Abstract: Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as an important therapeutic option for patients with homologous recombination repair (HRR)–deficient cancers, especially those with BRCA1/2 mutations. Since the initial US Food Administration approval of olaparib in 2014, PARP inhibitors have shown efficacy across ovarian, breast, and prostate cancers, although differences in trial design and biomarker strategies have resulted in tumor-specific indications. Homologous recombination deficiency (HRD) arises from germline or somatic mutations in HRR genes or from epigenetic inactivation, and it can be assessed through genomic “scars” such as loss of heterozygosity and mutational signatures. Although BRCA1/2 alterations confer the strongest sensitivity to PARP inhibitors, non-BRCA HRR gene mutations demonstrate heterogeneous responses, highlighting the need for more precise HRD assessment, including the role of biallelic vs monoallelic inactivation. Despite initial success, both primary and acquired resistance—through reversion mutations, replication fork stabilization, and therapy-induced clonal hematopoiesis—limit the durability of the response to PARP inhibition. Ongoing studies are evaluating rational combinations targeting complementary DNA damage response pathways (ATR/CHK1/WEE1, PI3K/AKT) and integrating immunotherapy or hormonal agents to extend benefit. Moving forward, harmonizing HRD testing across tumor types, accounting for germline, somatic, and liquid biopsy–derived alterations, and refining patient selection will be essential to maximize therapeutic efficacy and safely expand PARP inhibitor use beyond canonical BRCA-mutated cancers.
Introduction
The first poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (Lynparza, AstraZeneca), was approved in 2014 for patients who had advanced ovarian carcinoma with germline BRCA1/2 mutations. Since then, the clinical use of PARP inhibitors has been studied in various cancer types and stages.1 The use of PARP inhibitors in solid tumor malignancies like ovarian, breast, and prostate cancers has been shown to be effective for patients with pathogenic mutations in BRCA and other genes involved in homologous recombination repair (HRR). Although the mechanisms of action of various PARP inhibitors remain grossly the same, differences in clinical trial design have contributed to distinct indications for each of the drugs. Further, data regarding toxicity and resistance patterns are emerging that suggest that drugs in this family can differ in regard to normal tissue tolerance as well as resistance mechanisms. In addition to exploring the prevalence of homologous recombination deficiency (HRD) in ovarian, breast, and prostate cancers, this review examines currently approved uses of PARP inhibitors to treat these malignancies, highlighting the differences among tumor types. Additionally, it addresses key challenges in optimizing PARP inhibitor therapy, including pinpointing the ideal patient populations most likely to benefit, understanding the mechanisms behind emerging drug resistance, and exploring the potential for expanding PARP inhibitor applications beyond cancers with pathogenic HRR gene mutations.
PARP Mechanism of Action
PARPs are a family of 17 enzymes involved in cellular stress responses, chromatin remodeling, DNA repair, and apoptosis. Among them, PARP1 and PARP2 detect and repair single-strand DNA breaks through base excision repair and other pathways, such as nucleotide excision repair and nonhomologous end joining.2 When these enzymes sense DNA damage, their catalytic activity relaxes chromatin and recruits repair machinery to the site of injury.
In cancers such as breast, ovarian, and prostate cancers, loss or dysfunction of HRR genes (eg, BRCA1/2) through mutation, epigenetic silencing, or genomic alteration creates HRD.3 These tumors rely on alternative repair mechanisms, including PARP-mediated base excision repair. Inhibition of PARP1/2 leads to an accumulation of single-strand breaks that collapse into double-strand breaks during replication. In HRD cells unable to repair such lesions, PARP inhibition results in synthetic lethality and tumor cell death. PARP inhibition also promotes error-prone nonhomologous end joining, further enhancing cytotoxicity.
By exploiting synthetic lethality in HRD tumors, PARP inhibitors selectively target cancer cells while sparing normal tissue—a strategy that has revolutionized treatment for ovarian, breast, and prostate cancers during the past decade.4
HRD Prevalence and Measurement
BRCA1 and BRCA2 play central roles in HRR, and their loss through germline or somatic mutation, chromosomal rearrangement, or epigenetic silencing is the most studied cause of HRD in breast, ovarian, and prostate cancers.5 Pathogenic alterations in other HRR genes (eg, PALB2, ATM, CHEK2, ARID1A, ATRX) can also produce HRD phenotypes. In a molecular profiling study of more than 17,000 solid tumors, HRR gene mutations were detected in 17.4% of cases—most frequently in ARID1A (7.2%), BRCA2 (3.0%), BRCA1 (2.8%), ATM (1.3%), ATRX (1.3%), and CHEK2 (1.3%).5 Ongoing trials continue to define the predictive value of non-BRCA HRR genes for PARP inhibitor response.6,7
HRD can be assessed by identifying its causes (deleterious HRR gene alterations via germline or somatic sequencing) or its effects (the genomic “scars” that reflect defective HRR).3,8 These scars—loss of heterozygosity (LOH), telomeric allelic imbalance, large-scale state transitions, and mutational signatures such as SBS3—form the basis of composite HRD scores (eg, the MyChoice CDx HRD test).8-11,12 However, all HRR gene mutations do not confer equivalent HRD, and genomic scars may persist even after HRR function is restored (eg, via BRCA reversion mutations).5-6 Thus, although HRD assays provide valuable insights, their predictive accuracy for therapeutic sensitivity to PARP inhibitors is constrained by tumor heterogeneity, assay variability, and the potential for acquired resistance mechanisms.
Ovarian Cancer
Approximately 41% to 50% of ovarian carcinomas exhibit HRD due to either genetic or epigenetic alterations of HRR pathway genes, particularly serous and endometrioid histologic subtypes.13-14 The Cancer Genome Atlas (TCGA) project has consistently shown that high-grade serous ovarian cancers are characterized by frequent genetic and epigenetic alterations of HRR pathway genes, most commonly the BRCA1 and BRCA2 genes.15 The TCGA demonstrated an 8.5% prevalence of germline BRCA1 mutations and a 6.3% prevalence of BRCA2 mutations. Similarly, the prevalence of somatic BRCA1 mutations was 3.2% and the prevalence of somatic BRCA2 mutations was 2.9%. The frequency of both germline and somatic changes (mutation, deletion, or amplification) in non-BRCA HRR genes in ovarian carcinoma is much lower and more heterogeneous.
Breast Cancer
Germline BRCA1 and BRCA2 mutations account for up to 7% of all breast cancers and have been found in approximately 11% to 15% of patients with triple-negative breast cancer (TNBC).16-18 BRCA1 mutations are most commonly associated with the TNBC clinical subtype, whereas BRCA2 mutations are more frequently associated with estrogen receptor (ER)–positive tumors.19 Additional germline mutations in other non-BRCA1/2 HRR-related genes (eg, PALB2, ATM, CHEK2, BARD1, and RAD51D) have been associated with an increased risk of breast cancer. In a study of more than 113,000 women with breast cancer, both ATM and CHEK2 were more strongly associated with ER-positive breast cancers.19 In contrast, BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D were more strongly associated with ER-negative disease.19 In more recent studies, both functional and genomic metrics of HRD have been used to assess HRD in breast cancer; stricter HRD criteria were found to have a higher concordance with BRCAness, high tumor-infiltrating lymphocyte density, or high programmed death ligand 1 expression among both TNBC and non-TNBC subtypes, suggesting that a more refined definition of HRD could help predict functional HRD more precisely.20
Prostate Cancer
Deleterious genomic abnormalities in HRR genes have been described in 10% of patients with localized prostate cancer and up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC).21 Of those patients, approximately 8% to 12% with advanced prostate cancer harbor a germline mutation in a gene associated with DNA repair.21 The most commonly altered genes in the HRR pathway in advanced prostate cancer include BRCA1 or BRCA2 (11%-13%), ATM (4%-6%), CHEK2 (1.4%-2%), CHEK1 (0.9%-2%), CDK12 (1.3%-8%), PALB2 (0.3%-3%), BARD1 (1.2%-1.4%), and FANCL (1.2%).23 Marshall and colleagues found that these alterations are significantly enriched in tumors with relatively aggressive pathologic features; men with Gleason grade group 3 or higher or pathologic stage pT3 to pT4 disease were roughly twice as likely to carry HRR mutations as were men with lower-grade or earlier-stage disease.24 When both a high Gleason grade and advanced pathologic stage were present, the prevalence rose to higher than 20% for any HRR gene mutation and nearly 12% for a BRCA1/2 or ATM mutation. In contrast, clinical T stage and nodal status were not strongly associated with mutation prevalence. These findings suggest that even in patients with localized disease, higher-risk pathologic features may help identify those most likely to benefit from DNA repair gene testing and potentially HRR-targeted therapies.
Currently Approved Clinical Indications for PARP Inhibitors
Ovarian Cancer
The concept of synthetic lethality between BRCA-mutated cells and PARP inhibition was first demonstrated in 2005 and was led to clinical translation with Study 42. This phase 2 trial of olaparib in heavily pretreated patients with BRCA1/2-mutated ovarian cancer showed an overall response rate of 34% and resulted in the first US Food and Drug Administration (FDA) approval of a PARP inhibitor in 2014.2,25-26 Subsequent approvals for rucaparib (Rubraca, Clovis Oncology) and niraparib (Zejula, GSK) followed in both the first-line and recurrent settings.
Three phase 3 trials—SOLO-1 (olaparib, 2018),27 PRIMA (niraparib, 2019),28 and ATHENA-MONO (rucaparib, 2022)29—established first-line maintenance PARP inhibitor benefit in stage III to IV ovarian, peritoneal, or fallopian tube cancers responding to platinum therapy. SOLO-1 enrolled patients with BRCA-mutated tumors, whereas PRIMA and ATHENA-MONO included patients with all biomarker groups; all studies showed significant improvement in progression-free survival (PFS), particularly among patients with BRCA-mutated or HRD-positive tumors, leading to FDA approvals of olaparib and niraparib for first-line maintenance. In PAOLA-1,30 olaparib plus bevacizumab further improved PFS and overall survival (OS) in HRD-positive patients, resulting in approval of the combination regimen; similar findings were observed with niraparib plus bevacizumab in OVARIO.31
In the setting of recurrent, platinum-sensitive disease, olaparib gained approval as maintenance monotherapy on the basis of Study 19 and SOLO-2, followed by niraparib (NOVA) and rucaparib (ARIEL3).32-35 Initial approvals spanned all biomarker groups, but updated analyses showed that OS benefit was limited to BRCA-mutated cohorts. This finding prompted label restrictions of niraparib and rucaparib in 2022 to relapsed, platinum-sensitive, germline BRCA-mutated ovarian cancers.36-37
For later-line therapy, olaparib (Study 42), rucaparib (ARIEL2), and niraparib (QUADRA) initially received approvals for BRCA-mutated or HRD-positive recurrent disease.2,38-39 However, final OS analyses from SOLO-3 and ARIEL4 suggested diminished or adverse survival outcomes with PARP inhibition vs chemotherapy in heavily pretreated patients, leading to the voluntary withdrawal of these later-line monotherapy indications.40-41 Table 1 summarizes the current FDA approvals of PARP inhibitors for patients with advanced ovarian cancer.
Breast Cancer
At present, the FDA has approved two PARP inhibitors for the treatment of breast cancer: olaparib and talazoparib (Talzenna, Pfizer). The OlympiAD trial evaluated olaparib monotherapy vs single-agent chemotherapy in patients with a germline BRCA mutation and human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer who had received no more than 2 prior chemotherapy regimens for metastatic disease.42 Median PFS was significantly longer with olaparib than with chemotherapy (7.0 vs 4.2 months). In the final OS analysis, however, no significant difference was detected in median OS in a comparison of olaparib vs chemotherapy. OS benefit was greater for patients treated with olaparib in the first-line metastatic setting than for those in a later-line setting. The results of this study led to the FDA approval of olaparib monotherapy in germline BRCA-mutated, HER2-negative metastatic breast cancer in January 2018. More recently, the National Comprehensive Cancer Network (NCCN) guidelines now include the use of PARP inhibition for HER2-negative metastatic breast cancer with somatic BRCA1/2 or germline PALB2 mutations on the basis of the TBCRC 048 study.7
Similarly, the subsequent EMBRACA study compared talazoparib monotherapy with standard-of-care therapy in patients who had advanced breast cancer harboring a germline BRCA mutation and who had received no more than 3 prior chemotherapy regimens for advanced breast cancer.43 Median PFS was longer in the talazoparib group than in the standard-of-care group (8.6 vs 5.6 months), leading to the approval of talazoparib for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated HER2-negative breast cancer in October 2018. Talazoparib did not improve OS in comparison with standard-of-care therapy; however, a significant improvement in health-related quality of life and a delay in time to deterioration were noted.
In the adjuvant setting, the phase 3 OlympiA trial evaluated 1 year of olaparib monotherapy vs placebo after chemotherapy in patients with high-risk HER2-negative breast cancer harboring a germline BRCA mutation.44 Olaparib reduced the risk of recurrence (4-year invasive disease–free survival rate, 83% vs 75%; hazard ratio [HR], 0.63 [95% CI, 0.50-0.78]; P<.001) and demonstrated a 32% reduction in risk of death (4-year OS, 90% vs 86%; HR, 0.68 [95% CI, 0.47-0.97]; P=.01).45 In 2022, these results led to the approval of olaparib for the adjuvant treatment of patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative, high-risk early breast cancer who had been treated with neoadjuvant or adjuvant chemotherapy.
Prostate Cancer
In 2020, rucaparib was the first PARP inhibitor approved for mCRPC after the phase 2 TRITON2 trial demonstrated robust activity in patients with BRCA-mutated disease: prostate-specific antigen (PSA) responses in 52% and RECIST responses in 44% of evaluable patients.46 The subsequent phase 3 TRITON3 trial confirmed these findings, supporting the role of rucaparib in this setting.47
The phase 3 PROfound trial compared olaparib with physician’s choice of enzalutamide (Xtandi, Astellas) or abiraterone in patients with HRR gene–mutated mCRPC that had progressed on prior androgen receptor (AR) pathway inhibitors.48 Olaparib significantly improved radiographic PFS (18.5 vs 15.1 months) and OS49, particularly among those with BRCA1/2 or ATM mutations50, leading to its FDA approval for mCRPC with deleterious HRR alterations in genes beyond BRCA (ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L).
Building on preclinical synergy between PARP inhibition and AR blockade, PARP inhibitor/AR pathway inhibitor combinations have been evaluated as first-line therapy.51 In PROpel, olaparib plus abiraterone and prednisone (AAP) prolonged radiographic PFS in comparison with AAP alone in all-comers,52 although OS benefit was seen mainly in patients with BRCA-mutated tumors—prompting the 2023 FDA approval of olaparib plus AAP for BRCA-mutated mCRPC.53 Similarly, MAGNITUDE demonstrated improved PFS with niraparib plus AAP in patients with BRCA mutations but not in subgroups with other HRR gene mutations or without HRR gene mutations, so that approval was restricted to BRCA-mutated mCRPC.54-55
Finally, TALAPRO-2 evaluated talazoparib plus enzalutamide vs enzalutamide alone in mCRPC, showing a significant radiographic PFS improvement, with the greatest benefit in patients with HRR gene–mutated tumors.56-57 This resulted in the FDA approval of talazoparib plus enzalutamide for patients with deleterious alterations in at least one of 12 HRR genes (BRCA1/2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, and CDK12).58 Table 2 summarizes all currently FDA-approved PARP inhibitors for patients with advanced prostate cancer.
The clinical development of PARP inhibitors has yielded differing indications across ovarian, breast, and prostate cancers, largely reflecting nuances in trial design. In ovarian cancer, early pivotal studies such as SOLO-127 and ARIEL259 prospectively incorporated both BRCA status and functional HRD assays, establishing efficacy not only in BRCA-mutated tumors but also in genomically unstable, BRCA wild-type subgroups.35 In breast cancer, by contrast, registration trials were restricted to patients with germline BRCA mutations, and exploratory studies such as TBCRC 048 demonstrated that responses were far more limited in patients with non-BRCA HRR gene alterations, reinforcing a narrower approval.7 Prostate cancer trials such as PROfound and TALAPRO-2 employed broader gene panels that included BRCA1/2, ATM, and other HRR genes, which led to approvals encompassing multiple DNA damage response alterations—although subgroup analyses consistently showed that clinical benefit was most pronounced in BRCA2-mutated disease.48,50-52 Collectively, these differences underscore how eligibility criteria, biomarker strategies, and prespecified subgroups in trial design directly shaped the regulatory landscape, resulting in PARP inhibitor indications in ovarian and prostate cancers broader than the more selective approvals in breast cancer.
Current Challenges and Future Directions: Defining HRD
As is evident from the variable subgroup analyses and subsequent regulatory approvals of PARP inhibitors based on trial design, one of the major challenges in PARP inhibitor use remains developing a consensus regarding HRD definition so that the patients most likely to benefit from this therapy can be selected more accurately.
BRCA vs Non-BRCA Mutations
Ovarian Cancer. It is generally thought that deleterious mutations of BRCA1 or BRCA2 confer some form of HRD. Therefore, early clinical trials assessing the use of PARP inhibitors in ovarian cancer often focused primary analysis or exploratory subgroup analysis on BRCA mutation status, as seen in the SOLO-1 trial or Study 42.27,60 These studies concluded that patients with a non-BRCA HRR gene–mutated tumor derived benefit from PARP inhibitor treatment vs placebo, although to a lesser extent than those with a BRCA-mutated tumor. Other randomized controlled trials investigating the use of PARP inhibition in ovarian cancer also evaluated patients on the basis of functional HRD status. In the ARIEL2 trial, in addition to BRCA mutation status, patients were assessed for percentage of genomic LOH in pretreatment biopsy specimens to provide an overall prediction of sensitivity to rucaparib.34, 38 The FoundationOne NGS assay (Foundation Medicine) was used to stratify participants into 3 predefined HRD subgroups: tumor BRCA-mutated, BRCA wild-type/LOH-high, and BRCA wild-type/LOH-low.59 Similarly, in both QUADRA and PAOLA-1, in addition to determining tumor BRCA mutation status, the MyChoice HRD Plus assay (Myriad Genetic Laboratories) was used to determine a prespecified tumor HRD status retrospectively before primary analysis; a positive test result was defined as a tumor BRCA mutation and/or a genomic instability score of at least 42.39,61
Breast Cancer. The PARP inhibitors olaparib and talazoparib are currently approved for the treatment of HER2-negative breast cancers in the metastatic and adjuvant settings only for patients harboring a germline BRCA1/2 mutation. That said, the phase 2 TBCRC 048 trial sought to assess the efficacy of olaparib in patients who had metastatic breast cancer with a germline or somatic mutation in a non-BRCA HR-related gene or with a somatic BRCA1/2 mutation. Of the 54 patients enrolled, 87% had mutations in PALB2 (germline), BRCA1/2 (somatic), ATM (germline), or CHEK2 (germline).7 Confirmed responses to olaparib monotherapy were seen in patients with germline PALB2 mutations (median PFS, 13.3 months), whereas no responses were observed in patients with ATM or CHEK2 mutations alone. On the basis of the results of this study, the NCCN has incorporated the use of PARP inhibitors for patients who have metastatic breast cancer with somatic BRCA1/2 mutations or germline PALB2 mutations into its guidelines.
Prostate Cancer. PARP inhibitor sensitivity in non-BRCA HRR-related gene–mutated tumors has been most frequently explored in mCRPC, given the high frequency of HRR gene mutations in prostate cancer. Numerous studies have documented a more aggressive phenotype and poorer outcomes in patients with BRCA2-mutated tumors than in those with BRCA1-mutated or non-BRCA HRR gene–mutated tumors.62 In the PROfound trial, a prespecified secondary endpoint analysis demonstrated better image-based PFS with olaparib monotherapy than with standard-of-care therapy in the overall study population, which included patients with at least one qualifying deleterious alteration in 1 of 15 prespecified HRR genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L).48 Improved PFS was particularly noted in cohort A, which included patients with BRCA1, BRCA2, or ATM mutations. This finding led to the approval of olaparib monotherapy after progression on a novel AR pathway inhibitor for patients with mCRPC or for any patient with a qualifying deleterious alteration in 1 of the 15 HRR-related genes previously noted. Of note, a significant OS benefit was seen in cohort A but not in the overall population.49 Post hoc subgroup analysis of the patients who had mCRPC with BRCA alterations showed prolonged responses to olaparib (16.6 months vs not reached) in those with BRCA2 homozygous deletion.50 Similarly, the phase 3 TALAPRO-2 study demonstrated significantly better PFS with talazoparib plus enzalutamide than with placebo plus enzalutamide in the HRR gene-mutated population (median PFS, not reached vs 13.8 months; HR, 0.45; 95% CI, 0.33-0.61; P<.0001), and this result led to the FDA approval of enzalutamide in the first-line setting for mCRPC.56 Follow-up analysis demonstrated improved OS with the addition of talazoparib to first-line enzalutamide, both in patients with HRR-deficient mCRPC and in the overall unselected population.58 Of note, in an exploratory analysis by BRCA mutation status, the HR for radiographic PFS was 0.20 (95% CI, 0.11-0.36) in patients with BRCA-mutated mCRPC and 0.72 (95% CI, 0.49-1.07) in patients with non-BRCA HRR gene-mutated mCRPC, findings that suggested an improved clinical benefit for those with a BRCA1 or BRCA2 mutation.63 Therefore, recent NCCN guidelines recommend that tumor testing for HRR gene mutations (BRCA1, BRCA2, ATM, CHEK2, PALB2, FANCA, RAD51D, and CDK12) be considered for all men with metastatic, regional, or clinically localized high-risk prostate cancer.
Further studies have assessed if different HRR gene mutations result in differences in sensitivity to PARP inhibition in prostate cancer. Consistently higher PSA response rates to androgen deprivation therapy plus PARP inhibition are seen in patients with BRCA2-altered prostate cancer than in those with other HRR gene alterations.46,64-66 Fallah and colleagues noted that the benefit of PARP inhibitors plus AR pathway inhibitors in mCRPC varied substantially by HRR gene; they showed the strongest effect on survival endpoints in patients with BRCA2 mutations (radiographic PFS HR, ~0.31; OS HR, ~0.66), some benefit in those with CDK12 and BRCA1 mutations, and no clear improvement in those with ATM and CHEK2 mutations.67 Similarly, Orme and colleagues found that responses to PARP inhibitors were markedly better in patients with both BRCA2 and SPOP mutations than in those with BRCA2 mutations alone; they demonstrated higher PSA responses, longer PFS, and longer OS.68 Co-occurring SPOP mutations were associated with elevated HRD signature (SBS3) scores, suggesting increased functional HRR deficiency in the double mutants. These findings suggest not only that different HRR genes drive very different magnitudes of PARP inhibitor sensitivity but also that the presence of co-occurring somatic mutations (eg, SPOP) can modulate response in prostate cancer, possibly by intensifying HRD or related phenotypes.
Germline vs Somatic Mutations
Almost half of all high-grade serous tubo-ovarian carcinomas have either a germline or somatic pathogenic variant in BRCA1/2.69 Studies have shown that germline BRCA1/2 pathogenic variants are associated with favorable survival, a higher rate of response to platinum-based chemotherapies, and increased sensitivity to PARP inhibitors.14 Somatic BRCA1/2 mutations have been assumed to confer a similar phenotype. Hollis and colleagues compared somatic BRCA1/2 vs germline BRCA1/2 variants in ovarian cancer and found that germline and somatic BRCA1/2 mutations are equivalent in their association with prolonged survival.69 Similarly, both germline and somatic BRCA1/2 variants were associated with high HRD scores. In breast cancer, the phase 2 TBCRC 048 trial sought to assess the efficacy of olaparib in patients who had metastatic breast cancer with a germline or somatic BRCA1/2 mutation.7 The study showed that for those with somatic BRCA1/2 mutations, the median PFS on olaparib was 6.3 months. This was less than the median PFS for those with germline PALB2 mutations, which was 12.3 months.
Research directly comparing the association of somatic vs germline HRD-related pathogenic variants with clinical outcomes is limited in prostate cancer.
Biallelic vs Monoallelic Mutations
The hypothesis of PARP-induced synthetic lethality theoretically requires biallelic inactivation; however, biallelic loss is rarely reported in many PARP inhibitor trials. Studies have shown that biallelic inactivation of BRCA1, BRCA2, RAD51C, and PALB2 is the most frequent genetic cause of HRD cancer across types in both primary and metastatic cancer. However, research on the clinical implications of biallelic vs monoallelic mutations is limited.70 In a phase 2 study by Marshall and colleagues looking at the effect of olaparib in patients with biochemically recurrent prostate cancer following prostatectomy, PSA50 responses were more frequent in patients with biallelic than in those with monoallelic HRR gene alterations.64
Liquid Biopsy for HRD Assessment and the Confounding Role of Clonal Hematopoiesis
Plasma-based assays can assess HRD by detecting pathogenic alterations in HR-related genes, by evaluating genomic scar scores such as LOH, large-scale transition, and telomeric allelic imbalance, or by identifying mutational signatures consistent with HRD. Although these liquid biopsy approaches overcome the limitations of tissue testing, interpretation is complicated by clonal hematopoiesis (CH), in which age- or therapy-related hematopoietic clones shed DNA into the circulation that can be mistakenly attributed to the tumor. Large-scale studies, including the Circulating Cell-free Genome Atlas (CCGA) exploratory analysis, have demonstrated that CH is common and increases with age, with many cases involving genes relevant to DNA repair.71
CH frequently affects genes such as ATM and CHEK2, which overlap with HRD-associated pathways. Misclassification of these alterations as tumor-derived can falsely increase the prevalence of HRD and lead to inappropriate treatment with PARP inhibitors. Marshall and colleagues reported that CH is particularly enriched among patients with solid tumors who have received prior systemic therapy, further heightening the risk of plasma cell-free DNA misinterpretation.72 In prostate cancer specifically, Jensen and colleagues showed that CH in DNA repair genes interfered directly with cell-free DNA test interpretation, with ATM mutations a recurrent source of false-positive tumor calls.73
Mitigation strategies include sequencing paired white blood cells to filter out CH, applying conservative bioinformatic algorithms to flag variants in CH-prone genes, and requiring additional supporting evidence, such as biallelic loss, concordant tissue findings, or HRD-associated genomic scars. Isolated ATM variants particularly should be interpreted with caution because clinical benefit from PARP inhibitors in ATM-mutated prostate cancer has been inconsistent even when alterations are tumor-derived.
In summary, liquid biopsy can contribute significantly to HRD assessment, but CH—especially in DNA damage response (DDR) genes like ATM—poses a well-documented risk of misclassification. The incorporation of white blood cell controls, multiple signal confirmation, and careful clinical interpretation are essential to avoid inappropriate categorization and therapeutic decision making.71-73
Mechanisms of PARP Inhibitor Resistance and Combination Strategies
Despite the efficacy of PARP inhibitors in HRR-deficient tumors, resistance—both primary and acquired—remains a major challenge. In the best-known mechanism, secondary “reversion” mutations restore BRCA1/2 or other HRR gene function, thereby reconstituting homologous recombination. Recent studies have identified polyclonal reversion events with convergent evolution, in which distinct secondary mutations simultaneously restore HRR capacity.74 Additional mechanisms include replication fork stabilization, reduced PARP1 trapping, altered drug efflux, and rewiring of DNA damage response pathways.75 Notably, PARP inhibitors can also select for DDR–related CH, potentially contributing to resistance and poor outcomes.76-78
To counter resistance, rational combinations are under study. Targeting ATR/CHK1/WEE1 can disrupt replication stress responses and resensitize tumors with restored HRR, whereas PI3K/AKT inhibition suppresses BRCA1/2 and induces synthetic lethality.79-80 Other promising approaches include pairing PARP inhibitors with immune checkpoint blockers, antiangiogenic agents, or AR inhibitors in prostate cancer.81-82 Collectively, these strategies aim to delay or overcome resistance and extend PARP inhibitor benefit across HRR-deficient and even HRR-proficient disease.
Conclusion
Across breast, ovarian, and prostate cancers, PARP inhibitors have expanded the therapeutic options for patients with HRD. However, gene-specific effects, biomarker definitions, trial designs, underlying disease biology, co-occurring molecular drivers, and differences in existing treatment landscapes have driven divergent regulatory approvals and clinical expectations. Germline and somatic BRCA alterations remain the ones most predictive of benefit, whereas non-BRCA HRR genes show variable sensitivity, underscoring the need for gene- and disease-specific selection. Resistance through reversions, fork protection, reduced PARP1 trapping, and therapy-induced DDR-CH is common, but rational combinations (ATR/CHK1/WEE1, PI3K/AKT targeting agent, antiangiogenic agent, AR pathway inhibitor, and immunotherapy) may extend efficacy.
Moving forward, the precision use of PARP inhibitors will require harmonizing cross-tumor insights and emphasizing biallelic vs monoallelic alterations, given their differing effects on PARP inhibitor response. Future trials should integrate functional HRD assays, account for somatic vs germline and CH contributions, and test rational combinations to refine indications and maximize benefit.
Disclosures
The authors have no financial disclosures.
References
1. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244-250.
2. Yelamos J, Farres J, Llacuna L, Ampurdanes C, Martin-Caballero J. PARP-1 and PARP-2: new players in tumour development. Am J Cancer Res. 2011;1(3):328-346.
3. Stewart MD, Merino Vega D, Arend RC, et al. Homologous recombination deficiency: concepts, definitions, and assays. Oncologist. 2022;27(3):167-174.
4. Pettitt SJ, Ryan CJ, Lord CJ. Exploiting synthetic lethality in cancer—lessons learnt from PARP inhibitors. In: Cancer Treatment and Research. Cham, Switzerland: Springer International Publishing; 2023:13-23.
5. Heeke AL, Pishvaian MJ, Lynce F, et al. Prevalence of homologous recombination-related gene mutations across multiple cancer types. JCO Precis Oncol. 2018;2018:1-13.
6. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66(16):8109-8115.
7. Tung NM, Robson ME, Ventz S, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38(36):4274-4282.
8. Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer. 2012;107(10):1776-1782.
9. Popova T, Manié E, Rieunier G, et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 2012;72(21):5454-5462.
10. Birkbak NJ, Wang ZC, Kim JY, et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. 2012;2(4):366-375.
11. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130.
12. COSMIC. COSMIC SBS (single base substitution) mutational signatures. Version 3.4. Published online. Accessed October 2025. https://cancer.sanger.ac.uk/signatures/sbs/.
13. Moschetta M, George A, Kaye SB, Banerjee S. BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer. Ann Oncol. 2016;27(8):1449-1455.
14. Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20(3):764-775.
15. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615.
16. Sharma P, Klemp JR, Kimler BF, et al. Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing. Breast Cancer Res Treat. 2014;145(3):707-714.
17. Bayraktar S, Gutierrez-Barrera AM, Liu D, et al. Outcome of triple-negative breast cancer in patients with or without deleterious BRCA mutations. Breast Cancer Res Treat. 2011;130(1):145-153.
18. Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33(4):304-311.
19. Dorling L, Carvalho S, Allen J, et al. Breast cancer risk genes – association analysis in more than 113,000 women. N Engl J Med. 2021;384(5):428-439.
20. Yndestad S, Engebrethsen C, Herencia-Ropero A, et al. Homologous recombination deficiency across subtypes of primary breast cancer. JCO Precis Oncol. 2023;7:e2300338.
21. Armstrong AJ, Taylor A, Haffner MC, et al. Germline and somatic testing for homologous repair deficiency in patients with prostate cancer (part 1 of 2). Prostate Cancer Prostatic Dis. 2025;28(3):652-661.
22. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453.
23. Armenia J, Wankowicz SAM, Liu D, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018;50(5):645-651.
24. Marshall CH, Fu W, Wang H, Baras AS, Lotan TL, Antonarakis ES. Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage. Prostate Cancer Prostatic Dis. 2019;22(1):59-65.
25. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913-917.
26. Kim G, Ison G, McKee AE, et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015;21(19):4257-4261.
27. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505.
28. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402.
29. Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO). J Clin Oncol. 2022;40(36):3952-3964.
30. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428.
31. Hardesty MM, Krivak TC, Wright GS, et al. OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum chemotherapy with bevacizumab. Gynecol Oncol. 2022;166(2):219-229.
32. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392.
33. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274-1284.
34. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
35. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949-1961.
36. Zejula (niraparib) prescribing information. GlaxoSmithKline; 2022.
37. Coleman RL, Oza A, Lorusso D, et al. Overall survival results from ARIEL3: a phase 3 randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma [IGCS abstract O003/#557]. Int J Gynecol Cancer. 2022;32(suppl 3).
38. Oza AM, Tinker AV, Oaknin A, et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol. 2017;147(2):267-275.
39. Moore KN, Secord AA, Geller MA, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20(5):636-648.
40. Oza AM, Lisyanskaya AS, Fedenko AA, et al. Overall survival results from ARIEL4: phase III study assessing rucaparib vs chemotherapy in advanced, relapsed ovarian carcinoma with BRCA1/2 mutation [ESMO abstract 518O]. Ann Oncol. 2022;33(7)(suppl).
41. Scambia G, Villalobos Valencia R, Colombo N, et al. Olaparib as treatment versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer: phase III SOLO3 study final overall survival results. J Clin Oncol. 2025;43(12):1408-1416.
42. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533.
43. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763.
44. Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405.
45. Geyer CE Jr, Garber JE, Gelber RD, et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann Oncol. 2022;33(12):1250-1268.
46. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38(32):3763-3772.
47. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732.
48. de Bono J, Fizazi K, Saad F, et al. Olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102.
49. Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383(24):2345-2357.
50. Mateo J, de Bono JS, Fizazi K, et al. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations in BRCA1 and/or BRCA2 in the PROfound trial. J Clin Oncol. 2024;42(5):571-583.
51. Polkinghorn WR, Parker JS, Lee MX, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3(11):1245-1253.
52. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022; 1(9):EVIDoa2200043.
53. Saad F, Clarke N, Oya M et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(10):1094-1108.
54. Chi KN, Rathkopf D, Smith MR, et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(18):3339-3351.
55. Chi KN, Sandhu S, Smith MR, et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol. 2023;34(7):772-782.
56. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10398):291-303.
57. Fay AP, Fizazi K, Matsubara N, et al. First-line talazoparib plus enzalutamide versus placebo plus enzalutamide in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: patient-reported outcomes from the randomised, double-blind, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet Oncol. 2025;26(4):481-490.
58. Fizazi K, Azad AA, Matsubara N, et al. Talazoparib plus enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: final OS results from TALAPRO-2. SSRN. 2025.
59. Swisher EM, Kwan TT, Oza AM, et al. Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (parts 1 and 2). Nat Commun. 2021;12(1):2487.
60. Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140(2):199-203.
61. Ray-Coquard I, Leary A, Pignata S, et al. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann Oncol. 2023;34(6):681-692.
62. Castro E, Romero-Laorden N, Del Pozo A, et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2019;37(6):490-503.
63. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102.
64. Marshall CH, Teply BA, Lu J, et al. Olaparib without androgen deprivation for high-risk biochemically recurrent prostate cancer following prostatectomy: a nonrandomized controlled trial. JAMA Oncol. 2024;10(9):1400-1408.
65. Marshall CH, Sokolova AO, McNatty AL, et al. Differential response to olaparib treatment among men with metastatic castration-resistant prostate cancer harboring BRCA1 or BRCA2 versus ATM mutations. Eur Urol. 2019;76(4):452-458.
66. Taza F, Holler AE, Adra N, et al. Differential activity of PARP inhibitors in BRCA1- versus BRCA2-altered mCRPC [ASCO GU abstract 100]. J Clin Oncol. 2021;39(6)(suppl).
67. Fallah J, Xu J, Weinstock C, et al. Efficacy of poly(ADP-ribose) polymerase inhibitors by individual genes in homologous recombination repair gene–mutated metastatic castration-resistant prostate cancer: a US Food and Drug Administration pooled analysis. J Clin Oncol. 2024;42(14):1687-1698.
68. Orme JJ, Taza F, De Sarkar N, et al. Co-occurring BRCA2/SPOP mutations predict exceptional poly (ADP-ribose) polymerase inhibitor sensitivity in metastatic castration-resistant prostate cancer. Eur Urol Oncol. 2024;7(4):877-887.
69. Hollis RL, Churchman M, Grimes GR, et al. Somatic BRCA1/2 mutations are associated with a similar survival advantage to their germline counterparts in tubo-ovarian high grade serous carcinoma. Eur J Cancer. 2025;219:115299.
70. Al Assaad M, Hadi K, Levine MF, et al. Whole-genome landscape analysis of homologous recombination deficiency in a pan-cancer cohort. medRxiv. Preprint posted June 30, 2024. https://doi.org/10.1101/2024.06.28.24309592.
71. Swanton C, Venn O, Aravanis A, et al. Prevalence of clonal hematopoiesis of indeterminate potential (CHIP) measured by an ultra-sensitive sequencing assay: exploratory analysis of the circulating cell-free genome atlas (CCGA) study [ASCO abstract 12003]. J Clin Oncol. 2018;36(15)(suppl).
72. Marshall CH, Gondek LP, Luo J, Antonarakis ES. Clonal hematopoiesis of indeterminate potential in patients with solid tumor malignancies. Cancer Res. 2022;82(22):4107-4113.
73. Jensen K, Konnick EQ, Schweizer MT, et al. Association of clonal hematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference. JAMA Oncol. 2021;7(1):107-110.
74. Fatteh M, Wehr J, Karaindrou K, et al. Poly (ADP-ribose) polymerase inhibitor resistance driven by emergence of polyclonal mutations with convergent evolution: a molecular tumor board discussion. JCO Precis Oncol. 2024;8:e2400254.
75. Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16(2):110-120.
76. Bolton KL, Ptashkin RN, Gao T, et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet. 2020;52(11):1219-1226.
77. Marshall CH, Gondek LP, Daniels V, et al. Association of PARP inhibitor treatment on the prevalence and progression of clonal hematopoiesis in patients with advanced prostate cancer. Prostate. 2024;84(10):954-958.
78. Arends CM, Kopp K, Hablesreiter R, et al. Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer. Leukemia. 2024;38(6):1378-1389.
79. Yazinski SA, Comaills V, Buisson R, et al. ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev. 2017;31(3):318-332.
80. Ibrahim YH, García-García C, Serra V, et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2012;2(11):1036-1047.
81. Ding L, Kim HJ, Wang Q, et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 2018;25(11):2972-2980.e5.
82. Asim M, Tarish F, Zecchini HI, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017;8(1):374.