Bicky Thapa,1,* Navonil De Sarkar,2– 4,* Subhajit Giri,2,3 Komal Sharma,2– 4 Mingee Kim,5 Deepak Kilari1

1Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 2Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA; 3Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA; 4Data Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA; 5School of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

Abstract: Metastatic castrate-resistant prostate cancer (mCRPC) is associated with poor prognosis. DNA damage response (DDR) genes are commonly altered in mCRPC rendering them as promising therapeutic targets. Poly (ADP ribose) polymerase inhibitors (PARPi) demonstrated antitumor activity in mCRPC patients with DDR gene mutations through synthetic lethality. Multiple clinical trials with PARPi monotherapy exhibited encouraging clinical outcomes in selected patients with mCRPC. More recently, three Phase III randomized clinical trials (RCTs) combining PARPi with androgen receptor signaling inhibitors (ARSIs) demonstrated improved antitumor activity compared to ARSI monotherapy in mCRPC patients as the first-line therapy. Clinical benefit was more pronounced in patients harboring DDR alterations, specifically BRCA1/2. Interestingly, antitumor activity was also observed irrespective of DDR gene mutations, highlighting BRCAness phenotype with androgen receptor blockade resulting in synergistic activity between ARSIs and PARPi. In this review, we discuss the clinical efficacy and safety data of the combination of PARPi plus ARSI in all Phase 3 randomized controlled trials (RCTs), emphasizing strategies for patient selection and highlighting emerging trends based on clinical trial data.

Introduction

Prostate cancer has become the leading cancer diagnosis among American men in 2024, with a staggering 299,010 new cases estimated, highlighting a critical public health challenge.1 The management of prostate cancer has long centered around targeting the androgen receptor (AR).2 Nevertheless, the formidable challenge arises as alterations within the AR signaling pathway provoke resistance, propelling the progression to castration-resistant prostate cancer (CRPC).2,3 Historically, patients with metastatic CRPC (mCRPC) had limited therapeutic options and poor prognoses. Despite notable recent strides in therapeutic innovation, the five-year relative survival rate for metastatic prostate cancer hovers at a mere 34%.4 A recent Swedish population-based study has further underscored the gravity of the situation, reporting a median overall survival of a mere 1.86 years for individuals with CRPC, irrespective of metastatic status.5

Docetaxel is one of the preferred choices of treatment for chemotherapy-naïve mCRPC based on the findings from SWOG 99–16, and the TAX327 trial.6,7 Subsequently, 2nd-generation androgen receptor signaling inhibitors (ARSIs) such as abiraterone, apalutamide, and enzalutamide have demonstrated improved clinical outcomes as 1st line systemic treatment. However, there has been no direct comparative trial conducted between ARSIs and chemotherapy. Although these advancements heralded improved outcomes, the median radiographic progression-free survival (PFS) with first-line ARSI plateaued at around 20 months. Additionally, the limited benefit observed upon switching ARSIs upon progression accentuates the pressing need for novel and more effective therapeutic regimens in the pre-chemotherapy setting.8–12 Aside from docetaxel and ARSIs, there are additional approved first-line treatments for a specific subset of mCRPC patients. These include PARP inhibitors in combination with ARSI, pembrolizumab for patients with microsatellite instability-high status (MSI-high), sipuleucel-T, and Radium-223 for those with symptomatic bony metastases.

Genomic profiling studies demonstrated notable heterogeneity in the genomic alterations in the different stages of prostate cancer. For example, mCRPC patients often have genomic alterations in AR, TP53, and RB1 compared to localized prostate cancer. Specific alterations such as TMPRSS2-ERG fusions, and changes in PTEN, SPOP, and FOXA1, mark distinct subtypes, including those related to DNA damage repair (DDR).13–17 Pritchard et al reported germline DDR mutations in 4.6% of localized prostate cancer, with more than twofold increase in mCRPC (11.8%).18 The Cancer Genome Atlas (TCGA) study reported DDR gene aberrations in 19% of localized cases,19 while a similar mCRPC focused study showed aberrations in 23% of the case series (SU2C east coast dream team study).13 These prevalence statistics are supported by extensive molecular profiling on localized, oligometastatic, and mCRPC case series.14,20–25 Notably, disruptions in homologous recombination-mediated repair (HRR) pathways have garnered significant interest due to their susceptibility to poly-(ADP ribose) polymerase (PARP) inhibitors (PARPi) via synthetic lethality mechanisms.26–28 Encouragingly, multiple randomized clinical trials have showcased the promising clinical efficacy of PARP inhibitor monotherapy in mCRPC patients. These findings underscore the potential of targeting DDR gene aberrations, particularly through PARP inhibition, in the therapeutic landscape of advanced prostate cancer.

Within the landscape of prostate cancer, the Androgen Receptor (AR) gene and its aberrant signaling pathways play a crucial role, shaping the trajectory of disease progression. Notably, a body of prior research has underscored the intricate relationship between AR signaling and the expression of various genes within the DNA damage repair (DDR) pathway.29 Preclinical investigations have shed light on the phenomenon wherein the suppression of the Homologous Recombination Repair (HRR) pathway, triggered by Androgen Deprivation Therapies (ADT), instigates heightened activity of Poly-(ADP ribose) polymerase (PARP), indicative of a nuanced interplay between AR pathways and DDR genes.30 These intriguing insights hint at the potential induction of BRCAness, offering a compelling rationale for exploring synthetic lethality through combined inhibition of Androgen Receptor Signaling and PARP. Noteworthy clinical trials have recently demonstrated promising responses to such combination therapies, even among metastatic castration-resistant prostate cancer (mCRPC) patients lacking specific DDR gene alterations.

This review examines key clinical trial outcomes to understand the clinical significance of PARP inhibitor monotherapy and combination therapies with AR signaling inhibitors (ARSI), emphasizing patient stratification and outcomes.

Therapeutic Implications of Dysfunctional DNA Damage Response Pathways

Cancer cells deploy sophisticated DNA repair strategies to sustain cellular balance, with critical pathways addressing single- and double-strand DNA breaks to prevent malignancy. PARP proteins, particularly PARP1, are crucial for DNA repair and have important implications for treatment. Using PARP inhibitors (PARPi) for cancers that lack the HRR mechanism could be of significance in treating mCRPC patients, as a substantial number of patients can have genomic aberrations in DNA repair genes. Comprehensive genomic profiling facilitates treatment personalization, a concept supported by the National Comprehensive Cancer Network (NCCN), marking a transition to precision oncology designed to improve patient outcomes. In breast and ovarian cancers with BRCA1/2 mutations, platinum-based chemotherapy improves survival. Although not standard for mCRPC, retrospective studies indicate patients with DDR gene alterations may benefit from platinum chemotherapy, pending validation from prospective studies.

Poly(ADP-Ribose) Polymerase Inhibitors and Synthetic Lethality

Poly(ADP-ribose) polymerase inhibitors (PARPi) are stratified into categories based on their potential to induce allosteric changes in target proteins. There are three types: Type I inhibitors such as EB-47 that mimic benzamide adenine dinucleotide; Type II inhibitors, including talazoparib and olaparib; and Type III inhibitors, such as niraparib, rucaparib, and veliparib.31

At present, the US Food and Drug Administration (FDA) has approved four PARPi for metastatic castration-resistant prostate cancer (mCRPC): rucaparib, niraparib, olaparib, and talazoparib. Of importance, talazoparib and olaparib exhibit a moderate increase in DNA binding affinity without affecting the allosteric sites of PARP1. Preclinical studies have shown that the cytotoxicity of PARPi correlates with their PARP trapping efficacy, with talazoparib emerging as the most potent trapper followed by olaparib among the evaluated PARPi.32–34 Rucaparib and niraparib, while effective catalytic inhibitors of PARP1, do not trap as efficiently as talazoparib.32–34 The first in human, Phase 1 clinical trial with olaparib in advanced solid tumors with germline BRCA1/2 mutations exhibited anti-tumor activity with durable responses, especially in a patient with BRCA2-mutated CRPC.35 Subsequently, phase 1 studies in molecularly selected advanced prostate cancer with germline BRCA1/2 mutation PARPi (olaparib, talazoparib) showed anti-tumor activity.36,37

PARPi Monotherapy Clinical Trials in mCRPC

Several clinical trials have explored the efficacy and safety of PARP inhibitors as monotherapy in mCRPC patients with DNA repair gene alterations. The TOPARP-A (NCT01682772) and TOPARP-B (NCT01682772) trials evaluated olaparib, which showed promising results in mCRPC patients with DDR gene alterations, particularly in those with BRCA1/2 mutations.38,39 These trials demonstrated improved radiologic progression-free survival (rPFS) and overall survival (OS) in biomarker-positive patients compared to biomarker-negative patients (median 9.8 months vs 2.7 months; p<0.001). However, dose-dependent toxicities, such as anemia, were observed, necessitating dosage adjustments.38 Similarly, the PROfound (NCT02987543) trial confirmed the efficacy of olaparib in mCRPC patients with DDR gene alterations, leading to its FDA approval in May 2020.40 Patients were assigned to cohort A based on the presence of DDR alterations in BRCA1, BRCA2, or ATM, while those with other DDR genes (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L) were enrolled in cohort B. Notably, olaparib significantly prolonged PFS (median 7.4 months vs 3.6 months; p<0.001) and OS (median 18.5 months vs 15.1 months; p=0.02) in cohort A when compared to standard treatments like enzalutamide or abiraterone.

In the TRITON2 (NCT02952534) trial, rucaparib was evaluated in BRCA-altered mCRPC patients, showcasing an overall response rate (ORR) of 43.5% (95% CI, 31.0%–56.7%) and a prostate-specific antigen (PSA) response in 54.8% of patients.41 This led to the FDA’s accelerated approval of rucaparib for BRCA-altered mCRPC patients. In addition, this study explored rucaparib’s efficacy in non-BRCA mutated DDR genes. While responses were limited in patients with ATM, CDK12, and CHEK2 alterations, promising anti-tumor activity was reported in other DDR gene cohorts, including PALB2, FANCA, BRIP1, and RAD51B. The study reported manageable adverse events, predominantly myelosuppression. Subsequently, a phase 3 randomized study, TRITON3 (NCT02975934) evaluated the efficacy of rucaparib in mCRPC patients with BRCA1/2 and ATM alterations.42 In this study, rucaparib was compared with the control group, which is the physician’s choice of treatment, ie, 2nd generation ARSIs or docetaxel. Rucaparib demonstrated significant improvement in imaging-based PFS in the BRCA subgroup with a median PFS of 11.2 months vs 6.4 months as compared to the control group with HR of 0.50 (95% CI, 0.36–0.69; p<0.001 by og rank test). Similarly, PFS was longer in intention to treat population, median PFS of 10.2 months in the rucaparib arm vs 6.4 months in the control group; HR of 0.61 (95% CI, 0.47–0.80, p<0.001 by log rank test). No significant difference in PFS was observed in the ATM subgroup. Likewise, the GALAHAD (NCT02854436) trial, which was the first to assess the efficacy of niraparib in heavily pretreated mCRPC, demonstrated its activity in BRCA-altered mCRPC patients.43 The study found a significant ORR of 34.2% (26 of 76 patients) in the BRCA cohort and 10.6% (5 of 47 patients) in the non-BRCA group, with rPFS of 8.08 months and 9.93 months in the respective cohorts. The most common adverse events observed with niraparib included nausea, anemia, and vomiting.

Talazoparib, another potent PARP inhibitor, exhibited significant anti-tumor activity in heavily pretreated mCRPC patients with DDR gene mutations in the TALAPRO-1 (NCT03148795) trial.44 Both BRCA1/2 and non-BRCA mutated cohorts showed favorable response rates, with an rPFS of 5.6 months (95% CI, 3.7–8.8) in the overall cohort and 11.2 months (95% CI 7.5–19.2) in the BRCA1/2 cohort. Notably, the study found no difference in clinical outcomes between germline and somatic DDR gene alterations. Common adverse events included anemia, nausea, decreased appetite, and asthenia. Overall, these trials highlight the evolving landscape of targeted therapy in mCRPC and the potential of PARP inhibitors for patients with specific DDR gene alterations. Table 1 summarizes the clinical outcome of PARPi monotherapy in mCRPC.

Table 1 Summary of Phase II and III Clinical Trials in mCRPC Patients with PARPi Monotherapy. Table summarizing results from 7 landmark PARPi monotherapy trials. All trials led one common inference that patients with BRCA loss yielded highest measurable response

PARPi and ARSI in mCRPC and Its Clinical Outcome

Preclinical studies have demonstrated a synergistic effect between androgen receptor signaling inhibitors (ARSI) and poly(ADP-ribose) polymerase inhibitors (PARPi). There are claims that blocking the androgen receptor may enhance sensitivity to PARPi by inducing a BRCAness phenotype.45,46 Based on this concept, the Phase 2 randomized clinical trial was conducted to evaluate the efficacy and tolerability of olaparib in combination with abiraterone (NCT01972217).47 In this study, metastatic CRPC patients were enrolled regardless of HRR genomic alteration status. Of the 142 eligible mCRPC patients, 71 randomized to olaparib plus abiraterone and the other 71 patients to placebo and abiraterone. The median radiographic progression-free survival (rPFS) was significantly higher in olaparib arm; 13.8 months as compared to 8.2 months in the placebo arm; hazard ratio (HR) 0.65, [95% CI 0.44–0.97; P=0.034]. The encouraging preclinical and clinical outcome data with the combination therapy-led investigators to further evaluate the efficacy of PARPi and ARSI as 1st line combination therapy in phase 3 prospective randomized clinical trials. Tables 2–4 summarizes the patients selection criterion and clinical outcomes in mCRPC with combination therapy.

Table 2 Summary of Patient Selection Criterion in Phase 3 Clinical Trials

Table 3 Summary of Clinical Outcomes (Primary Endpoints) in Phase 3 Randomized Clinical Trials Evaluating Efficacy of PARPi and ARSI combinations in mCRPC Patients in 1st Line Treatment Setting

Table 4 Summary of Secondary or Other Exploratory End Points and Patient Safety Data

(i) BRCAaway (NCT03012321, Phase 2, n=61): The encouraging results from biomarker guided phase 2 clinical trial BRCAAway garnered attention at the recent ASCO GU 2024 event.51 The study evaluated the efficacy of abiraterone/prednisone (Arm I) vs olaparib (Arm II) vs olaparib + abiraterone/prednisone (Arm III) in mCRPC patients with BRCA1/2 or ATM alterations. A total of 61 patients were randomized to the 3 arms: Arm I (n=19), Arm II (n=21), and Arm III (n=21). The median PFS was 8.4 months in Arm I, 14 months in Arm II and 39 months in Arm III. The objective response rates observed in the trial were 29% for the combination of Olaparib and Abiraterone (Arm III), 9.5% for Olaparib alone (Arm II), and 21% for Abiraterone alone (Arm I). Despite being a study with a small cohort of patients, the combination of olaparib with abiraterone/prednisone showed promising clinical efficacy, resulting in an extended progression-free survival (PFS) in mCRPC patients with BRCA1/2 or ATM mutations.

(ii) MAGNITUDE (NCT03748641, Phase 3 randomized study, n=423): The randomized clinical trial investigated the efficacy of combining niraparib with abiraterone and prednisone (Abi/Pred) versus a placebo with Abi/Pred in the management of patients with mCRPC in a first-line treatment setting.50 The trial’s inclusion criteria mandated patients to be at least 18 years of age with a confirmed mCRPC diagnosis defined by homologous recombination repair (HRR) gene alteration status. A panel of nine predefined genes (BRCA1/2, ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2) were scrutinized for mutations. Exclusion criteria encompassed patients who previously received systemic therapies such as ARSI (enzalutamide, apalutamide, darolutamide) or docetaxel in a castration-resistant context. Nonetheless, systemic therapies for non-metastatic and metastatic castrate-sensitive scenarios did not preclude study participation. Prior to randomization, enrolled subjects were permitted up to four months of Abi/Pred therapy for mCRPC. Subjects were stratified into two cohorts based on HRR mutation status (HRR deficient or HRRd and HRR efficient or non-HRRd) and were randomized in a 1:1 ratio to receive either the investigative combination of niraparib with Abi/Pred or the control regimen of placebo with Abi/Pred. Table 2 summarizes the patient’s selection criteria.

The study’s primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included time to initiation of cytotoxic chemotherapy (TCC), time to prostate-specific antigen (PSA) progression (TPP), objective response rate (ORR), and patient reported outcomes (PRO). In this study, the functional assessment of cancer therapy-prostate (FACT-P) total score was employed to assess the patient-reported quality of life changes (Table 4).

A total of 423 patients were enrolled in the HRRd cohort, and 233 patients were in the non-HRRd cohort. In the HRRd cohort, 212 were randomized to the niraparib + Abi/Pred arm, and 211 were assigned to the Abi/Pred + Placebo arm. In the HRRd cohort, niraparib + Abi/Pred improved rPFS compared to the placebo group (16.5 vs 13.7 months); HR 0.73 (95% CI, 0.56–0.96; P=0.022). In subgroup analysis in patients with BRCA1/2 alterations, median rPFS was significantly longer in the intervention arm, 16.6 vs 10.9 months in the placebo arm; HR 0.53 (95% CI, 0.36–0.79; P=0.001). In the non-HRRd cohort (n=233), 117 were assigned to niraparib + Abi/Pred and 116 to placebo + Abi/Pred. The evaluation in the non-HRR cohort revealed no therapeutic advantage with niraparib, as indicated by the lack of improvement in rPFS and/or time to PSA progression, with an HR of 1.09 (95% CI, 0.75–1.57; P=0.66). Subsequently, the non-HRR cohort was stopped prematurely after meeting a pre-defined futility endpoint. OS data were immature at the time of primary data analysis. Table 3 summarizes the clinical outcomes. In HRRd cohort, niraparib + Abi/pred showed clinical benefits with delay in TCC, TPP, and TSP (highlighted in Table 4). Anemia and hypertension were the most common grade ≥3 adverse events. Based on these data, the FDA approved niraparib + Abi/Pred as 1st line treatment for mCRPC patients with BRCA1/2 alterations.

(iii) PROpel (NCT03732820, Phase 3 double-blind randomized study, n=796): The randomized trial evaluated the efficacy of Abi/Pred ± Olaparib in biomarker unselected (ie, irrespective of HRR status) mCRPC patients as 1st line treatment.49 Metastatic CRPC patients (except for ADT) must be treatment-naive to be eligible for enrollment in the clinical trial. First-generation ARSI, such as bicalutamide, flutamide, and nilutamide, were permitted till four weeks prior to the randomization. Docetaxel in the setting of non-metastatic prostate cancer and mCSPC were allowed if there was no evidence of disease progression. Patients who received treatment with 2nd generation ARSIs (except for abiraterone) for mCSPC were eligible for the study if no disease progression during treatment and systemic treatment was stopped 12 months before randomization. Table 2 outlines the patients selection criteria.

The pivotal study focused on rPFS as its primary endpoint, while secondary endpoints included time to subsequent anti-cancer therapy, pain progression, OS, and PRO, with ORR, disease control rate, PSA response, and TSP serving as exploratory objectives. Like MAGNITUTE trial, FACT-P total score was utilized to understand the how patients reported changes in their quality of life (Table 4). Investigators pre-specified a comprehensive panel of HRR genes for enrolling 796 patients, leading to 399 assigned to the olaparib arm and 397 to placebo. Within the cohort, 28.4% had HRR alterations. Notably, the median rPFS was significantly longer in the olaparib plus Abi-Pred group at 24.8 months compared to 16.6 months in the placebo arm, with a hazard ratio of 0.66 (95% CI, 0.54–0.81; P<0.001). The ORR in the olaparib arm was 58.4% compared to 48.1% in the placebo arm, with an odds ratio of 1.60 (95% CI, 1.02–2.53). The PSA50 response rate was higher in the olaparib arm at 79.3% versus 69.2% in the placebo. In patients with HRR alterations, the median rPFS was not reached in the olaparib arm, contrasting with 13.9 months in the placebo group (HR of 0.50, 95% CI 0.34–0.73). In the non-HRR-altered cohort, the median rPFS was 24.1 months for olaparib versus 19.0 months for placebo (HR of 0.76, 95% CI 0.60–0.97). Table 3 outlines the clinical outcome in this trial. The most prevalent treatment-emergent adverse events in the olaparib cohort included anemia, fatigue, and nausea (Table 4). The updated analysis of overall survival did not show a significant difference between the olaparib and placebo arms (HR of 0.81, 95% CI 0.67–1.00; P=0.054), yet the median OS in the olaparib group was 42.1 months compared to 34.7 months in the placebo group.52Table 4 summarizes the other exploratory endpoints. These findings underpinned the FDA’s approval of olaparib in combination with Abi/Pred for the treatment of mCRPC patients with BRCA1/2 alterations.53

(iv) The TALAPRO-2 (NCT03395197, Phase 3 double-blind randomized; n=805): This randomized, double-blind, placebo-controlled, phase 3 clinical trial evaluating the efficacy and safety of talazoparib plus enzalutamide vs placebo plus enzalutamide in the first-line setting with mCRPC.48 Eligible mCRPC patients must be asymptomatic or minimally symptomatic at enrollment. Patients who received prior docetaxel and Abi/Pred or orteronel in the mCSPC setting were eligible for enrollment. However, patients were ineligible for enrollment if they received previous systemic therapy for localized CRPC or mCRPC, except for ADT and first-generation ARSIs. Metastatic CRPC patients were excluded if prior treatment with 2nd generation ARSIs (enzalutamide, darolutamide, apalutamide, abiraterone), PARPi, cyclophosphamide, mitoxantrone, platinum-based chemotherapy within six months of randomization, and investigational drugs within four weeks of randomization. Table 2 summarizes the patient’s selection criterion. The study enrolled mCRPC patients regardless of HRR alterations. Investigators prospectively assessed the 12 prespecified HRR gene alterations (BRCA1/2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12). The primary endpoint of the clinical trial was rPFS. Secondary endpoints were OS, ORR, PSA50 response, TPP, TCC, time to initiation of subsequent antineoplastic therapy, time to 1st skeletal events, time to disease progression or death, safety, and patient reported outcomes (PRO). In this study, PRO were analyzed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30), Table 4. Eight hundred-five patients were enrolled in the study; 402 were randomly assigned to the talazoparib arm and 403 to the placebo arm. Talazoparib was dosed at 0.5 mg PO daily, and in patients with moderate renal impairment, 0.35 mg PO daily was the recommended dose, enzalutamide 160 mg PO daily. HRR gene alteration was noted in 21% (n=169) patients, and 79% (n=636) had no HRR gene alteration. BRCA1/2 alteration was noted in 7% (n=27) patients in the talazoparib arm, and 8% (n=32) in the placebo arm. In the talazoparib arm, 21% (n=86) received prior docetaxel and 6% (n=23) received ARSI (abiraterone and orteronel) vs 23% (n=93) and 7% (n=27) in the placebo arm. Median rPFS was not reached for the talazoparib arm (95% CI, 27–5 months-not reached) vs 21.9 months (95% CI, 16.6–25.1) in the placebo arm. The HR for disease progression or death was 0.63 (95% CI, 0.51–0.78, P<0.0001). Talazoparib plus enzalutamide showed benefit in different subgroup; the risk of radiographic progression was 54% lower in HRR gene-altered patients with HR of 0.46 (95% CI, 0.30–0.70; P=0.0003) versus HR of 0.70 (0.54–0.89; P=0.0039) in non-HRR gene altered or unknown patients as compared to placebo group. Patients with BRCA1/2 alteration garnered remarkably better rPFS with HR of 0.23 (95% CI, 0.10–0.53; P=0.0002) compared to the placebo arm. The non-BRCA1/2 altered group also demonstrated an improvement in rPFS with talazoparib HR of 0.66 (95% CI, 0.39–1.12, P=0.12). The clinical benefit was observed with talazoparib plus enzalutamide compared to the placebo arm irrespective of prior docetaxel in mCSPC setting, HR 0.56 (95% CI, 0.38–0.83, P=0.0038). Overall, clinical benefit was noted across all prespecified subgroups such as site of metastasis, HRR gene altered, non-HRR altered, BRCA1/2 altered, non-BRCA1/2. Table 3 highlights the clinical outcome (primary end points) and Table 4 outlines the secondary or exploratory end points.

Biomarkers for PARP Inhibitor Sensitivity

Across all clinical trials, mCRPC with BRCA1/2 alterations consistently demonstrated improvement in clinical outcomes with different PARPi (Table 1 and Table 3). Clinical benefits were noted irrespective of germline or somatic BRCA mutation. This is clinically important as approximately 10%–13% of mCRPC patients harbor BRCA alterations with the majority of patients with BRCA2 mutations and only ~1–2% harboring BRCA1.13,54–56 In the biomarker study from TOPARP-B trial, homozygous BRCA2 deletions showed exceptional response with olaparib.57 The authors also found that patients with loss of ATM expression in immunohistochemistry and biallelic PALB2 loss were associated with the clinical response with PARPi. The exploratory subgroup analysis from the phase III PROfound trial showed clinical benefit with olaparib in mCRPC patients with BRCA alterations.58 In the BRCA2 cohort (n=128), the median PFS was 10.8 months in the olaparib arm vs 3.5 months in the control arm. On the other hand, in the BRCA1 cohort (n=13), the median PFS was 2.1 months vs 1.8 months. Particularly, prolonged clinical response with olaparib was observed in patients harboring BRCA2 homozygous deletions (n=16) with the median rPFS of 16.6 months.58 Beyond BRCAness, several genomic scores are now emerging to be strong predictors of PARPi response,20,59–69 eg, the Homologous Recombination Deficiency (HRD) score, which integrates genomic scarring markers like loss of heterozygosity (LOH) and telomeric allelic imbalance (TAI), has been validated in various cancers to predict PARPi sensitivity.69

A retrospective multi-institutional study showed important clinical findings of differential clinical response with PARPi in mCRPC patients with BRCA1 and BRCA2 mutations.70 Reduced efficacy was observed with PARPi in patients with BRCA1 mutation as compared to BRCA2. In another retrospective study, PARPi demonstrated superior clinical activity in mCRPC patients harboring both BRCA2 and speckle-type POZ protein (SPOP) mutation.71

A meta-analysis by Messina C et al reported the efficacy of combination treatment with PARPi plus ARPI from three-phase III RCTs (PROPEL, MAGNITUDE, and TALAPRO-2).72 The clinical benefits of combination treatment were noted in 2 randomized clinical trials (RCTs) (PROPEL and TALAPRO-2) in molecularly unselected mCRPC patients, highlighting a synergy between ARSI and PARPi. The pooled analysis from 6 clinical trials, 4 RCTs (PROPEL, MAGNITUDE, TALAPRO-2, PROFOUND), and 2 single-arm clinical trials (TRITON-2, TALAPRO-1), revealed variable responses of PARP inhibitors across different DDR gene mutations.73 The highest clinical benefit with PARPi was noted in mCRPC patients with BRCA1/2, CDK12, and PALB2 mutations. No obvious benefit was observed in patients harboring ATM and CHEK2 mutations. These insights are pivotal for advancing biomarker-driven patient selection and optimizing PARPi-based therapies, ultimately aiming to improve clinical outcomes for patients with HRR deficiencies.

CRPC Patient Selection for PARP Inhibitors in the Clinical Practice

PARP inhibitors are typically considered for mCRPC patients harboring DDR gene alterations such as BRCA1/2.38–41,47,48,51,72,74–81 However, there are challenges in determining which PARP inhibitor to use in real-world practice, as improvement in clinical outcomes was demonstrated in multiple phase 3 clinical trials (both monotherapy and combination treatment).47,48,81 In terms of monotherapy, PARP inhibitors (olaparib and rucaparib) monotherapy is the preferred choice in mCRPC patients harboring pathogenic BRCA mutation (germline or somatic) who progressed on ARSI agents. In addition, olaparib monotherapy can be considered in mCRPC patients harboring non-BRCA mutations (ATM, BRIP1, BARD1, CHEK1, CHEK2, CDK12, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L).

PARP inhibitors, in combination with ARSI, demonstrated improved clinical outcomes. However, no comparative trials have evaluated PARP monotherapy vs combination treatment. In context of treatment sequence, before the approval of combination therapy, ARSIs were used for treatment in the 1st line metastatic setting, with subsequent administration of PARP inhibitors following disease progression.

Data from PROPEL and TALAPRO-2 suggest benefit of combination treatment with PARPi and ARSI; however, olaparib and abiraterone is FDA approved for mCRPC patients with only BRCA1/2 alterations. On the other hand, talazoparib and enzalutamide is FDA approved for mCRPC patients with any of the 12 HRR gene alterations, namely, BRCA1/2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, and CDK12. Talazoparib and enzalutamide showed rPFS benefits across all subgroups regardless of HRR gene status; however, maximum clinical benefits were observed in patients harboring BRCA1/2 mutation; HR 0.23 (95% CI, 0.10–0.53, p=0.0002). The survival follow-up for this trial is ongoing, and currently, data is immature. The post-hoc exploratory analysis data from the TALAPRO-2 demonstrated improved rPFS with talazoparib plus enzalutamide in patients harboring TMPRSS2-ERG and RB1 mutation.82 The study suggested the possibility of synthetic lethality with PARPi via TMPRSS-ERG mediated repression of NHEJ.82 Regarding safety profile, talazoparib plus enzalutamide was associated with grade≥3 adverse events in 75% of patients. The most common all cause adverse events were anemia, neutropenia, and fatigue. Therefore, safety considerations should be given to frail elderly patients who are susceptible to serious life-threatening side effects.

Based on the clinical trial data, all 3 combinations of PARP inhibitors with ARSI can be utilized as first-line systemic treatment. Picking one combination over others is a challenging decision as there is no head-to-head comparison of the trials. The overall survival data is either not yet available or remains immature, representing a notable limitation of the studies. In contrast to the BRCAAway study, the absence of crossover from the control group presents a challenge in assessing the relative efficacy of combination therapy vs sequential PARP inhibitor therapy. The studies also did not assess the correlation of clinical outcomes with other common somatic mutations such as AR alterations, tumor suppressor genes, and PI3K pathways in mCRPC, which are known to contribute to the aggressive nature of the disease.

PARP Inhibitors as Maintenance Therapy Agent in Advanced Cancer

PARP inhibitors (PARPi) have become crucial in the maintenance therapy landscape for patients with ovarian cancer, as evidenced by pivotal trials such as SOLO1 and OlympiAD.83–85 These trials demonstrated that olaparib significantly extended progression-free survival (PFS) in ovarian and breast cancers with BRCA1/2 mutations, outperforming standard therapeutic options. Specifically, in the SOLO1 trial, olaparib reduced the risk of disease progression or death by 70% compared to placebo.83 This success has spurred further exploration of PARPi as maintenance therapy agents in various cancers, particularly for patients with defects in homologous recombination repair (HRR) mechanisms.

The PROfound trial’s success led to the growing interest in using olaparib as a maintenance therapy agent in mCRPC patients, particularly with HRR gene alterations. This expansion has provided compelling data for personalized treatment strategies, emphasizing the need for continuous research to refine their application.40 While PARPi have shown promise, determining optimal dosing schedules, whether continuous or intermittent, remains critical to balancing efficacy and minimizing toxicity. This underscores the need for further clinical research and real-world data to establish comprehensive guidelines for the use of PARPi in maintenance therapy for mCRPC.

Overcoming Challenges with PARP Inhibitors: Next-Generation Strategies and Innovations

Despite the promise of PARPi in treating mCRPC, several challenges limit their efficacy. Emerging evidence indicates that 40–50% of eligible mCRPC patients with HR mutations show limited or no response to PARPi, despite exhibiting HRD markers.77,78 Resistance mechanisms, such as secondary mutations restoring HRR function, complicate treatment further.78,86,87 Current genomic signatures like HRDetect and iHRD rely on accumulated genomic scars and lack real-time HRD detection sensitivity.20,59 Additionally, systemic toxicity and poor tumor tissue accumulation hinder PARPi’s bioavailability and efficacy. Another significant concern with the present generation of PARPi lies within a substantial fraction of patients who show grade 3 myelosuppression.33,88–92 Next-generation PARPi aim to overcome these limitations through enhanced selectivity, potency, and bioavailability. Strategies include designing PARPi to counter resistance mechanisms, exploring combination therapies, and using liposomal formulations to improve tumor targeting and reduce toxicity.

Modulating the tumor microenvironment and using biomarker-driven patient selection with comprehensive panels and next-generation sequencing aim to better predict PARPi response. Combining PARPi with chemotherapy, radiation, immune checkpoint inhibitors, and targeted therapies is being evaluated to enhance efficacy and overcome resistance. These advancements promise to maximize PARPi’s therapeutic potential, providing more effective treatment options for patients with HRR deficiencies and improving overall treatment outcomes in mCRPC.

Discussion

The advent of precision oncology has heralded a new era in the management of metastatic castration-resistant prostate cancer, shifting the therapeutic landscape towards more targeted interventions. Among these, PARPi have emerged as a pivotal therapy, especially for patients harboring DDR gene mutations. This review elucidates the significant strides made in understanding and treating mCRPC, underscoring the role of PARPi as a cornerstone of precision medicine in this context.

Lessons Learned from PARPi Monotherapies in the mCRPC Cohort

The clinical translation of PARPi for mCRPC management, particularly for tumors with DDR mutations, has been underpinned by robust clinical trials. Seminal studies such as TOPARP-A, PROfound, TRITON2, and GALAHAD have demonstrated the therapeutic potential of PARPi, with significant improvements in radiographic progression-free survival (rPFS) and, in some cases, overall survival (OS) among patients harboring specific DDR mutations.39–41,43 The PROfound study,40 which evaluated olaparib in mCRPC patients with alterations in DDR genes, underscored the clinical benefit of PARPi, showcasing a notable improvement in rPFS compared to standard-of-care treatments. Similarly, the TRITON2 trial41 illustrated rucaparib’s efficacy in mCRPC patients with BRCA mutations, reinforcing the premise that targeting DDR defects can elicit significant antitumor activity.

In a phase 3 randomized clinical trial, niraparib maintenance treatment in patient with platinum sensitive recurrent ovarian cancer showed clinical benefits regardless of HRD status.93 Similarly, olaparib maintenance in germline BRCA1/2 altered platinum sensitive metastatic pancreatic cancer demonstrated longer PFS.94 With similar innovative idea, a phase II, single arm clinical trial (NCT04288687) is ongoing to evaluate the clinical outcome of niraparib maintenance in platinum sensitive mCRPC patients harboring predefined somatic or germline DDR genes (BRCA1/2, ATM, FANCA, CDK12, RAD51B, RAD54L, PALB2, CHEK2, HDAC2, or BRIP1).95

Is the New Therapy Combination PARPi+ARSI a Leap Forward?

The interplay between DDR mechanisms and AR signaling pathways suggests a synergistic potential for combining PARPi with ARSI. Preclinical studies have revealed that AR signaling modulates the expression of genes involved in DDR, positing that AR inhibition could sensitize prostate cancer cells to PARPi.45,46 Clinical investigations, such as the combination of talazoparib and Enzalutamide in the TALAPRO2 study,40 have begun to explore this synergy, reporting enhanced clinical outcomes compared to either agent alone.

This combinatory approach heralds a promising avenue for mCRPC treatment, potentially overcoming resistance mechanisms to monotherapy and addressing a broader patient population. However, the intricacies of drug–drug interactions, optimal dosing strategies, and the identification of patients who would most benefit from such combinations necessitate further exploration. It is also essential to acknowledge that all three RCTs (TALAPRO-2, PROpel, and MAGNITUDE) testing efficacy of PARPi+ARSI had very distinctive clinical outcomes, possibly due to difference in study designs, patient selection criteria and most critically due to different characteristics of the respective PARPi. For example, enrolled mCRPC patients were allowed to have abiraterone plus prednisone up to 4 months before the randomization of mCRPC in the MAGNITUDE study, therefore about 1/3rd of the enrolled patients had ARSIs at the time of enrollment. Interestingly, these three clinical trials chose a distinctively different set of gene mutation status as the criterion to assign a patient HRRd status as well (Table 2). Conversely, the TALAPRO-2 study did not include mCRPC patients who had been treated with ARSIs within the six months prior to randomization. However, the study did permit the inclusion of patients who had previously been treated with docetaxel and abiraterone in the context of mCSPC. The PROpel study enrolled treatment-naïve mCRPC patients, and patients who received abiraterone in mCSPC setting were excluded from the study. Besides, patients on 2nd generation ARSIs except for abiraterone were eligible for the study if no disease progression and treatment was stopped 12 months before randomization. The PROpel and MAGNITUDE studies permitted the participation of individuals who had previously received docetaxel therapy, provided this treatment occurred before the progression to the metastatic castration-resistant prostate cancer (mCRPC) phase. Table 2 highlights the proportion of patients in all three RCTs who received systemic therapies before enrollment in the trial. Of importance, due to drug–drug interaction concerns the MAGNITUDE trial chose 200 mg once daily Niraparib dose in combination with abiraterone as compared to 300 mg once daily as monotherapy. With regard to toxicity, both olaparib and niraparib, in combination with abiraterone, had similar grade 3 and above toxicities when compared with monotherapy clinical trials (Table 1 and Table 4). However, talazoparib with enzalutamide was associated with significantly high grade ≥3 adverse events compared to monotherapy clinical trials. This underscores the need for more accurate patient selection criterion in the real-world setting for better clinical outcomes with manageable side effects with different PARPi. Currently, olaparib plus abiraterone and niraparib plus abiraterone are cleared by the FDA for mCRPC patients with BRCA1/2 mutation, whereas talazoparib plus enzalutamide is FDA-approved for mCRPC patients with 12 DDR gene alterations as described above.

While the three phase 3 randomized trials focused on showing the efficacy of PARPi+ARSI against ARSI monotherapy as control arm; the relatively small-scale phase 2 study BRCAaway design convince us of the true essence of PARPi+ARSI treatment synergy.51 The BRCAaway trial represents a significant leap forward, showcasing the potent synergy between Olaparib, a PARPi, and abiraterone, an ARSI, especially in patients harboring BRCA1/2 or ATM mutations. The trial’s design was meticulous, targeting a cohort of mCRPC patients with these specific genetic aberrations, which are known to compromise DNA damage response (DDR) mechanisms. The outcomes were compelling, with the combination therapy arm (Arm III) achieving a median progression-free survival (PFS) of 39 months, a remarkable improvement compared to monotherapy arms that are crossed over (ARSI monotherapy arm crossed over to a PARPi or vice versa).51 Such statistical evidence underscores the trial’s success, highlighting the critical role of PARPi+ARSI combination therapy synergy in treating patients with metastatic prostate cancer. Such an outstanding observation indeed preaches for moving the combination as upfront therapy, although it is yet to be learned the impact of the introduction of PARPi as an upfront therapeutic agent in treating prostate cancer patients. Although promising (based on studies with ovarian cancers), long-term PARPi therapy-associated potential toxicity, especially in germline HRD-mutated prostate cancer patients, is yet to be formally studied.96–99 The observation strongly supports considering the PARPi+ARSI combination as a potential upfront therapy option. Nevertheless, there remains a gap in our understanding of the long-term risks associated with continuous PARPi treatment, especially concerning potential toxicities in prostate cancer patients with inherited HRD mutations. This gap points to a need for thorough clinical investigation to fully grasp the long-term effects of early PARPi intervention in the treatment of prostate cancer in the near future.

Talazoparib as a Treatment Option for Patients with mCRPC

Talazoparib is a PARP inhibitor with a strong PARP trapping ability. Its efficacy as a monotherapy in BRCA-mutated breast cancer is noteworthy, and this extends to its use in combination with enzalutamide for treating metastatic castration-resistant prostate cancer, where it has significantly improved radiographic progression-free survival. The safety and toxicity profile of talazoparib is an essential factor in its therapeutic application. The TALAPRO-2 trial indicated that its use, particularly in combination with enzalutamide, aligns with the known safety profiles of each drug. However, serious adverse reactions such as anemia, fracture, and even Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) have been observed, albeit at a relatively low incidence.

When comparing talazoparib to other PARP inhibitors like Olaparib, Rucaparib, or Niraparib, its increased myelosuppression stands out, potentially due to its higher potency for PARP trapping.31,88,100 This highlights the importance of individualized treatment plans, as the choice of a PARP inhibitor often hinges on the cancer type, genetic makeup, and the patient’s tolerance to the medication. In clinical settings, it is essential to consider the benefits of talazoparib against its potential risks, tailoring treatment to each patient’s unique genetic profile and health background. In research settings, there is a growing interest in conducting systematic studies that compare the efficacy and toxicity of PARPi, specifically between PARP trappers, like talazoparib, and new generations of PARP degraders.101 The goal is to optimize treatment outcomes while managing adverse effects, ensuring that the use of talazoparib is as safe and effective as possible for the intended patient population.

As the therapeutic landscape of mCRPC continues to evolve, several challenges and opportunities emerge. Firstly, the need a structured and comprehensive genomic profiling to identify patients with DDR mutations who are likely to benefit from PARPi underscores the importance of integrating alternative biomarkers (beyond standard genomic mutation-based HRD determination) that accurately predicts PARPi therapy response into routine clinical practice. Secondly, understanding the mechanisms underlying resistance to PARPi and real-time follow-up of resistance signatures remains crucial for developing next-generation combination therapies and more robust clinical practice. Moreover, the exploration of PARPi beyond BRCA1/2 and core HRD pathway gene mutations towards a broader spectrum of DDR aberrations (including epigenetic factors involved in HRD, eg aberrations in genes like ATRX, CHD1), could expand the therapeutic applicability of these agents.20,102–104 In the context of combined PARPi and ARSI therapy, the molecular mechanisms underlying acquired resistance in prostate cancer remain to be fully delineated. Comprehensive longitudinal studies are imperative to elucidate these resistance pathways, which is crucial for the informed design and development of future therapeutic strategies. Finally, ongoing and future clinical trials combining PARPi with other therapeutic modalities, including immune checkpoint inhibitors, radiotherapy, and novel targeted agents, promise to further refine and personalize treatment strategies for mCRPC. The advent of PARPi represents a paradigm shift in the management of mCRPC, particularly for tumors harboring DDR gene mutations. By leveraging our growing understanding of prostate cancer’s genetic landscape, these targeted therapies offer a beacon of hope for patients with advanced disease. The integration of molecular diagnostics, continued research into resistance mechanisms, and the exploration of combination therapies will be pivotal in realizing the full potential of PARPi in the oncology therapeutic arsenal, marking a significant step towards precision medicine in prostate cancer care.

Disclosure

Dr. Navonil De Sarkar reports grants from Amrican Cancer Society pilot grant through MCW cancer center, outside the submitted work. Dr Subhajit Giri reports grants from Advancing a Healthier Wisconsin Endowment (AHW), outside the submitted work. Dr Deepak Kilari reports consulting for Pfizer, outside the submitted work. The authors report no other conflicts of interest in this work.

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