Version May 2024
INTRODUCTION — Androgen deprivation therapy is a highly effective therapy for males with advanced metastatic prostate cancer, providing at least temporary disease control in the vast majority of cases. However, virtually all patients eventually develop progressive disease. These males are considered to have castration-resistant prostate cancer (CRPC). A number of standard systemic therapies have been shown to prolong survival in this setting (table 1). (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
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. As these cellular pathways are being understood, new potential therapeutic targets are being identified, through molecular testing of both the tumor and the germline, for which there may be targeted agents with activity against advanced disease. 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. (See "Molecular biology of prostate cancer".)
One strategy for treating advanced metastatic CRPC relies on targeting tumors that are deficient in homologous recombination repair (HRR). Genes that are directly or indirectly implicated in HRR include BRCA1, BRCA2, CHEK2, ATM, PALB2, FANCA, and RAD51D, among others. HRR is a DNA repair pathway of clinical interest due to the sensitivity of HRR deficient cells to poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, and potentially platinum-containing chemotherapy.
This topic will review the biology and identification of HRR in males with prostate cancer and will review DNA repair-targeted therapies in metastatic CRPC with HRR deficiency. An overview of therapy for CRPC (both nonmetastatic and metastatic) is provided elsewhere, as is a separate discussion of immunotherapy for CRPC. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)" and "Immunotherapy for castration-resistant 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 (NHEJ) [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 (HBOC). 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-containing chemotherapy' below.)
Poly(ADP-ribose) polymerase (PARP) activity is essential for the repair of single-strand DNA breaks via the base excision repair pathway, which is a primary repair pathway for DNA single-strand breaks [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]. The trapped PARP-DNA complexes are more cytotoxic than unrepaired single-strand breaks caused by PARP inactivation alone [9].
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 castration-resistant prostate cancer (CRPC) and alterations associated with HRR deficiency [10]. For patients without tissue-based genomic testing, treatment may be based on actionable mutations in cell free (circulating tumoral) DNA (ctDNA).
Cancer cells with pathogenic or likely pathogenic variants in BRCA1 or BRCA2 have defective HRR function, and the unrepaired DNA breaks that result after treatment with poly(ADP-ribose) polymerase (PARP) inhibitors eventually can lead to cancer cell death [11,12]. 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 [13,14].
The available evidence suggests that response rates to PARP inhibitors are highest in individuals with germline or somatic BRCA1/2 mutations [15-18]. However, there may be a differential benefit from PARP inhibitor therapy across subgroups with BRCA1/2 alterations [19]. 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 [20,21].
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 [22]. In prostate cancer, these genes include:
●ATM [23,24]
●CHEK2 [24]
●PALB2 [24]
●FANCA [24-26]
●RAD51B [24]
●BRIP1 [24]
The list of genes involved in HRR is far from complete, and the number of prostate cancer cases likely to respond to PARP inhibitors is expected to expand over time [27].
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 [28]. The majority of males with advanced prostate cancer will have been referred for germline genetic testing as this is recommended by several groups, including NCCN 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).
If NGS is chosen, the optimal choice of sample depends on the availability of primary or metastatic tissue, the availability of ctDNA (which is related to high disease burden), or sample availability that is limited to germline DNA from blood (leukocytes) or saliva. The quality of available tissue, including sample age, biopsy site, and tumor purity, impacts sequencing results [29]. 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 [29,30]. (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 [31].
●Archival biopsy/primary tumor tissue, preferably less than five years old [32].
●ctDNA; although assay of ctDNA may miss deletions unless disease burden is high [33].
●Blood or saliva sample (germline-only testing).
The PARP inhibitor rucaparib is approved in the United States for BRCA1/2-mutated CRPC based on the presence of a deleterious BRCA1/2 mutation (germline and/or somatic) in a plasma sample. However, the United States Prescribing Information for rucaparib advises that a negative result for BRCA1/2 mutations from a plasma specimen should prompt further genomic testing using tumor specimens. (See 'Rucaparib' below.)
Furthermore, there is a high frequency of false positives with assay of ctDNA because of interference from clonal hematopoiesis alterations of indeterminate potential (CHIP) [34-37]. This has led to the recommendation that clinical cell-free DNA testing include a paired whole-blood control to exclude CHIP variants [35]. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)
On the other hand, in the United States Prescribing Information for olaparib, the identification of a pathogenic or likely pathogenic germline or somatic variant in one of several genes associated with HRR deficiency from samples derived from tumor, blood, or plasma is permitted for eligibility for males with metastatic CRPC. As with rucaparib, a negative result for pathogenic variants from a plasma specimen should prompt further genomic testing using tumor specimens. (See 'Olaparib' below.)
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:
●Responses to PARP inhibitors are similar for germline and somatic alterations [30,38].
●Germline-only testing will miss almost one-half of BRCA1/2 alterations [29] 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 testing' below and "Immunotherapy for castration-resistant prostate cancer", section on 'PD-1 pathway inhibition'.)
●Germline testing for all males with metastatic prostate cancer is recommended in guidelines from the National Comprehensive Cancer Network (NCCN). (See "Genetic risk factors for prostate cancer", section on 'Who needs referral for genetic evaluation'.)
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 involving 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 [39]. 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 [40-43]. (See "Genetic risk factors for prostate cancer", section on 'Prognostic impact'.)
Somatic testing — There is increasing interest in and use of somatic (tumor) genomic sequencing approaches to 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 'Olaparib' below and 'Rucaparib' below and 'Platinum-containing chemotherapy' below.)
The frequency of somatic alterations affecting HRR genes was explored in a prospective case series of 3476 prostate cancer tissue samples [44]. Overall, 23 percent had potentially actionable alterations in an HRR pathway-related gene.
Do patients need both? — In principle, all patients with germline pathogenic or likely pathogenic variants in a gene associated with HRR should have that same variant detected (if looked for) in the tumor. Targeted tumor testing that identifies a pathogenic variant(s) in such genes might be interpreted as likely somatic or germline, but most tests cannot reliably distinguish between the two, and this may not be reported uniformly by all the different companies that provide this service. Furthermore, pathogenic germline variants (PGVs) may be missed by tumor testing alone 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.
Because of these issues, tumor testing cannot substitute for germline testing in patients for whom a PGV, such as in a gene associated with HRR, might influence treatment decisions; both are complementary:
●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 30.5 percent overall and in 38.5 percent of the prostate cancers [45]. 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 an HRR gene; germline analysis identified only approximately one-half of these patients [29].
BENEFIT OF PARP INHIBITORS — Accumulating data have shown that males with metastatic castration-resistant prostate cancer (CRPC) and a pathogenic variant in an HRR gene may respond to treatment with a poly(ADP-ribose) polymerase (PARP) inhibitor, while continuing androgen deprivation therapy (ADT) with injectable or oral agents (algorithm 1). Of all of the HRR genes involving DNA damage response pathways, BRCA2 variants appear to be associated with the greatest benefit from PARP inhibitors [15,16,18,46]. Several PARP inhibitors (olaparib, talazoparib, and rucaparib) are approved for treatment of males with CRPC and alterations associated with HRR deficiency [47-49]. However, the approval for rucaparib is limited to those with pathogenic variants in BRCA1 or BRCA2, while the approvals for olaparib and talazoparib include several genes that have not individually been shown to predict for responsiveness to PARP inhibition [49,50]. (See "Genetic risk factors for prostate cancer", section on 'DNA repair genes'.)
PARP inhbitor monotherapy, with continuation of ADT
Olaparib — The benefits of olaparib have been shown in several studies, leading to the US Food and Drug Administration (FDA) approval of this agent in May 2020; the indication is for metastatic CRPC with a pathogenic or likely pathogenic variant in a HRR gene in the germline or in the tumor after an androgen receptor pathway inhibitor with or without docetaxel:
●In a landmark early phase I study, the PARP inhibitor olaparib was studied in 49 evaluable males with CRPC; all had received at least two prior regimens for CRPC, and all had received prior docetaxel chemotherapy [23]. All patients had tumor tissue assessed for the presence of abnormalities in a predetermined panel of HRR-associated genes. Abnormalities were detected in 16 patients (33 percent), the most common of which were in BRCA2.
The primary endpoint of the study was a composite response rate that included an objective response (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) in those with assessable disease, a 50 percent or greater decrease in serum prostate-specific antigen (PSA), and/or a decrease in circulating tumor cells. Among the males with an HRR deficiency, 14 (88 percent) had a response based upon these criteria. By contrast, only 1 of 33 (3 percent) without an identified HRR gene abnormality had a response. Radiologic progression-free survival was significantly longer in those with biomarker-positive disease compared with biomarker-negative disease (9.8 versus 2.7 months), as was overall survival (13.8 versus 7.5 months).
●The activity of olaparib was further evaluated in the TOPARB-B study, in which 98 males with metastatic CRPC and a pathogenic variant in an HRR gene (BRCA2 [31 percent], ATM [21 percent], CDK12 [21 percent], PALB2 [7 percent], CHEK2 [5 percent], FANCA [5 percent] and others) were randomly assigned to one of two olaparib doses, 300 or 400 mg, twice daily [25]. At a median follow-up of 25 months, composite responses were slightly more common in the 400 mg dose group (54 versus 39 percent); radiologic response was achieved in 24 percent versus 16 percent; and a 50 percent reduction in PSA was achieved in 37 versus 30 percent. When subgroup analysis was performed according to genetic test findings, the BRCA1/2 subgroup had the highest number of responses and the longest median radiographic progression-free survival. Responses were also noted in the ATM and PALB2 as well as other subgroups, but there were no confirmed responses in the CDK12 subgroup.
●The randomized phase III PROfound trial compared olaparib (300 mg twice daily) versus second-generation hormonal therapy (physician's choice of abiraterone or enzalutamide) in 387 males with metastatic CRPC; all had alterations in any of 15 predefined genes with direct or indirect roles in HRR (245 males with pathogenic variants in BRCA1, BRCA2, or ATM [cohort A; the primary cohort] and 142 males with alterations in other genes [cohort B]) [51,52]. FANCA was not included. All 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.
The olaparib-treated males in cohort A (pathogenic variants in BRCA1/2 or ATM) had significantly longer median radiographic progression-free survival (7.4 versus 3.6 months, hazard ratio [HR] 0.34, 95% CI 0.25-0.47), and they also had a higher objective response rate (33 versus 2 percent) [51]. Benefits persisted when both cohorts were included in the analysis, although they were less prominent (median radiographic progression-free survival 5.8 versus 3.5 months). In a later analysis, despite substantial crossover from control therapy to olaparib, survival was substantially improved for both cohorts (cohort A: median 19.1 versus 14.7 months; cohort B: median 14.1 versus 11.5 months); for the entire population, the corresponding durations were 17.3 and 14 months [52]. A sensitivity analysis that adjusted for crossover to olaparib showed an HR for death of 0.42 (95% CI 0.19-0.91) for cohort A, 0.83 (95% CI 0.11-5.98) for cohort B, and 0.55 (95% CI 0.29-1.06) for the overall population.
In exploratory gene level analysis, the median overall survival benefit for initial olaparib among the 128 males with BRCA2 mutations was 24.8 versus 15.2 months (HR 0.59, 95% CI 0.37-0.95), while for the small group of individuals with BRCA1 mutations (n = 13), the corresponding values were 11.7 versus 9.4 months (HR 0.42, 95% CI 0.12-1.53), and for those with ATM mutations (n = 86), the values were 18 versus 15.6 months (HR 0.93, 95% CI 0.53-1.75). The HR for death for those with an alteration in any non-BRCA gene, after adjustment for crossover, was 0.82 (95% CI 0.25-2.68).The authors concluded that among males with metastatic CRPC who had tumors with at least one alteration in BRCA1, BRCA2, or ATM, and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to olaparib had a significantly longer survival duration than did those receiving enzalutamide or abiraterone.
In the original report, the most common adverse events with olaparib were anemia (46 versus 15 percent for hormone therapy), nausea (41 versus 19 percent), anorexia (30 versus 18 percent), and fatigue/asthenia (41 versus 32 percent) [51]. Mostly, these are low grade, and generally manageable without the need for treatment discontinuation [53]. 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 second-generation hormonal therapy [54,55].
A later analysis of 181 cohort A patients who gave consent for plasma sample ctDNA testing revealed that 139 (77 percent) were informative, and BRCA/ATM alterations were identified in 111 (79.9 percent of the informative tests), and the benefits of olaparib in this subgroup were comparable to those seen in the entire cohort A group [56].
This trial was criticized by some for having a control arm (clinician choice of enzalutamide or abiraterone) that allowed only a class of drugs that the patient had already received prior to protocol enrollment and was known to have generally limited benefit [57]. Nevertheless, largely based upon these data, on May 19, 2020, the FDA approved olaparib for adults with metastatic CRPC who have disease progression following treatment with enzalutamide or abiraterone and have a germline or somatic pathogenic variant in an HRR gene, based on testing of one or more of the following [47,58]:
•Tumor tissue – ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L
•Germline (via testing of lymphocytes from blood) – BRCA1 or BRCA2
•Circulating tumor DNA (ctDNA; via a plasma assay) – ATM, BRCA1 or BRCA2 mutations
The approved dose is 300 mg twice daily. Notably, this agent can be offered to metastatic CRPC patients independently of prior taxane chemotherapy use.
An important point is that the broad approval for olaparib includes several genes other than BRCA that, to date, have not individually been shown to predict for response to PARP inhibition, including ATM, CDK12, and CHEK2 [59]. One unintended consequence of using such a permissive biomarker strategy for selecting patients for a PARP inhibitor may be that patients who have an unclear chance of benefit are exposed to toxicities and delays in receiving more effective therapies [50]. In addition, this broad approval could hamper efforts to enroll patients in studies designed to better delineate the ability of relatively rare mutations to predict response to PARP inhibitors.
●Additional data on the benefit of olaparib in BRCA1/2-mutated prostate cancer are available from the TAPUR study [60]. Of 25 evaluable patients who were heavily pretreated, nine had objective responses (36 percent) and eight had stable disease for 16 weeks or longer (overall disease control rate, 68 percent).
Rucaparib — The benefit of rucaparib has been shown for BRCA1/2-mutated metastatic CRPC with some evidence of benefit for BRCA-related genes that are less commonly altered.
●BRCA-mutated cancers – The radiographic benefit of rucaparib for BRCA1/2 mutated metastatic CRPC was confirmed in the randomized TRITON3 study, where patients with metastatic CRPC harboring a BRCA1, BRCA2, or ATM alteration who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI) but had not received a taxane for CRPC were randomly assigned to rucaparib or a clinician's choice control (docetaxel or a second generation ARPI, either abiraterone acetate or enzalutamide) [61]. In the BRCA1/2 subgroup, the median duration of imaging-based progression-free survival (PFS) was longer with rucaparib than control (11.2 months versus 6.4 months, respectively, HR 0.50, 95% CI 0.36-0.69). The most frequent adverse events with rucaparib were fatigue and nausea. The PFS benefit was observed both when an ARPI was investigated as the control arm and when docetaxel was investigated as the control arm.
These results are consistent with the previous single-arm TRITON2 study, 157 males with CRPC and HRR deficiency (as determined by germline testing, next-generation sequencing of tumor tissue, or assay of ctDNA) received rucaparib at a dose of 600 mg twice daily. In an analysis of the 115 males with BRCA1/2-mutated CRPC, 62 of whom had measurable disease, the confirmed objective response rate by blinded independent review was 44 percent, and the median duration of response was not reached at the time of data review [38]. The PSA response rate was 63 percent. The median duration of radiographic PFS was nine months. There was no clear difference in response rate for germline or somatic alterations in BRCA2/BRCA1.
Based on these data, the FDA granted accelerated approval to rucaparib for patients with metastatic CRPC and deleterious BRCA1/2 mutations (germline and/or somatic), who have previously been treated with androgen receptor-directed therapy and taxane-based chemotherapy [48,62].
●HRR deficient cancers without BRCA alterations – In a separate analysis of the TRITON2 study, a small number of radiographic and PSA responses were described for males with non-BRCA alterations associated with HRR directly or indirectly [24]. Among males evaluable for each endpoint, radiographic and PSA response rates were observed in only 2 of 19 (10.5 percent) and 2 of 49 (4.1 percent) males with ATM mutations, 0 of 10 and 1 of 15 (6.7 percent) of those with CDK12 mutations, and in 1 or 9 (11.1 percent) and 2 of 12 (16.7 percent) of those with CHEK2 mutations. On the other hand, responses were observed in males with alterations in the DNA damage repair genes PALB2, FANCA, BRIP1, and RAD51B, although the number of patients enrolled with these rare alterations was limited. Likewise, a radiographic PFS benefit was not observed in the ATM-altered metastatic CRPC population in TRITON3.
Niraparib — Niraparib is a third PARP inhibitor that has been evaluated in metastatic CRPC. In a phase I dose escalation study, niraparib showed activity in prostate cancer patients with pathogenic variants in BRCA1 or BRCA2 [63]. The utility of niraparib in males with metastatic CRPC and HRR gene abnormalities was addressed in the phase II GALAHAD trial [64]. All males had previously received docetaxel and next-generation androgen receptor-targeted therapies. At a median follow-up of 10 months, the objective response rate in those with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 and measurable disease (n = 76) was 34.2 percent (2 complete and 24 partial), and the median response duration was 5.55 months. Among the 47 patients with measurable disease and other non-BRCA HRR alterations, the objective response rate was 10.6 percent (5 partial responses). All secondary endpoints, including radiographic progression-free survival, overall survival, time to radiographic progression, time to PSA progression, and duration of objective response generally favored the BRCA compared with the non-BRCA cohort, which included individuals with deleterious variants in ATM, BRIP1, CHEK2, FANCA, HDAC2, and PALB2. In the overall BRCA cohort (n = 142), 12- and 24-month event-free survival rates were 56 and 15 percent, respectively; while in the non-BRCA cohort (n = 81), the corresponding rates were 41 and 11 percent, respectively. 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.
Notably, the response rate in the BRCA1/2 group was not higher than seen in comparable studies of other PARP inhibitors (eg, TRITON2, TALAPRO-1) implying that requiring biallelic loss of function of these genes does not improve patient selection for PARP inhibitor therapy.
Talazoparib — The benefit of talazoparib was assessed in the phase II TALAPRO-1 study, conducted in 128 males with metastatic CRPC and DNA damage repair mutations who had previously received one or two prior chemotherapy regimens [65]. 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 progression-free survival 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 [66].
PARP inhibitor combinations — There is interest in combinations of PARP inhibitors with androgen receptor signaling inhibitors in metastatic CRPC.
First-line metastatic castration-resistant disease — Olaparib and niraparib both have regulatory approval by the FDA for use in combination with abiraterone with BRCA mutated, metastatic CRPC [67,68]. These approvals were based on the results of the PROPEL and MAGNITUDE trials. Ideally, one of these combinations (olaparib and abiraterone or niraparib and abiraterone) is administered to patients reaching the metastatic CRPC state who have not previously received treatment with abiraterone or enzalutamide.
Several trials have investigated the role of a PARP inhibitor combination for first-line therapy of metastatic CRPC, after failure of ADT alone, all of which suggest a PFS benefit for patients with BRCA1/2 alterations, but only one has demonstrated overall survival benefits with this approach:
●Overall survival data are available from the PROPEL trial, in which 796 males with metastatic CRPC 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 [69]. Docetaxel was allowed if administered for metastatic castration-sensitive prostate cancer, and a prior next-generation hormonal was permitted, although few patients received one. The addition of olaparib was associated with a significant prolongation in median radiographic PFS (median 24.8 versus 16.6 months; HR 0.66, 95% CI 0.54-0.81). In predefined subgroup analysis, the benefit of olaparib was seen 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) [68].
●A PFS benefit from combining niraparib plus abiraterone for first-line treatment of metastatic CRPC was shown in the MAGNITUDE trial [70]. In this phase III placebo-controlled multicenter trial patients with first-line metastatic CRPC 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 next-generation hormonal agent 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 improved the time to radiographic disease progression or death (median 16.5 versus 13.7, p = 0.0217). In the subgroup with BRCA1/2 alterations, the benefit was larger (median 16.6 versus 10.9 months, p = 0.0014). Overall survival data were not mature at the time of presentation (median follow-up 18.6 months).
●A PFS benefit from combining talazoparib plus enzalutamide for first-line treatment of metastatic CRPC was shown in the TALAPRO-2 trial. In this phase III placebo-controlled multicenter trial, patients with first-line metastatic CRPC were randomly assigned to enzalutamide with either talazoparib or placebo [71]. Like PROPEL and MAGNITUDE, docetaxel for metastatic castration-sensitive prostate cancer was permitted, as was a prior next-generation hormonal agent for castration-sensitive prostate cancer or non-metastatic CRPC (although only 6 percent of patients received one). The study met its primary endpoint of prolonged radiographic PFS in the talazoparib arm. The benefit was most pronounced for patients with HRR gene mutations, although a lesser radiographic PFS benefit was also observed in patients without HRR mutations identified via prospective tumor testing. As of last reporting, overall survival data were immature.
●The BRCAAWAY trial directly compared abiraterone, olaparib, or abiraterone plus olaparib for first-line treatment of metastatic CRPC in 161 patients with a germline or somatic HRR defect in BRCA1, BRCA2, or ATM [72]. As reported at the 2022 ASCO annual meeting, the combination of abiraterone plus olaparib was well tolerated and resulted in longer 12-month PFS, 95 percent (95% CI 0.85-1.0) versus 42 percent (95% CI 0.22-0.80) for abiraterone (unadjusted HR for combined therapy versus abiraterone 0.19, 95% CI 0.06-0.61) and 44 percent (95% CI 0.25-0.76) with olaparib alone (unadjusted HR for combined therapy versus olaparib alone 0.14, 95% CI 0.04-0.43). The rate of undetectable PSA also favored combined therapy (37 versus 24 and 24 percent). Overall survival was not reported.
Previously treated metastatic castration-resistant disease — The benefits of combining an androgen signaling inhibitor such as abiraterone with a PARP inhibitor in patients with HRR deficiency who were previously treated for metastatic CRPC remain uncertain, and we do not offer combined therapy outside of a clinical trial.
●Preclinical studies suggesting that PARP inhibition diminishes androgen receptor (AR) activity and sensitizes prostate cancer cells to both DNA damage and androgen depletion [73] prompted a phase II randomized trial comparing abiraterone plus prednisone versus abiraterone plus prednisone and veliparib in 148 males with metastatic CRPC who had received up to two prior chemotherapy regimens [74]. There were no significant differences in PSA response rate (72 versus 64 percent) or in progression-free survival (11 versus 10.1 months) with the addition of veliparib. A defect in an HRR gene was present in 20 of 75 evaluable patients (27 percent), and in these patients, the differences in the PSA response rates (90 versus 56 percent) and the measurable disease response rates (88 versus 38 percent) were significantly better with combined therapy.
●Additionally, the benefit of combined therapy with olaparib plus abiraterone was addressed in a double-blind phase II trial in which 142 males with biomarker-unselected metastatic CRPC were randomly assigned to abiraterone plus either olaparib or placebo [75]. All males had received prior docetaxel chemotherapy for metastatic CRPC. Post hoc analysis for HRR deficiency revealed pathogenic variants in the germline, tumor, or ctDNA in 15 percent of cases; pathogenic variants were not identified in 25 percent, and genes were only partially characterized in 61 percent. Combining abiraterone with olaparib significantly improved radiographic progression-free survival compared with abiraterone alone (median 13.8 versus 8.2 months, HR 0.65, 95% CI 0.44-0.97).
In the overall genomically unselected population, there was significantly more treatment-related toxicity with combined therapy. Grade 3 or 4 adverse events were more common with combined therapy (54 versus 28 percent), especially anemia (21 versus 0 percent), pneumonia (6 versus 4 percent), and myocardial infarction (6 versus 0 percent).
Given the common shared toxicity of cytopenias, it has been challenging to combine poly(ADP-ribose) polymerase (PARP) inhibitors with cytotoxic chemotherapy. At least one trial failed to demonstrate benefit for veliparib plus temozolomide in an unselected population of CRPC [76]. This, as well as the negative experience of combining PARP inhibitors and chemotherapy agents in other cancers, has tempered enthusiasm to investigate such combinations in the metastatic CRPC setting.
PLATINUM-CONTAINING CHEMOTHERAPY — Although prospective data are lacking, the use of platinum-based chemotherapy is a reasonable option in males with metastatic castration-resistant prostate cancer (CRPC) and pathogenic or likely pathogenic variant in an HRR gene. The available data are more robust for BRCA2 than for those with other HRR alterations.
In vitro, platinum sensitivity is a feature of HRR-deficient cells [77], 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' and "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'Incorporation of carboplatin'.)
In unselected males with metastatic CRPC, platinum-based chemotherapy confers palliative benefit, with some objective responses and longer progression-free survival in phase II studies, but it is not clear that overall survival is improved [78-81]. 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 metastatic CRPC, 64 of whom were taxane refractory and poly(ADP-ribose) polymerase (PARP) inhibitor naïve [82]. Within this subset, 16 had somatic or germline HRR gene alterations, and these patients had a sevenfold higher likelihood of having a decline in prostate-specific antigen (PSA) of 50 percent or more, although there was no survival advantage. Of the eight patients with an 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 [83]. 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 men.
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 metastatic CRPC and a germline BRCA2 mutation, six of whom (75 percent) had a >50 percent PSA decline within 12 weeks of starting carboplatin plus docetaxel [84]. This rate was substantially higher than the PSA response rate of 133 noncarriers to this same combination (23 of 133, 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
●Somatic and germline genomic testing – All males with advanced metastatic prostate cancer who might be candidates for targeted therapy should undergo molecular testing of their tumor and germline DNA to identify potential molecular targets for therapy.
One strategy for treating advanced castration-resistant prostate cancer (CRPC) relies on targeting tumors that are deficient in homologous recombination repair (HRR). HRR is a DNA repair pathway of clinical interest due to the sensitivity of HRR-deficient cells to poly(ADP-ribose) polymerase (PARP) inhibitors, and potentially to platinum-containing chemotherapy. Deficient HRR can result from pathogenic variants in BRCA1, BRCA2, PALB2, and RAD51D. Pathogenic variants in other genes such as ATM, CHEK2, and FANCA, which also play a role in HRR, may also be relevant. (See 'DNA repair and HRR deficiency' above.)
Several types of samples can be used to identify HRR alterations using next-generation sequencing:
•Fresh biopsy of a metastatic lesion, which is preferred, if feasible
•Archival biopsy/primary tumor tissue
•Circulating tumor DNA
•Blood or saliva (to identify germline variants)
●PARP inhibitors – HRR deficiency in the tumor or germline DNA identifies males who might benefit from treatment with a PARP inhibitor (algorithm 1). Initial treatment for castration-sensitive prostate cancer and CRPC is similar to that of individuals who do not have HRR deficiency. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer" and "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
Of all the HRR genes involving DNA damage response pathways, males with somatic or germline pathogenic variants in BRCA2 appear to benefit the most from a PARP inhibitor. Nevertheless, treatment with a PARP inhibitor could be considered for all males with a pathogenic or likely pathogenic variant in an HRR gene (especially BRCA1, BRCA2, or PALB2), as additional gene-specific response data emerges. (See 'Benefit of PARP inhibitors' above.)
•BRCA variants
-For males with metastatic CRPC who previously received an androgen receptor signaling inhibitor, we suggest olaparib monotherapy rather than other treatments (Grade 2C). Patients on PARP inhibitor monotherapy are generally continued on androgen deprivation therapy with injectable or oral agents. For those who also received a taxane, rucaparib is an acceptable alternative. For males with first-line metastatic CRPC who are naïve to an androgen receptor signaling inhibitor, acceptable options include the combinations of olaparib or niraparib plus abiraterone or enzalutamide/talazoparib. (See 'PARP inhibitor combinations' above.)
•Other variants – For males with pathogenic or likely pathogenic variants in other HRR genes (ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L), irrespective of prior taxane use, we suggest consideration of olaparib, with the understanding that gene-level response data are limited, and that low response rates have been reported for some of these genes (eg, ATM, CHEK2, CDK12) that have varying biologic roles in HRR. (See 'Olaparib' above.)
●Platinum chemotherapy – Although prospective data are lacking, the use of platinum-based chemotherapy is a reasonable alternative in males with metastatic CRPC and HRR alterations. The available data are more robust for individuals with pathogenic variants in BRCA2 than for those with other HRR alterations. (See 'Platinum-containing chemotherapy' above.)
ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.
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