eligible patients had progressed on or after abiraterone or enzalutamide (but not both) and docetaxel. Radiographic progression-free survival (4.4 versus 4.2 months) and overall survival (15.8 versus 14.6 months) were similar between the two groups [54].

●CDK12-altered – There are emerging data that patients with CDK12-altered prostate cancer may have responses to PD-1 targeted therapy. CDK12 is a tumor suppressor gene that is associated with homologous recombination DNA repair [55]; these patients present with an increased neoantigen load and lymphocytic infiltration [42]. One retrospective study identified nine males with metastatic CRPC who had CDK12 alterations and were treated with PD-1 inhibitors [42]. Three of nine patients had a sustained PSA decline of 50 percent, including one patient whose PSA went to undetectable. One study suggested that the proportion of prostate cancer patients with CDK12 genomic alterations was only 5.6 percent [56].

These patients may also be good candidates for a PARP inhibitor. Studies are underway exploring combined ICI immunotherapy and PARP inhibitors in these patients [57]. (See "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency", section on 'DNA repair and HRR deficiency'.)

Combined therapy with enzalutamide — The benefits of combing ICI therapies with androgen receptor targeting agents are just beginning to be explored, and this approach, while promising, cannot yet be considered a standard approach outside of the confines of a clinical trial. The following data are available from clinical trials:

●In a phase II study in which pembrolizumab was added to enzalutamide in males with metastatic CRPC progressing while taking enzalutamide, a PSA decline >50 percent was seen in 5 of 28 patients [58].

●The benefit of adding atezolizumab, an anti PD-L1 monoclonal antibody, to enzalutamide compared with enzalutamide alone was shown in the IMbassador250 trial, which was conducted in 759 males with metastatic CRPC and disease progression on abiraterone [59]. While the primary endpoint, improved overall survival, was not reached with combined therapy, in preplanned subgroup analysis a progression-free survival with combined therapy was suggested in those with high levels of PD-L1 expression or high levels of tumoral CD8-positive T cell infiltration. These results should be seen as hypothesis generating only.

Safety — Side effects of immune checkpoint inhibition include inflammation of normal tissues. Because blocking these pathways essentially releases inhibition of the immune system, it can unmask a subclinical autoimmune process and cause inflammation in any organ system. Typically, this can be treated by withholding the immunotherapy alone or by adding in additional immunosuppression and other supportive care measures as needed. (See "Toxicities associated with immune checkpoint inhibitors" and "Rheumatologic complications of checkpoint inhibitor immunotherapy" and "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors" and "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy" and "Immune checkpoint inhibitor colitis".)

EXPERIMENTAL IMMUNOTHERAPY APPROACHES — A variety of experimental immunotherapies are being tested in prostate cancer, including chimeric antigen receptor (CAR)-T cell therapies, and eligible individuals should be encouraged to enroll in available trials testing new strategies.

Ipilimumab — Ipilimumab is a monoclonal antibody that blocks signaling through a different immune checkpoint than programmed cell death-1 (PD-1), the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 can bind to CD80 and CD86 and send a negative signal to the T cell, shutting down its function. Constitutive endocytosis keeps the expression level of CTLA-4 low; however, on T cell activation, CTLA-4 is upregulated. (See "Principles of cancer immunotherapy", section on 'CTLA-4'.)

Initial studies of ipilimumab showed that some patients with metastatic CRPC had prolonged decreases in prostate-specific antigen (PSA) and objective responses. However, two large, randomized phase III studies showed no overall survival benefit for the use of ipilimumab in patients with prostate cancer (either before or after docetaxel-based chemotherapy) [60,61], although in one of these studies, there was an "excess of long-term survivors" in the ipilimumab group [62].

In patients with treatment-naïve advanced or metastatic melanoma compared with single-agent PD-1 pathway inhibitor, the combination of a PD-1 pathway inhibitor plus ipilimumab improves outcomes, and in a standard approach subgroup analysis of these studies suggested that PD-1 targeted antibodies alone appeared to be just as effective as the combination approach in patients who had evidence of an underlying immune activation (programmed cell death ligand 1 [PD-L1] expression ≥1 percent in the tumor). However, for PD-L1 negative tumors, there appeared to be improved activity with the combination regimen over PD-1 inhibition alone. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab plus ipilimumab (preferred)'.)

Given that prostate cancer is associated with little or no underlying immune recognition and low levels of PD-L1 expression in many studies [45], a single arm (n = 90), two cohort combination study with ipilimumab (3 mg/kg) and nivolumab (an anti-PD-1 antibody, 1 mg/kg) was conducted in advanced prostate cancer [63]. The objective response rate was 25 percent in the prechemotherapy cohort and 10 percent in the postchemotherapy cohort. However, approximately 50 percent of patients had grade 3 or greater toxicity including 4 out of 90 patients who had treatment-related deaths. Despite the promising activity, toxicity has limited enthusiasm for this dosing regimen. Alternative combination regimens are under study [64-66].

Other vaccines — Besides sipuleucel-T, other vaccines have been tested in prostate cancer, and have not yet been found to be beneficial; as such they remain experimental. As examples:

●PROSTVAC is an experimental therapeutic pox-viral vaccine targeting PSA that was tested in approximately 1300 males with metastatic CRPC. Despite studies demonstrating activation of an immune response in the peripheral blood [67], and immune infiltrates within the tumor [68], a randomized controlled study showed no evidence of improved survival with vaccine compared with empty vector [69].

It is likely that either the numbers of effector cells induced are insufficient or that their activity is not sufficient in the immune-hostile tumor microenvironment. Many therapeutic vaccine strategies being tested also include agents targeting immune checkpoints, regulatory cells (myeloid-derived suppressor cells or T regulatory cells), or other immune inhibitory signals.

●Stapuldencel-T (DCVAC/PCa), an autologous dendritic cell-based vaccine which uses a human prostate cancer cell line (LNCaP) as a tumor-associated antigen rather than the recombinant fusion protein used for sipuleucel-T, failed to demonstrate any significant advantage when combined with docetaxel plus prednisone versus docetaxel plus prednisone plus placebo (nonactivated autologous dendritic cells) in the phase III VIABLE randomized trial [70].

Bispecific antibodies — Bispecific antibodies are engineered proteins that bind to more than one target. These include the US Food and Drug Administration-approved agents, such as blinatumomab, which targets T cells (via CD3) and B cell leukemia cells (via CD19). This binding can keep a T cell and a tumor cell in close proximity longer and facilitate immune-mediated recognition and killing. A number of bispecific antibodies are being investigated in prostate cancer [71,72]. Many of these bispecific antibodies target CD3 and prostate-specific membrane antigen (PSMA), which is found on virtually all prostate cancer cells. While early studies have shown PSA declines in 30 to 40 percent of patients, development issues include cytokine release syndrome and immunogenicity of the bispecific antibodies.

CAR-T cells — Tumor immunologists have had tremendous success in targeting tumor-associated antigens of a variety of hematologic malignancies using chimeric antigen receptor T (CAR-T) cells, which are autologous T cells genetically engineered to target specific antigens. The anti-target antibody is embedded in the T cell membrane and uses the same signaling domain as the T cell receptor. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'CAR-T' and "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Chimeric antigen receptor T cell therapy' and "Multiple myeloma: Treatment of third or later relapse", section on 'Chimeric antigen receptor T cells'.)

Unfortunately, this approach has not had comparable efficacy in solid tumors, although a number of CAR-T cell treatments are in clinical development in prostate cancer. PSMA is the target of a number of these experimental CAR-T cell products, some of which are "armored" with a receptor for transforming growth factor beta, in an attempt to reverse local immunosuppression [72-74].

ASSESSMENT DURING TREATMENT — For males with CRPC who are undergoing chemotherapy, 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 during treatment for advanced prostate cancer [75]. 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.

Assessment strategies during treatment for CRPC are discussed in more detail separately. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Assessment during treatment'.)

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

SUMMARY AND RECOMMENDATIONS

●Rationale for immunotherapy, selection, and integration into other treatments

•Prostate cancer cells express a number of tumor-associated antigens, including mutations, that can serve as targets for immunotherapy. However, because prostate cancer is considered to have a "cold" immune microenvironment, immunotherapies that have been successfully applied to other solid tumors have not shown comparable clinical efficacy in unselected males with advanced prostate cancer. (See 'Immunobiology of prostate cancer and rationale for immunotherapy' above.)

•Two immunotherapy strategies which may be beneficial in selected patients with metastatic castration-resistant prostate cancer (CRPC) are vaccine therapy with sipuleucel-T for those with minimally symptomatic disease and no visceral metastases, and immune checkpoint inhibitor immunotherapy for the small subset of patients with deficient DNA mismatch repair (dMMR) or high levels of tumor mutational burden (TMB). How these treatments should be sequenced with other systemic treatments for CRPC that have been shown to improve survival in randomized trials is not yet established. (See 'Current status of immunotherapy for prostate cancer' above.)

An overview of the available systemic therapies for initial treatment of CRPC, which includes an algorithmic approach to selecting therapy (algorithm 1), is presented separately. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)

●Sipuleucel-T

•Sipuleucel-T is an option for patients with asymptomatic or minimally symptomatic slowly progressive metastatic CRPC who lack visceral (especially hepatic) metastasis or cancer pain requiring opioids. Significant declines in prostate-specific antigen (PSA) or radiographically detectable objective antitumor responses are unlikely to occur, and as a result, this treatment is not appropriate for those with high-burden, highly symptomatic disease.

For most patients, we use this agent earlier rather than later during the treatment course of CRPC as this may optimize outcomes. (See 'Factors predicting benefit' above.)

•Until further information is available, we suggest sequential rather than concurrent use of sipuleucel-T with other active agents, such as enzalutamide or abiraterone (Grade 2C). (See 'Plus androgen receptor targeted therapy' above.)

•The absence of objective parameters to judge whether or not an individual patient is benefiting from vaccine therapy poses a major difficulty in determining when to consider sipuleucel-T ineffective and initiate alternative treatment, especially given the short treatment course (approximately four weeks). We individualize treatment decisions based on tumor growth characteristics (ie, evidence of rising PSA and/or radiographic progression) and patient preference. (See 'Assessing treatment response' above.)

●PD-1 pathway inhibition

•Pembrolizumab is an option for treatment of patients with metastatic CRPC who have tumors with dMMR or high levels of TMB (≥10 mutations per megabase) that has progressed following prior treatment and for whom there are no satisfactory alternative treatment options. Dostarlimab is an alternative to pembrolizumab for patients with dMMR metastatic CRPC that has progressed following prior treatment for whom there are no satisfactory alternative treatment options. (See 'dMMR/MSI-H, and high levels of TMB' above.)

Otherwise, a clear role for immune checkpoint inhibitor immunotherapy in other patients with metastatic CRPC (including those unselected for biomarkers, or with expression of programmed cell death ligand 1 [PD-L1] ≥1 percent) has not been established. (See 'Other patients' above.)

Because immune checkpoint inhibitors have good activity in only selected subpopulations with conventional prostate adenocarcinoma, germline and somatic genomic testing is important to determine if a patient is an appropriate candidate. (See 'Importance of genomic testing' above.)

•Immune checkpoint inhibitor immunotherapy is also an appropriate component of treatment for small cell undifferentiated (neuroendocrine) tumors arising in the prostate, which are treated as extrapulmonary small cell lung cancers. (See 'Small cell neuroendocrine prostate cancer' above.)

●Experimental approaches – A variety of experimental immunotherapies are being tested in prostate cancer, including chimeric antigen receptor (CAR)-T cell therapies, and eligible individuals should be encouraged to enroll in available trials testing new strategies. (See 'Experimental immunotherapy approaches' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate would like to acknowledge Philip W Kantoff, MD, who contributed to an earlier version of this topic review.

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.