Take Home Message

  • Significant recent advances have been made in the field of advanced metastatic cancer, and the numerous PARPi approvals within the last year have solidified the entrance of prostate cancer into the precision oncology space.

  • Future exciting directions to improve response from PARPi include initiation of these therapies in earlier disease spaces (localized, mHSPC); evaluation of PARPi in combination with both approved and novel therapeutics; as well as the evaluation of agents to further augment HRR (PARP1, ATR inhibitors), among others.

  • However, careful attention must also be paid to addressing and discovering potential mechanisms of resistance, with outstanding questions remaining regarding sequencing of therapies in advanced disease. These recent approvals, while exciting, must be cautiously interpreted to real-world populations, as it may be difficult to extrapolate and apply results to patient populations who receive second generation ARPI earlier, such as in the mHSPC space.

  • Lastly, while PARPi are efficacious in those patients identified with sensitizing mutations, comprehensive genomic profiling and subsequent identification of actionable alterations are seen in a minority of patients. More studies to identify actionable alterations in diverse patient populations, such that therapy can be tailored and personalized to this individual patient, are needed.

Rationale for PARPi in the management of prostate cancer

Prostate cancer is the second leading cause of cancer death in men and the most frequently diagnosed malignancy in men.1 Developing an understanding of the distinct molecular subtypes of prostate cancer and their sensitivities to targeted treatment regimens is essential to improving patient outcomes. The clinical challenge for practitioners is three-fold; 1) they must identify which patients have the optimal genomic profile predictive of benefit with the therapies currently available; 2) the strengths and weaknesses of these treatments must be weighed against the patient’s overall health; 3) these treatments must be offered in a way that minimize financial burden and toxicity for the patient.

Defective DNA repair has long been viewed as a hallmark of prostate cancer.2 The homologous recombination repair (HRR) pathway is responsible for repairing double-strand DNA breaks generated during DNA interstrand crosslinking.3,4 Prostate cancer cells with HRR deficiency (HRD) have an impaired ability to repair their DNA, and accumulation of double-stranded DNA breaks (DSB) eventually leads to cell death.3 Such alterations confer sensitivity to PARPi in prostate and other cancers. The response to PARP inhibition may occur through blocking of PARP1 poly-ADP ribosylation, trapping of the PARP enzymes on injured DNA, and preventing binding of incoming repair proteins.5 The trapped PARP-DNA complexes become cytotoxic, adding to the toxicity of the unrepaired single-strand breaks caused by PARP inactivation alone.6

Preclinical data also supports the synergy between androgen-receptor signaling inhibitors (ARSI) and PARPi. The precise relationship between the androgen receptor and DNA repair is still being studied, but through a complex transcriptional program, androgens acting through AR have been shown to regulate both prostate cancer growth and differentiation.7 Exposure to ARSI has been shown to downregulate DNA repair gene expression in CRPC xenografts.7 More recently, light has been shed on PARP1 acting as a cofactor for androgen receptor transcriptional activity.8 The dual functions of PARP-1 in DNA damage repair and transcription factor regulation can be leveraged to suppress growth pathways critical for prostate cancer cells by modulation of the DNA damage response and hormone signaling pathways.8

Germline and somatic mutation testing and identifying predictive biomarkers for PARPi

Advanced prostate cancers are frequently characterized by alterations in DNA damage repair and growth factor signaling pathways that control the cell cycle and apoptosis.2 Therapeutic targets lie within both tumor and germline DNA to target these aberrations; as such, many guidelines recommend both germline and somatic testing.9,10

Next-generation sequencing (NGS) is a common choice to assess for pathogenic germline and somatic variants. There are 4 types of specimens that may be used to identify HRR-related genetic variants, although fresh biopsy of a metastatic lesion is ideal.11 Archival biopsy or primary tumor tissue is also acceptable, preferably when the sample is less than 5 years old12; Finally ct (circulating tumor) DNA from blood or saliva may be used as well, although ctDNA assays generally require high disease burden. Thus, blood/saliva samples are more often used for germline-only testing.13 Separate somatic-only and germline-only testing is preferable because germline-only testing can miss up to one-half of BRCA1/2 alterations.14

For treating advanced mCRPC specifically, the use of PARPi’s relies on targeting tumors that are deficient in HRR. The prevalence of HRD mutations reported is ~12% in men with metastatic prostate cancer, and 6% in those with localized high-risk disease via germline testing, and 30% in patients with advanced or metastatic prostate cancer via somatic testing.15

In order of prevalence, genes most commonly reported via germline testing include: BRCA2 (44%), ATM (13%), CHEK2 (12%), BRCA1 (7%), PALB2 (4%), RAD51D (4%0, ATR (2%), NBN (2%, PSM2 (2%), GEN1 (2%), MSH2 (1%), MSH6 (1%), RAD51c (1%) among others.15–19 Somatic testing can also identify potentially targetable genomic alterations –in order of prevalence, these include: HRD pathway (23%), CDK12 (6%), Fanconi anemia (5%), and mismatch repair (4%). The list of HRD mutations is expected to change over time as each gene’s varying sensitivity to PARPi’s is explored further, and as VUS mutations are reclassified. It is essential to note that the clinical benefit of PARPi likely differs by which HRD gene is affected. In addition, these prior studies have limitations due to the underrepresentation of minority patients, and further studies in more diverse populations are urgently needed to identify actionable alterations.

Combination of PARPi with anti-androgen and other PARPi combinations as well as approved FDA indications

The first PARPi to be approved in the treatment of prostate cancer was rucaparib, based on the TRITON2 study. This Phase II study looked at patients with mCRPC associated with BRCA alterations treated with rucaparib 600 mg BID and demonstrated meaningful antitumor activity and a manageable safety profile for the drug.20 Rucaparib was approved in May 2020 for patients with BRCA 1/2 mutations only. A few days after, olaparib was approved in mCRPC based on the PROfound study which looked at patients with HRD mutations who had received a previous ARSI and were randomized to receive olaparib 300mg BID vs physician’s choice. This met its primary endpoint of rPFS.21

This year, there were three approvals for PARPi in combination with an ARSI: olaparib + abiraterone (PROPEL), talazoparib + enzalutamide (TALAPRO2), and niraparib + abiraterone (MAGNITUDE), all in the mCRPC setting. The PROPEL study, a double-blind phase 3 trial, evaluated abiraterone + prednisone (AAP) + olaparib versus AAP + placebo, in patients with mCRPC regardless of HRD status. HRD status was determined after enrollment and results showed that the combined olaparib + AAP significantly prolonged rPFS, and is approved for patients with BRCA mutations only.22 TALAPRO2 is a randomized, double-blind phase 3 trial that compared the efficacy and safety of talazoparib + enzalutamide versus placebo + enzalutamide in patients with mCRPC. The trial demonstrated the combination regimen improved rPFS in the HRR mutated population.23 MAGNITUDE assessed whether adding niraparib + AAP versus placebo + AAP improved outcomes in patients with mCRPC with or without altered HRR genes. Results showed that niraparib + AAP improved rPFS and other clinically relevant outcomes in patients with BRCA mutations, but demonstrated less benefit in other HRR mutations, and no evidence of benefit in HRR biomarker negative patients.24 A summary of the FDA approved PARPi, which HRR mutations were included, and primary endpoints is summarized in Table 1.

As noted above, it is extremely important to bear in mind that not all HRD are the same. Prior gene-by gene analysis suggests less benefit for patients with ATM, CHEK2, CDK12 mutations.25 Thus, although some of these approvals are for numerous HRD, clinicians must be weary of these discrepancies, and strongly consider which patients will benefit the most. In addition, many experts have raised concerns that the recent PARPi combination approvals have increased financial burden and toxicities, without a clear benefit, when a sequential treatment approach can be used instead. This question of sequential vs. concurrent treatment of ARPI + PARP combinations (based on hypothesized synergy) is still being explored.26

Table 1.FDA approved PARPi for mCRPC13–24
Drug Therapy Olaparib Rucaparib Olaparib + AAP Talazoparib + Enzalutamide Niraparib + AAAP
Trial PROfound TRITON2 PROpel TALAPRO-2 MAGNITUDE
FDA Approval May 19, 2020 May 15, 2020 May 31, 2023 June 20, 2023 August 11, 2023
Sensitive Biomarkers HRRm+
Cohort A: BRCA1/2 ATM
Cohort 2: BARD1 BRIP1 CDK12 CHEK1/2 FANCL PALB2 PPP2R2A RAD51B RAD51C RAD51D RAD54L		 BRCA 1/2 BRCA 1/2m
(n=85, 11% of ITT population)		 HRRm+
BRCA 1/2
ATM
ATR
CDK12 CHEK2 FANCA
MLH1 MRE11A
NBN
PALB2 RAD51C		 BRCA 1/2m
Primary endpoint rPFS (central review) ORR (investigator review) rPFS (investigator review) rPFS (central review) rPFS (central review)
All comers N/A N/A HR 0.66 [0.54, 0.81] HR 0.63
[0.51, 0.78]		 NR
HRR(-) N/A N/A HR 0.76
[0.6, 0.97]		 HR 0.69
[0.54, 0.89]		 HR 1.09
[0.75, 1.59]
HRR(+) HR 0.34
[0.25, 0.47]		 N/A HR 0.50
[0.34, 0.73]		 HR 0.45
[0.33, 0.61]		 HR 0.73
[0.56, 0.96]
BRCA+ HR 0.22
[0.15, 0.32]		 46% [35%-57%] HR 0.23
[0.12, 0.43]		 HR 0.20
[0.11, 0.36]		 HR 0.53 [0.36, 0.79]

Adverse Events and Toxicity Management

Although PARPi are generally considered to have a high safety profile, some common AEs include fatigue, gastrointestinal (GI) symptoms, and hematologic toxicity.27 Typically, these adverse reactions are mild to moderate. Fatigue and GI symptoms, specifically nausea and decreased appetite, are common adverse events associated across all PARPi. The single-agent rates of nausea were 41% for olaparib and 52.2% for rucaparib.20,21 Hematologic toxicity often occurs early. Anemia is the primary hematological AE, occurring in 46% of patients on single-agent olaparib 46%, and 43.5% of patients on single-agent rucaparib. One meta-analysis of 14 clinical trials found an no associated increase in the incidence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients who received PARPi compared to controls (IRR 5.43, 95% CI 1.51–19.60).28 However, there was a statistically significant increase in MDS/AML associated with PARPi in either the front-line setting or after fewer than two prior cycles of chemotherapy (IRR 5.43, 95% CI 1.51–19.60). Many of the AEs associated with PARPi can be managed supportively or with dose reductions and do not usually require discontinuation of treatment.21 Supportive management for anemia can involve blood transfusions and the addition of an erythropoiesis-stimulating agent. For patients experiencing nausea, supportive therapy is also effective with resolution of symptoms in a majority of patients. When supportive therapies fail to help, dose interruptions, dose reductions, and/or treatment discontinuation can be considered. Ultimately, dose interruption or reduction and discontinuation were found to be higher for anemia than other AEs.

The combination of PARPi with other drugs is also associated with increased toxicities. A recent meta-analysis of 17 clinical trials found that the common AEs associated with combined therapy varied depending on the therapy.29 PARPi in combination with androgen-receptor signaling inhibitors (ARSIs) were associated most commonly with thromboembolic events (7.5%), thrombocytopenia (5.8%), and hypertension (5.2%). For combination therapy with PARPi and immune checkpoint inhibitors (ICIs), the common AEs included transaminitis (12.5%), fatigue (7.9%), and neutropenia (6.5%). Severe AEs occurred in a third of patients treated either with PARPi monotherapy or combination therapy. For the management of AEs, treatment interruption was seen more frequently in patients on combination therapy with PARPi and ARSI (54.3%) relative to monotherapy (50.3%).29 Treatment discontinuation was also higher in patients on combination therapy with PARPi and ARSI or ICI (25.5%, 23.0% respectively) compared to monotherapy (13.9%). In contrast, dose reduction in response to AEs was more common for PARPi monotherapy (31.1%) compared to combination therapy with ARSI (25.8%).

Cross trial comparison is not feasible. However, Table 2 summarizes the notable and most frequent AEs for each of the FDA approved PARPi in prostate cancer.

Table 2.Toxicities of FDA Approved PARPi in mCRPC20–23
Drug Therapy Olaparib Rucaparib Olaparib + AAP Talazoparib + Enzalutamide Niraparib + AAP
Trial PROfound TRITON2 PROpel TALAPRO-2 MAGNITUDE
Adverse Event
Anemia 46% 43.5% 50% 66% 46.2%
Fatigue/Asthenia 41% 61.7% 39% 48% 42.0%
Nausea 41% 52.2% 31% 21% 23.6%
Appetite loss 30% 27.8% 17% 22% 14%

Ongoing Trials for PARPi

Many current clinical trials seek to investigate PARPi as monotherapy and in various combination therapies with the hope of enhancing efficacy and expanding the population of patients that may benefit from PARPi. As mentioned above, two drugs (olaparib and rucaparib) have been approved as monotherapy for the treatment of prostate cancer. While certain PARPi have been FDA approved for the treatment of breast (talazoparib) and ovarian (niraparib) cancers as a single agent, further research investigation is warranted in assessing these agents’ efficacy as monotherapies in the treatment of prostate cancer specifically. The TALAPRO-1 trial assessed talazoparib in patients with mCRPC with HRD who were pre-treated with at least a taxane and an ARSI.30 Similarly, the GALAHAD trial studied niraparib in patients with mCRPC. In contrast to TALAPRO-1, GALAHAD only included patients with biallelic HRR gene aberrations or germline alterations.31 Table 3 summarizes clinical trials assessing PARPi as monotherapy in prostate cancer treatment

Table 3.Overview of clinical trials with PARPi as monotherapy30–32
Drug Therapy Study Study Design Trial Population HRR Mutations Primary Endpoint(s)
Olaparib vs. Physician’s choice (abiraterone or enza.) PROfound Phase III, randomized, open label mCRPC Selected rPFS
Rucaparib vs. Physician’s choice (docetaxel, AAP, or enza.) TRITON-3 Phase II, randomized mCRPC Selected rPFS
Niraparib GALAHAD Phase II, single arm, open label mCRPC Selected Objective response rate
Talazoparib TALAPRO-1 Phase II, single arm, open label mCRPC Selected Objective response rate

Abbreviations: HRR = homologous recombination repair, enza. = enzalutamide, rPFS = radiological progression free survival, RT = radiotherapy , AAP = abiraterone plus prednisone, PCa = prostate cancer, DLT = dose-limiting toxicity

In addition to monotherapy, there are multiple other clinical trials assessing PARPi as combination therapy. The goal of combination therapy is to delay resistance to treatment with PARPi and to offer treatment options to patients who may be resistant to PARPi monotherapy. Currently, there are many therapeutic agents being studied in combination with PARPi to assess for efficacy. These agents include ARSIs, ICIs, anti-VEGF therapies, AKT/AKR inhibitors, radionuclides, and radiotherapy. Due to the optimistic data on PARPi in the treatment of mCRPC, there are also many clinical trials studying these drugs in other settings, such as metastatic hormone sensitive prostate cancer (mHSPC) or nonmetastatic/localized prostate cancer. Table 4, Table 5, and Table 6 briefly summarize the various combination therapies currently being investigated by clinical trials.

Table 4.Overview of clinical trials with PARPi and ARSI combination therapy33
Drug Therapy Study Name Study Design Trial Population HRR Mutations Primary Endpoint(s)
Talazoparib + enza. vs. Placebo + enza. TALAPRO-3 Phase III, randomized mHSPC Selected rPFS
Rucaparib + enza. vs. Placebo + enza. CASPAR Phase III, randomized mCRPC treatment naive Unselected rPFS, overall survival
Niraparib + RT + ARSI vs. Niraparib alone vs. RT + ARSI NADIR Phase II, randomized High risk localized or locally advanced PCa Unselected Maintenance of disease free state
Niraparib + AAP + leuprolide + RT ASCLEPIuS Phase I/II, single arm, open label High risk locally advanced PCa (cN+) Unselected DLT, biochemical failure (% of patients)
Niraparib + AAP vs. Placebo + AAP AMPLITUDE Phase III, randomized mHSPC Selected rPFS
Talazoparib + enza. vs. Enza. ZZ-First Phase II, randomized, open label mHSPC Unselected PSA-Complete Response

Abbreviations: HRR = homologous recombination repair, enza. = enzalutamide, rPFS = radiological progression free survival, RT = radiotherapy , AAP = abiraterone plus prednisone, PCa = prostate cancer, DLT = dose-limiting toxicity

Table 5.Overview of clinical trials with PARPi and ICI combination therapy33
Drug Therapy Study Name Study Design Trial Population HRR Mutations Primary Endpoint(s)
Olaparib + pembrolizumab vs. enza./AAP KEYLYNK-010 Phase III, randomized mCRPC Unselected overall survival, rPFS
Olaparib + pembrolizumab (cohort A) KEYNOTE-365 Phase Ib/II, nonrandomized mCRPC Unselected PSA response rate, ORR, safety
Olaparib + durvalumab NCT03810105 Phase II, single arm Biochemically recurrent nmCRPC Selected # of patients with undetectable PSA

Abbreviations: HRR = homologous recombination repair, enza. = enzalutamide, rPFS = radiological progression free survival, AAP = abiraterone plus prednisone, nmCRPC = nonmetastatic castration resistant prostate cancer

Table 6.Overview of clinical trials with PARPi and molecule/radionuclide combination therapy33
Drug Therapy Study Name Study Design Trial Population HRR Mutations Primary Endpoint(s)
Olaparib + 177Lu-PSMA LuPARP Phase I, single arm mCRPC N/A DLT, recommended phase II dose
Olaparib + Radium-223 vs. Radium 223 COMRADE Phase I/II, randomized mCRPC N/A rPFS, maximum tolerated dose
Niraparib + Radium-223 NiraRad Phase Ib, single arm mCRPC Unselected DLT
Olaparib + AZD6738 (ATR inhibitor) TRAP Phase II, nonrandomized mCRPC Selected Rate of response, PSA response >50% decline

Abbreviations: HRR = homologous recombination repair, rPFS = radiological progression free survival, DLT = dose-limiting toxicity

Conflicts of interest

NR has served on advisory boards for Sanofi, Exelexis, Janssen, and received compensation from AstraZeneca, EMD Serono, Merck, and Tempus outside the submitted work. All other authors have no disclosures.

Funding

N/A

Ethical statement

N/A

Acknowledgments

N/A

Authors contribution

I. conception and design: Mia Schmolze, Brandon Nguyen, Karine Tawagi, Natalie Reizine, Aaron Laviana
II. data collection and assembly: Mia Schmolze, Brandon Nguyen, Karine Tawagi, Natalie Reizine, Aaron Laviana
III. data analysis, manuscript writing: Mia Schmolze, Brandon Nguyen, Karine Tawagi, Natalie Reizine, Aaron Laviana

All authors have approved this manuscript.