Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency

INTRODUCTION — 

Prostate cancers are frequently characterized by abnormalities in a variety of growth factor signaling pathways that control the cell cycle and apoptosis, as well as aberrations in deoxyribonucleic acid (DNA) damage repair pathways. Homologous recombination repair (HRR) is a DNA repair pathway of clinical interest due to the sensitivity of HRR deficient cells to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, and potentially platinum-containing chemotherapy. Genes that are directly or indirectly implicated in HRR include BRCA1, BRCA2, CHEK2, ATM, PALB2, FANCA, and RAD51D, among others.

Accumulating data have shown that males with metastatic castration-resistant prostate cancer (mCRPC) and a pathogenic variant in a HRR gene may respond to treatment with a PARP inhibitor, while continuing androgen deprivation therapy (ADT). All males with advanced metastatic prostate cancer who might be candidates for genomically-targeted therapy should undergo molecular testing of their tumor and germline DNA to identify potential therapeutic molecular targets.

This topic will review the biology and identification of HRR in males with prostate cancer and will review DNA repair-targeted therapies in mCRPC with HRR deficiency. An overview of therapy for CRPC, immunotherapy for CRPC, and the molecular biology of prostate cancer is discussed elsewhere:

●(See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)

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

●(See "Molecular biology of prostate cancer".)

DNA REPAIR AND HRR DEFICIENCY

Basic biology — Each cell is equipped with DNA damage response mechanisms that guard the genome against mutational insults. Double-strand breaks are a particularly hazardous form of DNA damage, and they are repaired by two major repair pathways: error-free (high-fidelity) homologous recombination and non-homologous (low fidelity) end-joining [1,2].

Defective DNA repair is a common hallmark of cancer. HRR deficiency was initially described in cancers that arose in the setting of germline mutations in the tumor suppressors BRCA1 and BRCA2, which are associated with hereditary breast and ovarian cancer. It is now understood that genetic and epigenetic inactivation of other genes can lead to HRR deficiency in sporadic cancers as well, which some have termed "BRCA-ness" or a BRCA-like phenotype [3-6].

HRR is required for the repair of double-strand breaks that are generated during DNA interstrand crosslinking, which occurs during treatment with platinum-type chemotherapy drugs. For this reason, cells that have HRR deficiency may be particularly sensitive to platinum-containing chemotherapy, although platinum agents are not specifically approved by the US Food and Drug Administration for use in prostate cancer. (See 'Platinum-based chemotherapy' below.)

Poly(ADP-ribose) polymerase (PARP) activity is essential for the repair of single-strand DNA breaks via the base excision repair pathway [7,8]. In the nucleus, PARP1 and PARP2 enzymes sense single-strand DNA breaks and recruit DNA repair complexes to the site, which then result in post-translational modification of the DNA, a process known as PARylation or poly-ADP ribosylation. PARP inhibitors block this PARylation, and they may also trap the PARP enzymes on injured DNA, preventing binding of incoming repair proteins [7].

In HRR deficient cells the unrepaired DNA breaks that result after treatment with PARP inhibitors eventually can lead to cancer cell death [9,10]. This process is referred to as "synthetic lethality," in which two conditions that would independently not cause cell death when present in combination cause lethal injury to the cell [11,12].

Identifying patients who are likely to respond to PARP inhibitors — Genomic testing is indicated for males with advanced prostate cancer who might be eligible for treatment with molecularly targeted therapy. The American Society of Clinical Oncology (ASCO) has issued a provisional clinical opinion that supports both somatic and germline genomic testing in metastatic or advanced cancer, including prostate cancer, when there are genomic biomarker-linked therapies approved by regulatory agencies for the type of cancer, including PARP inhibitors for males with metastatic castration-resistant prostate cancer (mCRPC) and alterations associated with HRR deficiency [13].

The available evidence suggests that response rates to PARP inhibitors are highest in individuals with germline or somatic BRCA1/2 mutations [14-17]. However, there may be a differential benefit from PARP inhibitor therapy across subgroups with BRCA1/2 alterations [18]. In particular, due to the relative rarity of BRCA1 mutations compared with BRCA2 mutations in prostate cancer, the efficacy of PARP inhibition in the BRCA1 subset remains unclear and will be better defined in the future with additional data [19,20].

In addition to BRCA1 and BRCA2, preclinical and clinical studies indicate that pathogenic or likely pathogenic variants in other genes that are directly or indirectly involved in the HRR pathway might also be associated with varying levels of sensitivity to PARP inhibitors [21]. In prostate cancer, these genes include:

●ATM [22,23]

●CHEK2 [23]

●PALB2 [23]

●FANCA [23-25]

●RAD51B/C/D [23]

●BRIP1 [23]

Selecting which type of sample to use to identify HRR alterations using NGS — Pathogenic or likely pathogenic variants in genes that regulate HRR can be detected in a number of different ways [26]. The majority of males with advanced prostate cancer will have been referred for germline genetic testing as this is recommended by several groups, including National Comprehensive Cancer Network and ASCO. (See "Genetic risk factors for prostate cancer", section on 'Who needs referral for genetic evaluation'.)

There are several ways to assess for pathogenic or likely pathogenic variants, including germline testing and multipanel somatic gene testing using next-generation sequencing (NGS). The choice of method depends on patient factors (ie, whether a variant has been identified in other family members) as well as laboratory factors (ie, local availability/expertise).

The optimal choice of sample for NGS depends on the availability of primary or metastatic tissue, the availability of circulating tumor DNA (ctDNA; which is related to high disease burden), or sample availability that is limited to germline DNA from blood or saliva. The quality of available tissue, including sample age, biopsy site, and tumor purity, impacts sequencing results [27]. ctDNA analysis may have lower sensitivity to detect certain types of alterations, including deletions and rearrangements. Both somatic and germline sequencing are recommended, as alterations in BRCA1/2 occur at near-equal frequency in the germline and somatically, and the identification of a germline variant has implications for risks of other cancers in the patient and family members [27,28]. (See "Gene test interpretation: BRCA1 and BRCA2" and "Genetic risk factors for prostate cancer", section on 'Specific genes associated with inherited predisposition'.)

Broadly speaking, the four types of specimens that can be used for interrogation of HRR-related genetic variants are:

●Fresh biopsy of a metastatic lesion is ideal, if feasible [29]

●Archival biopsy/primary tumor tissue, preferably less than five years old [30]

●ctDNA; although assay of ctDNA may miss deletions unless disease burden is high [31]

●Blood or saliva sample (germline-only testing)

While interpreting the data received from testing, it is important to consider the type of assay that was performed. For instance, a negative result for pathogenic variants from a plasma specimen should prompt further genomic testing using tumor specimens. In addition, there is a high frequency of false positives with assay of ctDNA because of interference from clonal hematopoiesis alterations of indeterminate potential (CHIP) [32-35]. This has led to the recommendation that clinical cell-free DNA testing include a paired whole-blood control to exclude CHIP variants [33]. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

Somatic versus germline testing — As noted above, testing for both somatic and germline alterations is necessary, preferably through separate somatic-only and germline-only testing for the following reasons:

●Germline-only testing will miss almost one-half of BRCA1/2 alterations [27] and will miss most cases of microsatellite instability, which may be important for genetic counseling, and to identify those cancers that may respond to immune checkpoint inhibitor immunotherapy. (See 'Somatic mutations' below and "Immunotherapy for castration-resistant prostate cancer", section on 'PD-1 pathway inhibition'.)

●Tumor testing alone may miss pathogenic germline variants (PGVs) for a variety of reasons, including technical limitations of tumor sequencing (especially small copy number deletions, and large or complex insertions or deletions), differences in the interpretation of results of tumor and germline tests, or differences in the genes tested in the tumor and the germline.

Several studies have demonstrated the importance of obtaining both germline and somatic testing. Examples of these include:

●In one report in which 2023 patients with cancer unselected for family history underwent germline testing and previously had tumor DNA sequencing, including 221 prostate cancers, PGVs were found in 31 percent overall and in 39 percent of the prostate cancers [36]. In the entire cohort, 8.1 percent of the PGVs were missed by tumor sequencing alone.

●In a study of targeted DNA sequencing that evaluated tumor and matched blood (germline) samples for 451 patients with locally advanced or metastatic prostate cancer, 27 percent were found to have a somatic mutation and/or a PGV in a HRR gene; germline analysis identified only approximately one-half of these patients [27].

Frequency of HRR mutations in CRPC

Germline mutations — The frequency and distribution of germline pathogenic or likely pathogenic variants associated with HRR deficiency was reported in a pooled analysis of 692 males with metastatic prostate cancer who had NGS of germline DNA; 11.8 percent of those with metastatic disease carried a germline pathogenic variant in a DNA damage repair gene [37]. The most commonly affected gene was BRCA2 (5.3 percent); followed by CHEK2 (1.9 percent); ATM (1.6 percent); BRCA1 (1 percent); and RAD51D, PALB2, NBN (also called NBS1), and BRIP1 (<1 percent each). (See "Genetic risk factors for prostate cancer", section on 'DNA repair genes'.)

Males with localized and metastatic prostate cancer and a germline alteration directly or indirectly affecting HRR, such as a pathogenic variant in BRCA1/2 or ATM, are known to have a poorer prognosis and overall survival compared with those without such variants, although these prostate cancers may have a better response with appropriate genomically-targeted therapy [38-42]. (See "Genetic risk factors for prostate cancer", section on 'Prognostic impact'.)

Somatic mutations — Somatic (tumor) genomic sequencing approaches can identify prostate cancers with alterations that lead to HRR deficiency for therapeutic decision-making and clinical trial consideration. These assays may use tumor biopsies or ctDNA sampled from blood. In addition to germline pathogenic variants, variants that arise within the tumor also predict for response to PARP inhibitors and platinum-type drugs. (See 'Rucaparib, in selected patients' below and 'Platinum-based chemotherapy' below.)

The frequency of somatic alterations affecting HRR genes was explored in a prospective case series of 3476 prostate cancer tissue samples [43]. Overall, 23 percent had potentially actionable alterations in a HRR pathway-related gene.

Many commercial tumor sequencing assays report both somatic and germline variants without being able to distinguish between the two.

CASTRATION-SENSITIVE DISEASE — 

Patients with de novo metastatic disease or castrate sensitive recurrence with a BRCA1/2 genetic alteration or other HRR deficiency alteration are currently managed similarly to patients without such genetic aberrations. Management is discussed elsewhere. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer".)

Several ongoing clinical trials (NCT04821622) are examining the role of PARP inhibitors in the setting of first-line systemic therapy and results are awaited.

CASTRATION-RESISTANT DISEASE — 

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 castration-resistant prostate cancer (CRPC) (see "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Definition of castration resistance'). Males with metastatic CRPC (mCRPC) should continue ADT unless they have had surgical castration.

Accumulating data have shown that males with mCRPC and a pathogenic variant in a HRR gene may respond to treatment with a poly(ADP-ribose) polymerase (PARP) inhibitor (algorithm 1).

Several PARP inhibitors are approved for treatment of males with CRPC and alterations associated with HRR deficiency [44-46]. However, the approval for rucaparib and niraparib/abiraterone acetate is limited to those with pathogenic variants in BRCA1 or BRCA2, while the approvals for olaparib (alone or in combination with abiraterone acetate) and talazoparib/enzalutamide include several genes that have not individually been shown to predict for responsiveness to PARP inhibition [46,47]. Of all of the HRR genes involving DNA damage response pathways, BRCA2 variants appear to have the greatest associated benefit from PARP inhibitors [14,15,17,48]. (See "Genetic risk factors for prostate cancer", section on 'DNA repair genes'.)

There has been no direct comparison between agents. The choice of agent is based on patient-specific factors such as mutational status, prior therapy, comorbidities, and expected side effect profiles.

Androgen deprivation therapy as backbone of treatment — All patients with mCRPC should continue androgen deprivation therapy (ADT), unless they have undergone surgical castration. ADT is discussed elsewhere. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Benefits and methods for androgen deprivation therapy'.)

Patients with prior androgen receptor pathway inhibitors — For patients who have mCRPC and have progressed on prior androgen receptor pathway inhibitors (ARPI), but have not received a taxane for mCRPC, we suggest olaparib. Other options for males with first-line mCRPC include olaparib plus abiraterone, or enzalutamide plus talazoparib, but the benefit of these combinations in males who have already received a prior ARPI is unclear, as the studies that led to their approval included very few patients who had previously received such an agent (table 1).

In this setting, we typically start PARP inhibitor therapy prior to the use of docetaxel based on extrapolation from the results of the TRITON3 study, which showed that rucaparib is superior to clinician's choice therapy that included docetaxel [49]. Docetaxel may be used in the later line setting after a PARP inhibitor and is discussed elsewhere. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Chemotherapy'.)

Olaparib — In males with CRPC with a pathogenic variant in a HRR gene who progressed on an ARPI, olaparib improved progression free survival (PFS) compared with enzalutamide or abiraterone.

The randomized PROfound trial compared olaparib (300 mg twice daily) with an ARPI (clinician's choice of abiraterone or enzalutamide) in 387 males with mCRPC. All patients had experienced progression on a prior androgen receptor-targeted agent for metastatic disease (enzalutamide, abiraterone, or both), while one prior chemotherapy agent was also permitted but not required. All males received a concurrent gonadotropin hormone-releasing hormone analog or had prior bilateral orchiectomy.

Males in cohort A with pathogenic variants in BRCA1/2 or ATM treated with olaparib had a longer median radiographic PFS (7.4 versus 3.6 months; hazard ratio [HR] 0.34, 95% CI 0.25-0.47) and a higher objective response rate (33 versus 2 percent) when compared with clinician's choice [50]. Benefits persisted when an additional cohort of other gene alterations (cohort B) was included in the analysis, although they were less prominent (median radiographic PFS 5.8 versus 3.5 months). Despite substantial crossover from control therapy to olaparib, overall survival was also improved for both cohorts (cohort A: median 19.1 versus 14.7 months; cohort B: median 14.1 versus 11.5 months). In the entire population, the overall survival in the olaparib and control group was 17.3 and 14 months, respectively [51]. A subgroup analysis of patients by prior taxane receipt favored the use of olaparib both among those without prior taxane (HR 0.77, 95% CI 0.5-1.22) and among those with prior taxane (HR of 0.39, 95% CI 0.29-0.53).

The most common adverse events with olaparib were anemia (46 versus 15 percent for ARPI), nausea (41 versus 19 percent), anorexia (30 versus 18 percent), and fatigue/asthenia (41 versus 32 percent) [50]. Mostly, these were low grade, and generally manageable without the need for treatment discontinuation [52]. Olaparib also delayed deterioration in health-related quality of life (HRQoL) scores and was associated with a reduced pain burden and better HRQoL over time compared with an ARPI [53,54].

The US Food and Drug Administration (FDA) approved olaparib for adults with mCRPC who have disease progression following treatment with an ARPI and have a germline or somatic pathogenic variant in a HRR gene, based on testing of one or more of the following [44,55]:

•Tumor tissue – ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L

•Germline testing (preferably blood-based) – BRCA1 or BRCA2

•Circulating tumor DNA (ctDNA; via a plasma assay) – ATM, BRCA1 or BRCA2 mutations

Rucaparib, in selected patients — The benefit of rucaparib has been shown for BRCA1/2-mutated mCRPC. Regulatory approval in the United States has only been granted for males with BRCA1 or 2 mutations after they have received a taxane for mCRPC. Although we typically use a PARP inhibitor before a taxane for HRR deficient mCRPC, some patients alternatively may have been treated with a taxane first, and in such patients, either rucaparib or olaparib may be used as next line treatment. There have been no direct comparisons between these two options and decisions should be made based on patient comorbidities along with mutational status. Olaparib is discussed above. (See 'Olaparib' above.)

In males with mCRPC and BRCA1 or 2 mutations who have previously received a taxane for mCRPC, a single arm study (TRITON2) demonstrated a radiographic response rate with rucaparib of 44 percent and PFS of nine months [56]. There was no clear difference in response rate for germline versus somatic alterations in BRCA1/BRCA2. TRITON2 also included a subset of other HRR variants. Radiographic responses were observed in 10.5 percent of males with ATM mutations, 6.7 percent of males with CDK12 mutations, and 11.1 percent of males with CHEK2 mutations [23].

Based on these data, the FDA granted accelerated approval to rucaparib for patients with mCRPC and deleterious BRCA1/2 mutations (germline and/or somatic), who have previously been treated with androgen receptor-directed therapy and taxane-based chemotherapy [45,57].

The use of rucaparib was further investigated in males who had not received taxane-based therapy for castration-resistant disease in the randomized TRITON3 study [49]. In patients with a BRCA1, BRCA2, or ATM alteration who had progressed on one second-generation ARPI, rucaparib improved radiographic PFS relative to clinician's choice (docetaxel or the alternative second generation ARPI, either abiraterone acetate or enzalutamide) [49]. In the BRCA1/2 subgroup, the median duration of imaging-based PFS was longer with rucaparib than control (11.2 versus 6.4 months, respectively; HR 0.50, 95% CI 0.36-0.69). In the ATM group, PFS was 8.1 versus 6.8 months, a difference that was not statistically significant (HR 0.95, 95% CI 0.59-1.52). Despite these data, the use of rucaparib is only FDA approved for males who have received a taxane for mCRPC.

Patients without prior androgen receptor pathway inhibitors — For males who have not received any ARPI, we suggest initial treatment for first-line mCRPC with either abiraterone plus olaparib (BRCA1/2 alterations), abiraterone plus niraparib (BRCA1/2 alterations), or enzalutamide plus talazoparib (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) (table 1). There has been no direct comparison between the different options so decisions about which agents to use depends on patient comorbidities and mutational status. It is unclear whether the combination approach is superior to sequential use of an ARPI followed by olaparib (see 'Patients with prior androgen receptor pathway inhibitors' above). Sequential use therefore is a reasonable option in this setting [58,59].

Olaparib plus abiraterone — Olaparib has regulatory approval by the FDA for use in combination with abiraterone and either prednisone or prednisolone for patients with BRCA1/2-mutated mCRPC [60]. This is one of several appropriate combinations that we offer to patients who have not had prior ARPI for prostate cancer. Other options are discussed below. (See 'Talazoparib plus enzalutamide' below and 'Niraparib plus abiraterone' below.)

Several trials have investigated the role of a PARP inhibitor combination for first-line therapy of mCRPC, typically after failure of ADT alone, all of which suggest a PFS benefit for patients with BRCA1/2 alterations compared with placebo or abiraterone alone, but only one (the PROPEL trial) has demonstrated overall survival benefits with this approach:

●In the PROPEL trial, 796 males with mCRPC after failure of first-line ADT and independent of HRR status were randomly assigned to abiraterone plus a corticosteroid and either olaparib (300 mg twice daily) or placebo [61]. Docetaxel was allowed if administered for metastatic castration-sensitive prostate cancer, and a prior ARPI (except abiraterone) was permitted, although few patients received one. The addition of olaparib to abiraterone plus a corticosteroid improved radiographic PFS overall (median 25 versus 17 months; HR 0.66, 95% CI 0.54-0.81), and in those with (HR 0.50, 95% CI 0.35-0.73) and without (HR 0.76, 95% CI 0.60-0.97) HRR alterations, as determined by plasma ctDNA. In an exploratory analysis in patients with BRCA1/2 mutations, overall survival was improved with the addition of olaparib (not reached versus 23 months; HR 0.30, 95% CI 0.15-0.59) [60].

●In the BRCAAWAY trial, in 61 patients with BRCA1/BRCA2- or ATM-associated mCRPC without previous treatment for castration-resistant disease, abiraterone plus olaparib improved median PFS compared with abiraterone alone (39 versus 8.4 months; HR 0.28, 95% CI 0.13-0.65) and olaparib alone (39 versus 14 months; HR 0.32, 95% CI 0.14-0.75) [62].

Talazoparib plus enzalutamide — The FDA approved the combination of talazoparib plus enzalutamide in males with mCRPC and a HRR gene mutation in ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C. Among patients with HRR-mutated mCRPC treated in the first line, the TALAPRO-2 trial demonstrated a radiographic PFS benefit with the combination of talazoparib and enzalutamide compared with enzalutamide alone (median not reached versus 14 months; HR 0.45, 95% CI 0.33-0.61) [63,64]. Like PROPEL and MAGNITUDE, docetaxel for metastatic castration-sensitive prostate cancer was permitted, as was a prior ARPI for castration-sensitive prostate cancer or non-metastatic CRPC (although only 6 percent of patients received one). As of last reporting, overall survival data were still immature for the combination versus enzalutamide alone (HR 0.69, 95% CI 0.46-1.03).

Niraparib plus abiraterone — The FDA approved the combination of niraparib plus abiraterone in males with BRCA1/2-mutated mCRPC. A PFS benefit from combining niraparib plus abiraterone for first-line treatment of mCRPC was shown in the MAGNITUDE trial [65,66]. Males were randomly assigned to abiraterone plus prednisone with either niraparib or placebo. Like PROPEL, docetaxel for metastatic castration-sensitive prostate cancer was permitted, as was a prior ARPI for castration-sensitive prostate cancer or non-metastatic CRPC (although fewer than 5 percent of patients received one). Enrollment into the cohort without HRR alterations was stopped early after an interim analysis suggested futility for the addition of niraparib. Among those with any HRR alteration (n = 423), the addition of niraparib modestly improved radiographic PFS (median 16.5 versus 13.7 months, p = 0.0217). In the subgroup with BRCA1/2 alterations, the benefit was larger (median 19.5 versus 10.9 months), resulting in the FDA approval of this combination only for males with BRCA1/2 alterations.

Strategies without regulatory approval

●Niraparib – Niraparib is a third PARP inhibitor that has been evaluated in mCRPC but is not used routinely as a single agent in this setting.

The phase II GALAHAD trial addressed the utility of niraparib in 76 males with mCRPC and HRR gene abnormalities (either pathogenic germline or somatic biallelic alterations) [67]. All males had previously received docetaxel and next-generation ARPI. At a median follow-up of 10 months, the response rate was 34 percent (2 complete and 24 partial), and the median response duration was 5.6 months. Among the 47 patients with measurable disease and non-BRCA HRR alterations, the objective response rate was 11 percent (5 partial responses). In the safety analysis, which included all 289 enrolled patients, the most common grade 3 or 4 treatment-emergent adverse effects were anemia (33 percent), thrombocytopenia (16 percent), and neutropenia (10 percent); two adverse events had a fatal outcome.

●Talazoparib – The benefit of talazoparib was assessed in the phase II TALAPRO-1 study, conducted in 128 males with mCRPC and DNA damage repair mutations who had previously received one or two prior chemotherapy regimens [68]. Of the 104 males evaluable for objective response rate (the primary endpoint), the response rate was 30 percent overall; in independent blinded central review, the objective response rate was higher for those with BRCA2 and BRCA1 mutations (46 and 50 percent, respectively) than for those with PALB2 or ATM mutations (25 and 12 percent, respectively). The corresponding rates of median radiographic PFS were 11.2 months for those with BRCA1/2 mutations, compared with 5.6 months for those with PALB2 mutations and 3.5 months for those with ATM mutations. Similar patterns were observed for overall survival and time to PSA progression. Nonhematologic adverse events (nausea 33 percent, anorexia 28 percent, asthenia 23 percent) were generally mild to moderate; hematologic adverse events were more often grade 3 or 4, but manageable with dose modifications/supportive care [69].

After ARPI and PARP inhibitor

Platinum-based chemotherapy — Although prospective data are lacking, the use of platinum-based chemotherapy is a reasonable option in males with mCRPC and pathogenic or likely pathogenic variant in a HRR gene who have experienced progression on both an androgen receptor pathway inhibitors (ARPI) and a poly(ADP-ribose) polymerase (PARP) inhibitor (either sequentially or concurrently). The available data for platinum-based chemotherapy are more robust for BRCA2 than for those with other HRR alterations.

In vitro, platinum sensitivity is a feature of HRR-deficient cells [70], and both breast and ovarian tumors with pathogenic variants in BRCA1/2 have increased platinum sensitivity. (See "ER/PR-negative, HER2-negative (triple-negative) breast cancer", section on 'Germline BRCA mutation' and "Management of ovarian cancer associated with BRCA and other genetic mutations", section on 'Definition of platinum-sensitive versus platinum-resistant recurrence'.)

In unselected males with mCRPC, platinum-based chemotherapy confers palliative benefit, with some objective responses and longer PFS in phase II studies, but it is not clear that overall survival is improved [71-74]. Specific subpopulations of patients may derive the most benefit, including those with aggressive variants of prostate cancer or those with HRR-deficient tumors. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Aggressive prostate cancer variants'.)

Response to platinum chemotherapy based on HRR deficiency has been addressed in the following reports:

●In one series, 109 males received platinum-based chemotherapy for mCRPC, 64 of whom were taxane refractory and PARP inhibitor-naïve [75]. Within this subset, 16 had somatic or germline HRR gene alterations, and these patients had a sevenfold higher likelihood of having a decline in PSA of 50 percent or more, although there was no survival advantage. Of the eight patients with a HRR gene alteration who received platinum therapy after a PARP inhibitor, three of seven evaluable patients had a radiographic partial response or stable disease. None of the patients with ATM mutations had platinum responses regardless of prior PARP inhibitor exposure.

●Another case series studied the activity of platinum-based chemotherapy in 508 males with advanced prostate cancer, of whom 80 had HRR defects (44 BRCA2, 12 ATM, 3 BRCA1, and 21 "other"), 98 had no HRR defects, and 330 were not assessed for HRR defects [76]. Among those with pathogenic variants in HRR genes, platinum-based therapy was associated with higher levels of PSA response (defined as a ≥50 percent decline; 47 versus 36 percent of controls), more frequent soft tissue response (48 versus 31 percent among those with evaluable disease), and longer median overall survival from the start of platinum therapy (14 versus 9.2 months). None of these differences were statistically significant. In the group of males not assessed for HRR alterations, PSA responses were seen in 29 percent and soft tissue responses in 21 percent of evaluable males.

In the subgroup of 44 patients with BRCA2 mutations, PSA responses were noted in 64 percent and soft tissue responses in 50 percent of those with evaluable disease. Median overall survival from the start of platinum therapy was significantly different in the cohorts with different HRR alterations; it was 15.2 months (interquartile range 9.9 to 33.7) in those with BRCA2 alterations, 9.3 months (6.5 to 11) for ATM alterations, 4.1 months (3.8 to 4.4) in patients with BRCA1 alterations, and 4.9 months (3.6 to not reached) in those with alterations in other genes.

Additional information is available from a small retrospective series of eight males with mCRPC and a germline BRCA2 mutation, six of whom (75 percent) had a >50 percent PSA decline within 12 weeks of starting carboplatin plus docetaxel [77]. This rate was substantially higher than the PSA response rate in the 133 patients who did not have a BRCA2 mutation (17 percent).

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

●Biology – Poly(ADP-ribose) polymerase (PARP) activity is essential for the repair of single-strand DNA breaks via the base excision repair pathway. In homologous recombination repair deficient (HRR) cells the unrepaired DNA breaks that result after treatment with PARP inhibitors eventually can lead to cancer cell death. This process is referred to as "synthetic lethality," in which two conditions that would independently not cause cell death, when present in combination, cause lethal injury to the cell. (See 'Basic biology' above.)

●Somatic and germline genomic testing – All males with advanced metastatic prostate cancer should undergo molecular testing of their tumor and germline DNA to identify potential molecular targets for therapy. (See 'Identifying patients who are likely to respond to PARP inhibitors' above and 'DNA repair and HRR deficiency' above.)

●Treatment for castration-resistant, metastatic prostate cancer with HRR deficiency – Our approach to initial treatment for first-line metastatic castration-resistant prostate cancer (mCRPC) with HRR deficiency takes into account prior treatment for castration-sensitive disease and specific genetic alterations.

•For those who have progressed on prior androgen receptor pathway inhibitors (ARPI), we suggest olaparib rather than chemotherapy or other systemic agents (Grade 2C). However, if a taxane has already been administered for mCRPC, either rucaparib or olaparib may be used. Males with somatic or germline variants of BRCA1 or BRCA2 appear to benefit the most from a PARP inhibitor. We may offer patients with other HRR genes (eg, ATM, CHEK2, CDK12) treatment with a PARP inhibitor as well, recognizing that there are only limited data in this setting, and reported response rates are low (table 1).

-Alternatives to single-agent PARP inhibitors include olaparib plus abiraterone, or enzalutamide plus talazoparib, but the benefit of these combinations in males who have already received a prior ARPI is unclear, as the studies that led to their approval included very few patients who had previously received such an agent. (See 'Patients with prior androgen receptor pathway inhibitors' above.)

•For males who have not received any prior ARPI, we suggest with abiraterone plus olaparib, abiraterone plus niraparib, or enzalutamide plus talazoparib rather than chemotherapy or an ARPI alone (Grade 2C). There has been no direct comparison between the different options so decisions about which agents to use depends on patient comorbidities and mutational status (table 1). It is unclear whether the combination approach is superior to sequential use of an ARPI followed by olaparib. Sequential use therefore is a reasonable alternative in this setting. (See 'Patients without prior androgen receptor pathway inhibitors' above.)

●After ARPI and PARP inhibitor: Platinum-based chemotherapy – Although prospective data are lacking, platinum-based chemotherapy is a reasonable next line option in males with mCRPC with HRR deficiency who have experienced progression on both an ARPI and a PARP inhibitor (either sequentially or concurrently). (See 'Platinum-based chemotherapy' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Nicholas Vogelzang, MD, who contributed as a Section Editor to earlier versions of this topic review.