PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape

The treatment landscape of metastatic prostate cancer (mPCa) is rapidly evolving with the recent approvals of poly-ADP ribose polymerase inhibitors (PARPis) as monotherapy or as part of combination therapy with androgen receptor pathway inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC). Already part of the therapeutic armamentarium in different types of advanced cancers, these molecules have shaped a new era in mPCa by targeting genomic pathways altered in these patients, leading to promising responses. These agents act by inhibiting poly-ADP ribose polymerase (PARP) enzymes involved in repairing single-strand breaks in the DNA. Based on the PROfound and TRITON3 trials, olaparib and rucaparib were respectively approved as monotherapy in pretreated patients with mCRPC and alterations in prespecified genes. The combinations of olaparib with abiraterone (PROpel) and niraparib with abiraterone (MAGNITUDE) were approved as first-line options in patients with mCRPC and alterations in BRCA1/2, whereas the combination of talazoparib with enzalutamide (TALAPRO-2) was approved in the same setting in patients with alterations in any of the HRR genes, which are found in around a quarter of patients with advanced prostate cancer. Additional trials are already underway to assess these agents in an earlier hormone-sensitive setting. Future directions will include refining the treatment sequencing in patients with mCRPC in the clinic while taking into account the financial toxicity as well as the potential side effects encountered with these therapies and elucidating their mechanism of action in patients with non-altered HRR genes. Herein, we review the biological rationale behind using PARPis in mCRPC and the key aforementioned clinical trials that paved the way for these approvals.


Introduction
Prostate cancer (PCa) is the most common non-cutaneous malignant neoplasm in men, accounting for 29% of new cancer diagnoses, and the second leading cause of cancer-related death [1,2].The 5-year survival rate of patients with metastatic PCa (mPCa) remains low at about 32% despite advances in treatment regimens and strategies in the last decade [3,4].
Genomic instability is one of the hallmarks of cancer and is commonly caused by defective DNA damage repair pathways, including mutations in homologous recombination repair (HRR) genes such as BReast CAncer gene 1/gene 2 (BRCA1/2) [5].The prevalence of germline and somatic HRR mutations reaches 12% and 20-25%, respectively, in patients with metastatic castration-resistant prostate cancer (mCRPC) [6], exceeding their frequency in localized PCa of 3.5% and 8%, respectively [7,8].The most frequently mutated HRR gene in mCRPC is BRCA2 (44%), followed by ATM, CHEK2, and BRCA1, which account for 13%, 12%, and 7% of HRR mutations in patients with mCRPC, respectively [9].It is important to note that these patients have poor survival outcomes with characteristically more aggressive and poorly differentiated disease, stressing the need for more specialized therapeutic approaches in this patient subset [10].
Life 2024, 14,198 2 of 14 Poly-ADP ribose polymerases (PARPs) are nuclear enzymes that are involved in repairing single-strand breaks (SSBs) in the DNA, while double-strand breaks (DSBs) are repaired through either HRR or non-homologous end joining (NHEJ).PARP inhibitors (PARPis) are targeted drugs that inhibit the DNA-repairing mechanism of PARPs and are lethal in tumors harboring HRR mutations (HRRms) [11].Unrepaired SSBs caused by PARP inhibition, PARP trapping in the DNA by the same drug, and accumulation of DSBs ineffectively managed by error-prone NHEJ are the mechanisms leading to PARPi-mediated killing of HRR-altered cancer cells (Figure 1), which has been demonstrated in this subset of patients with mCRPC [12].Particularly, BRCA1 and BRCA2, which act downstream the PARP1 cascade in one of the two major pathways for DSB repair, are crucial for maintaining genomic integrity.Therefore, cells with germline/somatic BRCA1/BRCA2 mutations are highly vulnerable to PARPis [13,14].Herein, we review recent results from key phase III trials evaluating PARPis in patients with mCRPC.
account for 13%, 12%, and 7% of HRR mutations in patients with mCRPC, respectively [9].It is important to note that these patients have poor survival outcomes with characteristically more aggressive and poorly differentiated disease, stressing the need for more specialized therapeutic approaches in this patient subset [10].
Poly-ADP ribose polymerases (PARPs) are nuclear enzymes that are involved in repairing single-strand breaks (SSBs) in the DNA, while double-strand breaks (DSBs) are repaired through either HRR or non-homologous end joining (NHEJ).PARP inhibitors (PARPis) are targeted drugs that inhibit the DNA-repairing mechanism of PARPs and are lethal in tumors harboring HRR mutations (HRRms) [11].Unrepaired SSBs caused by PARP inhibition, PARP trapping in the DNA by the same drug, and accumulation of DSBs ineffectively managed by error-prone NHEJ are the mechanisms leading to PARPi-mediated killing of HRR-altered cancer cells (Figure 1), which has been demonstrated in this subset of patients with mCRPC [12].Particularly, BRCA1 and BRCA2, which act downstream the PARP1 cascade in one of the two major pathways for DSB repair, are crucial for maintaining genomic integrity.Therefore, cells with germline/somatic BRCA1/BRCA2 mutations are highly vulnerable to PARPis [13,14].Herein, we review recent results from key phase III trials evaluating PARPis in patients with mCRPC.

Single-Agent PARPis in the mCRPC Setting
The first phase III trials involving PARPis assessed the efficacy of these drugs as a single agent in patients with HRR-positive mCRPC after prior progression on an androgen receptor pathway inhibitor (ARPI).Olaparib and rucaparib were tested in the PROfound and TRITON3 trials, respectively (Table 1) [16,17].

Single-Agent PARPis in the mCRPC Setting
The first phase III trials involving PARPis assessed the efficacy of these drugs as a single agent in patients with HRR-positive mCRPC after prior progression on an androgen receptor pathway inhibitor (ARPI).Olaparib and rucaparib were tested in the PROfound and TRITON3 trials, respectively (Table 1) [16,17].

PROfound
This trial assessed olaparib in patients with mCRPC and prior progression on at least one ARPI [16].Patients were enrolled into two cohorts based on prospectively tested HRR status: cohort A (245 patients) with BRCA1/2 or ATM-altered tumors and cohort B (142 patients) with an alteration in any of 12 other HRR genes (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L).Both germline and somatic alterations were included in the study.In each cohort, patients were randomized to receive either olaparib (300 mg twice daily) (intervention arm) or the physician's choice of abiraterone or enzalutamide (control arm) at a 2:1 ratio.

TRITON3
TRITON3 was a randomized, controlled phase III trial that investigated the PARPi, rucaparib as monotherapy in patients with mCRPC with germline or somatic alterations in BRCA1, BRCA2, or ATM after disease progression on an ARPI [17].Patients (n = 405) were randomized 2:1 to receive either oral rucaparib (600 mg twice daily) or the physician's choice of treatment of either docetaxel or an ARPI, with rPFS as the primary outcome.Previous docetaxel was permitted in the metastatic castration-sensitive prostate cancer (mCSPC) setting only and was administered to 23% and 21% of patients in the treatment and the control arm, respectively.
Notably, 47% of patients in the control arm crossed over to receive rucaparib on progression, with fatigue (61%), nausea (50%), and anemia (47%) as the most frequent TEAEs associated with the drug.Eventually, rucaparib was approved in patients with BRCA1/2mutated mCRPC previously treated with an ARPI or taxane-based chemotherapy [20].

PARPi-Based Combinations
To extend the effectiveness of PARPis to a larger cohort of patients, clinical trials set out to test them in combination with ARPIs.This was based on preclinical evidence from in vitro models that demonstrated synergy of effect between the two drugs in cancer cells that were not deficient in HRR [21].ARPIs were found to inhibit the transcription of some genes responsible for DNA repair via homologous recombination, which mimics an HRRm-like state, thus priming these cells for PARP inhibition to block SSB repair on top and induce synthetic lethality in the cell, thus priming tumors for PARP inhibition [22].Moreover, PARP enzymes were found to enhance the androgen receptor signaling pathway by recruiting the androgen receptor to its transcription site on the genome, which possibly both initiates an androgen-independent tumor and sustains the castration-resistant state (Figure 2) [23,24].This preclinical evidence provided the rationale to investigate PARPis in combination with ARPIs in patients with mCRPC (Table 2).* Based on the preplanned futility analysis evaluating the composite endpoint of time to PSA progression and/or rPFS [25].** Inverse probability censoring weighting analysis of overall survival, a prespecified analysis of overall survival, adjusted for the imbalance between the two treatment groups receiving subsequent PARP inhibitors and other life-prolonging therapies [25].+ Based on the results of the HRR-deficient cohort of the TALAPRO-2 trial [26].Abbreviations: AE, adverse event; ARPI, androgen receptor pathway inhibitor; bid, twice daily; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HRRm, homologous recombination repair gene mutated; IQR, inter-quartile range; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; NA, not available; nmPC, non-metastatic prostate cancer; NR, not reached; ORR, objective response rate; OS, overall survival; PSA, prostate-specific antigen; qd, once daily; rPFS, radiographic progression-free survival; TEAEs, treatment-emergent adverse events.

PROpel
PROpel was a multicenter, double-blinded, placebo-controlled, randomized phase III trial that assessed the efficacy of olaparib plus abiraterone as a first-line treatment in patients with mCRPC regardless of HRR status [27].Patients were randomized 1:1 to receive abiraterone (1000 mg once daily) and prednisone or prednisolone (5 mg twice daily) with either olaparib (300 mg twice daily, 399 patients) or placebo (397 patients).Crossover from placebo to olaparib was not allowed.All patients underwent testing of DNA damage repair-related mutations through primary prostate tissue or cell-free DNA as well as blood testing to determine the germline/somatic HRRm status of testable genes.However, patient randomization was not based on this testing.The genes assessed via tumor tissue and cell-free DNA-based testing were based on the PROfound trial and included BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, RAD51B, RAD51C, RAD51D, RAD54L, FANCL, and PALB2.The genes assessed via germline blood testing were BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, RAD51C, RAD51D, and PALB2.HRRm status was established for 98% of patients, with HRRm found in 27.8% and 29% of patients in the intervention and control arms, respectively.The primary endpoint (rPFS according to investigator assessment) was significantly prolonged in the intervention arm compared with the control arm in the overall cohort (median 24.8 vs. 16.6 months, HR 0.66, 95% CI 0.54-0.81,p < 0.001) as well as in both the HRRm (median not reached vs. 13.9 months, HR 0.50, 95% CI 0.34-0.73)and non-HRRm (median 24.1 vs. 19 months, HR 0.76, 95% CI 0.6-0.97)patient subgroups.The prespecified OS analysis at 36.6 months median follow-up [23] showed a 7-month increase in OS with the combination therapy compared with the placebo (median 42.1 vs. 34.7 months, HR 0.81, 95% CI 0.67-1.00,p = 0.054) [28].In the BRCA-mutated subgroup, OS was significantly improved in patients receiving olaparib with abiraterone compared to those treated with placebo and abiraterone (median not reached vs. 23 months, HR 0.29, 95% CI 0.14-0.56).

MAGNITUDE
MAGNITUDE was a phase III randomized, double-blinded trial assessing the combination of niraparib plus abiraterone as first-line agents in patients with mCRPC [25].Patients enrolled were tested for germline and/or somatic pathogenic mutation in any of the study's biomarker gene panel (ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2).Subjects were then enrolled into two separate cohorts based on this prospectively tested HRR status and were randomly assigned 1:1 in each cohort to receive abiraterone (1000 mg once daily) and prednisone (5 mg twice daily) plus either niraparib (200 mg once daily) or placebo until disease progression, unacceptable toxicity, or death.
As for patients with non-HRR-altered tumors who had been enrolled in MAGNITUDE, the results of a preplanned futility analysis led to the cessation of this study arm.Analysis of the composite endpoints of rPFS and/or time to PSA progression showed an HR of 1.09 in the experimental arm (95% CI 0.75-1.57,p = 0.66) in 233 patients (117 receiving niraparib and 116 receiving placebo); therefore, futility was declared for PARPi combination therapy in patients not harboring a deleterious HRR mutation in the trial [25].
Following these results, the combination of niraparib plus abiraterone acetate earned FDA approval as a first-line treatment for patients with mCRPC harboring deleterious or suspected deleterious BRCA mutations [31].
Based on these results, the U.S. FDA approved the combination of talazoparib with enzalutamide as a first-line treatment in patients with mCRPC harboring HRRm in June 2023 [33].

Ongoing Investigation CASPAR
Another key phase III trial, CASPAR, has been designed to randomize 984 patients 1:1 to receive enzalutamide plus either PARPi rucaparib or placebo, with rPFS and OS as co-primary endpoints.The study's planned key secondary endpoints include differences in adverse events and quality of life outcomes as well as rPFS and OS compared between patients harboring BRCA1/2 or PALB2 mutations vs. patients with wild-type genes.This was the first and only study with a preplanned head-to-head comparison of survival outcomes according to HRRm status.Eligibility criteria include patients having received first-line treatment of mCRPC diagnosis, with abiraterone, darolutamide, or apalutamide allowed in the mCSPC setting.HRR alteration status will be assessed in all patients prior to enrollment but will not be a determinant of patient allocation (NCT04455750).However, the study is meeting challenges due to the bankruptcy of the manufacturer Clovis Oncology (Boulder, CO, USA).

Patient Selection in mCRPC
Recent approvals of PARPi monotherapy or PARPi-based combinations have enlarged the therapeutic armamentarium in patients with mCRPC.Previously approved regimens included taxane-based chemotherapy (docetaxel and cabazitaxel), ARPIs (abiraterone, apalutamide, and enzalutamide), Lutetium-177-PSMA-617 (in patients with high PSMA expression), Radium-223 (in patients with bone metastasis and minimal symptoms), and pembrolizumab (in patients with high microsatellite instability or mismatch repair deficiency) [3], thus stressing the need to refine patient counseling and treatment sequence selection in the clinic.Since PARPi-based treatments were approved according to HRR status, this highlights physicians' need to rely on genomic sequencing to optimize treatment choices.Patients with prior progression on ARPI and docetaxel and harboring deleterious germline and/or somatic BRCA1/2 alterations can benefit from rucaparib monotherapy (per TRITON3 trial), while patients with any germline or somatic HRR mutations mentioned above and with progression following prior ARPI can receive olaparib monotherapy (per PROfound trial) [3].
Patients with mCRPC and BRCA alterations can be offered the combination of abiraterone with either olaparib (per the PROpel trial) or niraparib (per the MAGNITUDE trial) as first-line treatment options.As for the enzalutamide plus talazoparib combination, the TALAPRO-2 trial showed improved survival outcomes in both patients with and without HRR alterations, yet it was only approved for patients with mCRPC with the abovementioned HRR gene alterations in the USA.However, this combination was approved in Europe for all patients with mCRPC, regardless of gene alterations.
In the era of androgen deprivation therapy (ADT) intensification regimens with ARPI in the mCSPC setting, there remains an unanswered question as to whether these patients should receive the combination of ARPI with PARPi in the mCRPC setting or only PARPi monotherapy.Other factors that affect treatment selection include patient insurance, copay burden, patient comorbidities, physician preference, and treatment toxicity profile.Since anemia, neutropenia, thrombocytopenia, hypertension, fatigue, and nausea were the most frequently experienced side effects of PARPis, these should be carefully monitored and managed.

Conclusions
With the recent approval of new treatment regimens in patients with mCRPC, the treatment landscape of mPCa is rapidly evolving.With growing evidence related to the presence of actionable mutations in these patients, tumor genomic testing will gain further importance in the coming years.The approval of PARPis has certainly shaped a new era and refined physicians' understanding of the disease.How this therapeutic class will be implemented in the clinic remains to be seen.Longer patient follow-up and monitoring will be mandatory to ensure patient safety and maintain treatment response.It is noteworthy that these molecules had a greater benefit in the subset of patients with BRCA1/2 alterations than those harboring ATM mutations (median rPFS 9.8 months vs. 5.4 months by independent review in the PROfound trial) [16].Future directions will include elucidating the underlying molecular correlates of response to these combinations of ARPI and PARPi in patients without HRR mutations.Furthermore, new trials assessing these combinations in the mCSPC setting are already underway, with the TALAPRO-3 (NCT04821622) and AMPLITUDE (NCT04497844) trials testing enzalutamide with talazoparib and abiraterone with niraparib, respectively.

Table 1 .
Summary of landmark phase III clinical trials investigating PARP inhibitors as monotherapy in patients with mCRPC.

Table 2 .
Summary of landmark phase III clinical trials investigating combined PARP inhibitors and ARPIs in a first-line mCRPC setting.

Table 2 .
Summary of landmark phase III clinical trials investigating combined PARP inhibitors and ARPIs in a first-line mCRPC setting.Prior taxane exposure (yes vs. no) Prior ARPI exposure (yes vs. no) Prior abiraterone use (yes vs. no) HRRm cohort: BRCA1/2 vs. other HRR gene alterations Prior abiraterone or docetaxel in mCSPC setting (yes vs. no) HRR alteration status (deficient vs. non-deficient/unknown)