Precision medicine and personalized medicine are 2 concepts that have pushed their way to the forefront of oncology practice.
Precision medicine and personalized medicine are 2 concepts that have pushed their way to the forefront of oncology practice. PARP inhibitors have historically been the best example for the practice of personalized and precision medicine in the treatment of patients with prostate adenocarcinoma.
The FDA has approved 2 PARP inhibitors for the treatment of patients with metastatic castration-resistant prostate cancer: rucaparib (Rubraca) for those with BRCA1/2-mutated disease based upon the phase 2 TRITON2 trial (NCT02952534)1 and olaparib for those with tumors that harbor homologous recombination deficiency (HRD), specifically pathogenic mutations (germline or somatic) in BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L based upon the PROFOUND trial (NCT02987543)2. While the FDA has approved these therapies for the above indications, patient selection for treatment in the metastatic castration-resistant setting demands more careful consideration given the accelerated pace of disease.
Within healthy cells, PARP1 is critical to base-excision and single strand break repair. If PARP were not present, then single strand breaks would convert to double strand breaks, triggering repair from homologous repair requiring proficient BRCA in addition to other proteins.
However, within cancer cells harboring HRD, if PARP function is inhibited then single strand breaks convert to double strand breaks which cannot be repaired, leading to cell death3. Outside of enzymatic catalytic inhibition via inhibition, PARP trapping on DNA is another important mechanism of action. Of the available studied PARP inhibitors discussed below, talazoparib (Talzenna) has a much higher relative PARP trapping potency compared with olaparib, rucaparib, and niraparib (Zejula).4 There is still some controversy over which mechanism is more important for clinical efficacy or if they are equally beneficial.
To examine the data in more detail, the phase 2 TRITON2 trial (NCT02952534) enrolled patients with one of 15 homologous recombination repair (HRR) genes to rucaparib 600 mg orally twice daily. The overall response rate (ORR) was 43.5% and the prostate-specific antigen (PSA) response rate was 54.8% in patients with BRCA1/2 alterations1. TRITON3 (NCT02975934) is a phase 3 study evaluating rucaparib monotherapy versus chemotherapy or second-line androgen deprivation therapy in patients with mCRPC with mutations in BRCA or ATM. Median radiographic progression-free survival (rPFS) was higher in the rucaparib-treated group among patients with BRCA mutations, 11.2 vs 6.4 months (P <.0001), and was 10.2 vs 6.4 months in the intent-to-treat population (P = .0003), including patients with ATM mutations5.
The phase 3 PROfound trial randomized 2 cohorts of patients with mCRPC 2:1 to either olaparib 300 mg orally twice daily or investigator’s choice of enzalutamide (Xtandi) or abiraterone acetate (Zytiga). Patients were divided into 2 cohorts: men with BRCA1, BRCA2, or ATM alterations (cohort A) and patients with 12 other HRR alterations (cohort B). Median progression free survival (mPFS) was 7.4 vs 3.6 months in cohort A (HR, 0.34; P <.001) and in the overall population, 5.8 months vs 3.5 months (HR, 0.49; P <.001).2 When subgroups were analyzed, it appeared that patients with BRCA1 and BRCA2 mutations had the most benefit (HR for progression or death in BRCA1; HR, 0.41; 95% CI 0.13-1.39; BRCA2, HR, 0.21; 95% CI, 0.13-0.32). Of note, other mutations seemed to have less clear benefit; those with ATM mutations had an HR of 1.04 (95% CI, 0.61-1.87).
Of course, the trial was not powered adequately to definitively answer these questions. Further data found that overall survival (OS) was significantly improved in cohort A at 19.1 months vs 14.7 months, respectively (HR, 0.69; P = .02) but not in cohort B (14.1 months vs 11.5 months; HR, 0.96)6.
Additional data have shown similar results with patients with BRCA mutations doing better than patients with ATM mutations7. It is important to note data from 2 additional PARP inhibitors that do not have an FDA-approved prostate cancer indication currently. Niraparib was studied in the phase 2 GALAHAD study, again with higher response rates in patients BRCA-altered prostate cancer (34.2%; 95% CI 23.7- 46.0%)8.
TALAPRO-1 (NCT03148795) was a phase 2 trial in patients with HRR mutations that showed greatest median PFS in patients with BRCA1/2-altered tumors followed by the overall population, and followed by the ATM group, at 11.2 months vs 5.6 months vs 3.5 months9. The ORRs were 45.9% in the BRCA1/2 subgroup, 25% in PALB2, 11.8% in ATM, and 0% in patients with other HRR alterations.
Among these 4 PARP inhibitors, toxicity often includes anemia, fatigue/asthenia, nausea, and decreased appetite. In these trials, grade 3 or higher adverse events were seen in approximately one-third to as many as half of patients.1,2,8-9
When considering appropriate patient selection for PARP inhibition in the mCRPC setting, these data provide insight that not all HRR mutations act as a similar biomarker. One possible reason is the role of these proteins in DNA repair within the cell. BRCA2 binds to RAD51 and DSS1 to interact directly on damaged DNA, and PALB2 interacts with BRCA1 to facilitate this complex to accomplish successful homologous recombination repair10. ATR and ATM help activate the BRCA proteins, but they do not produce a direct effect on DNA repair. We therefore should not expect that patients with alterations in these proteins would have similar response to PARP inhibition.
More recently, PARP inhibitor combinations with next-generation hormonal agents (NHA) have generated increased attention. Two phase 3 studies were presented at the 2022 Genitourinary Cancers Symposium: PROpel (NCT03732820) and MAGNITUDE (NCT03748641). PROpel randomized mCRPC patients 1:1 to abiraterone and prednisone (AAP) with olaparib at 300 mg twice daily vs AAP with placebo. Patients were enrolled irrespective of a HRR mutation biomarker and mPFS was greater in the olaparib-treated group at 24.8 months vs 16.6 months (HR, 0.66; P <.001)11. Of interest, the radiographic PFS benefit was seen across subgroups (HRR-mutated HR, 0.50; 95% CI 0.34-0.73; non-HRR HR, 0.76; 95% CI, 0.60-0.97). Of note, the biomarker was analyzed retrospectively after enrollment and randomization. Updated OS data were presented at the 2023 Genitourinary Cancers Symposium with 47.9% maturity.12 In the olaparib arm, median OS is higher at 42.1 months vs 34.7 months (HR, 0.81; P = .0544). Benefit is greater in patients with BRCA mutations (HR, 0.29; 95% CI, 0.14-0.56) compared with non-BRCA mutations (HR, 0.91; 95% CI, 0.73-1.13).
MAGNITUDE, however, had a different design. Patients with mCRPC were initially screened for their HRR status and then randomized within HRR biomarker-positive and -negative cohorts to either AAP and niraparib 200 mg daily or AAP and placebo13. PFS was increased with niraparib in the biomarker-positive group at 16.5 months vs 13.7 months with placebo (HR, 0.73; P =.0217) but not in the biomarker-negative group via composite progression endpoint as this cohort was stopped due to futility.
Of note, patients with BRCA1/2 mutations had the greatest benefit with niraparib (rPFS: 16.6 months vs 10.9 months; HR, 0.53; P = .0014). TALAPRO-2 is a phase 3 study that randomized patients to enzalutamide at 160 mg daily plus talazoparib at 0.5 mg daily or placebo14. Median imaging-based PFS (ibPFS) was significantly improved in HRR-deficient patients (27.9 vs 16.4 months; HR, 0.46; 95% CI, 0.30-0.70; P <.001) and HRR-nondeficient patients (HR, 0.66; 95% CI, 0.49-0.91; P = .009). OS data remain immature. These data are helpful, but patients with newly diagnosed mCRPC who have not seen a NHA is a shrinking population, as these drugs have been moved up to the metastatic castration-sensitive (mCSPC) setting. TALAPRO-3 is a study that randomized HRR biomarker-positive patients with mCSPC to enzalutamide and either talazoparib or placebo15 and data are pending.
As previously discussed, not all HRR mutations should be treated equally. However, with the PROpel data set, the synergy between PARP inhibition and androgen signaling inhibition must be considered. PROpel showed PFS benefit even in a biomarker-negative subgroup. Of note, NHA is thought to be able to induce a relative HRD state (BRCAness) and increase susceptibility to PARP inhibition, which has been reported to increase activity of NHA via AR-dependent transcription16,17.
Providing combination PARP inhibitors and NHA to patients with mCRPC and BRCA1/2 mutations should be considered a new standard of care as soon as regulatory approval is provided. Patients with these mutations have more aggressive disease, and there is now sufficient evidence to show benefit. However, without an OS benefit, I am still hesitant to provide PARP inhibition to all patients in the frontline mCRPC setting given the increased toxicity rate—up to 50% grade 3 toxicity. Additionally, there is long-term concern with bone marrow exhaustion that could potentially prohibit future lines of therapy.
As we begin to consider even earlier treatment in mCSPC treatment, careful consideration of biomarkers will prove more critical as these patients would be on more toxic therapy for longer periods of time. Additional novel combinations with PARP inhibitors are currently under investigation, including combinations with immunotherapy, radium-223 dichloride (Xofigo), chemotherapy, 177Lutitium-PSMA-617, VEGF inhibitors, and a variety of other compounds.
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2. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. New Eng J Med. 2020;382(22):2091-2102. doi: 10.1056/NEJMoa1911440
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7. 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. doi:10.1016/j.eururo.2019.02.002
8. Smith MR, Scher HI, Sandhu S, et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet Oncol.2022;23(3):362-373. doi:10.1016/S1470-2045(21)00757-9
9. de Bono JS, Mehra N, Scagliotti GV et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021; 22(9):1250-1264. doi:10.1016/S1470-2045(21)00376-4
10. Shailani A, Kaur RP, Munshi A. A comprehensive analysis of BRCA2 gene: focus on mechanistic aspects of its functions, spectrum of deleterious mutations, and therapeutic strategies targeting BRCA2-deficient tumors. Med Oncol. 2018;35(3):18. doi: 10.1007/s12032-018-1085-8
11. Clarke NW, Armstrong AJ, Thiery-Vuillemin A et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9):EVIDoa2200043. doi:10.1056/EVIDoa2200043
12. Clarke NW, Armstrong AJ, Thiery Vuillemin A, et al. Final overall survival (OS) in PROpel: abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl 6):LBA16. doi:10.1200/JCO.2023.41.6_suppl.LBA16
13. Chi KN, Rathkopf DE, Smith MR et al. Phase 3 MAGNITUDE study: first results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2022;40(6):12-12. doi:10.1200/JCO.2022.40.6_suppl.012
14. Agarwal N, Azad A, Carles J, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(6):LBA17. doi:10.1200/JCO.2023.41.6_suppl.LBA17
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17. Li L, Karanika S, Yang G et al. Androgen receptor inhibitor-induced "BRCAness" and PARP inhibition are synthetically lethal for castration-resistant prostate cancer. Sci Signal. 2017; 10.