A New Frontier: PARP Inhibitors Plus Antiandrogens in BRCA- or HRR-Mutated mCRPC

In 2023, FDA-approved indications for PARP inhibitors in combination with antiandrogens expanded into the metastatic castration-resistant prostate cancer (mCRPC) landscape. Three combination therapies consisting of niraparib (Zejula; GSK) plus abiraterone (Zytiga; Janssen Biotech, Inc), talazoparib (Talzenna; Pfizer, Inc) plus enzalutamide (Xtandi; Astellas Pharma US, Inc), and olaparib (Lynparza; AstraZeneca Pharmaceuticals, LP) plus abiraterone have been shown to be efficacious in patients who have either the BRCA mutation or homologous recombination repair (HRR) mutation.^1-3 On May 20, 2023, the FDA granted approval for olaparib plus abiraterone and prednisone in patients with mCRPC with the BRCA mutation.¹ The FDA granted approval for talazoparib plus enzalutamide in the same population on June 20, 2023.² Finally, on August 11, 2023, the FDA approved the combination of niraparib plus abiraterone for patients with BRCA-mutated mCRPC under a fixed-dose combination brand name (Akeega; Janssen Biotech, Inc).³

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Mechanisms of Action

PARP inhibitors, such as niraparib, talazoparib, and olaparib, work by inducing synthetic lethality in cells that have deficiencies in HRR or BRCA mutation.^4-6

Antiandrogens, such as enzalutamide, inhibit the androgen receptor (AR) nuclear translocation and DNA binding, leading to apoptosis and decreased prostate tumor volume.⁷ Abiraterone has a slightly different mechanism of action where it selectively and irreversibly inhibits CYP17, an enzyme needed for androgen biosynthesis.⁸ In vitro studies have suggested that androgen deprivation impairs nonhomologous end-joining repairs and leads to downregulation of DNA repair genes and that PARP1 activity has been implicated in supporting antiandrogen activity.^9-12 By inhibiting both PARP1 and AR simultaneously, this could decrease tumor growth and overcome potential resistance in patients with prostate cancer.^9-12

Dosage and Administration

Table 1 describes how each of these agents is taken.^4-8 Abiraterone is prescribed with prednisone to reduce the mineralocorticoid excess adverse effects because of CYP17 inhibition, and the prednisone dosing is 5 mg by mouth twice daily with or without food in patients with mCRPC.⁸ Additionally, there are phase 2 data supporting the administration of abiraterone 250 mg by mouth once daily with a low-fat meal; however, this dosing was not studied in combination with PARP inhibitors.¹³

AR, androgen receptor.

Clinical Data

Olaparib plus abiraterone was evaluated in the phase 3 PROpel trial (NCT03732820).¹⁴ Patients were eligible if they had mCRPC with at least 1 documented metastatic lesion, and patients were allowed to have received docetaxel for treatment of localized prostate cancer and metastatic hormone-sensitive prostate cancer. In terms of determining mutational status, patients were tested (either via tissue sample or circulating DNA) for several mutations including ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.¹⁴ Eligible patients were randomly assigned 1:1 to receive either abiraterone plus placebo or abiraterone plus olaparib with the primary end point of imaging-based progression-free survival (ibPFS) by investigator assessment.¹⁴ Secondary end points included overall survival (OS), time to first subsequent therapy or death, and time to second progression or death.¹⁴

Median ibPFS was significantly longer in the abiraterone and olaparib arm at 24.8 months compared with 16.6 months with abiraterone and placebo (HR 0.66; P < .001), but OS was too immature at the first data cutoff.¹⁴ Time to first subsequent therapy or death and time to second progression or death was 25 months and not yet reached, respectively, for those who received abiraterone and olaparib.¹⁴

Talazoparib plus enzalutamide was FDA approved based on the phase 3 TALAPRO-2 study (NCT03395197).¹⁵ Patients were eligible if they were deemed to have the HRR mutation, including ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C, and sensitive setting.¹⁵ Eligible patients were randomly assigned 1:1 to receive talazoparib plus enzalutamide or enzalutamide alone.¹⁵ Primary efficacy outcomes included radiographic PFS (rPFS), and secondary end points were OS and objective response rate.¹⁵ Improvement in rPFS in the population with HRR mutation treated with talazoparib plus enzalutamide was observed with the median that was not reached vs 13.8 months with enzalutamide alone (HR, 0.45; P < .0001).¹⁵ Additionally, benefit was seen in PFS in the BRCA-mutated population with the combination (HR, 0.20; 95% CI, 0.11-0.36).¹⁵

Niraparib and abiraterone were evaluated in combination in the phase 3 MAGNITUDE trial (NCT03748641), which randomly assigned patients 1:1 to receive niraparib plus abiraterone or abiraterone plus placebo.¹⁶ Eligible patients included those who were never treated in the mCRPC setting, but patients were allowed to have been treated with a short course of abiraterone or docetaxel in the earlier settings.16 Alterations in ATM, BRCA1, BRCA2, CDK12, CHEK2, FANCA, PALB2, and HDAC2 were allowed.¹⁶ The primary outcome was rPFS, which was significantly longer for the niraparib and abiraterone arm at 16.5 months vs 13.7 months, respectively (HR, 0.7; P = .022).¹⁶ Improvement in secondary outcomes, including time to symptomatic progression (HR, 0.69; P = .04) and time to initiation of cytotoxic chemotherapy (HR, 0.59; P = .011), was demonstrated.¹⁶

Adverse Effects

Table 2 describes notable adverse effects (AEs) of these combination products from the clinical trials.^14-16 Of note, the olaparib plus abiraterone clinical trial (PROpel) and the niraparib plus abiraterone clinical trial (MAGNITUDE) reported no cases of myelodysplastic syndrome or acute myeloid leukemia, a rare AE that is traditionally associated with olaparib and niraparib.^14,16 Most of the AEs that were observed in these trials were consistent with the individual agents and had similar rates of occurrences.

AR, androgen receptor.

Conclusions

The combination of a PARP inhibitor with an anti-androgen has demonstrated longer PFS with a tolerable AE profile and can be a good option for patients with mCRPC with BRCA mutation or other notable alterations. Patient factors, prior treatment history, other mutations, and performance status are some aspects to consider when choosing one of these combinations. Additionally, PARP inhibitors have been shown to enhance effects of therapies such as radium-223 and lutetium-177, but more information is needed to elucidate its place in therapy, especially with combination therapy and benefits of using the combination therapy in patients who previously received radium-223 or lutetium-177.17 Furthermore, more long-term follow-up will be needed to truly understand the place in therapy for these combination treatments in the mCRPC landscape.

References

1. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 31, 2023. Accessed November 30, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparibabiraterone-and-prednisone-or-prednisolone-brca-mutatedmetastatic-castration

2. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. June 20, 2023. Accessed November 30, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approvestalazoparib-enzalutamide-hrr-gene-mutated-metastaticcastration-resistant-prostate

3. FDA approves niraparib and abiraterone acetate plus prednisone for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. August 11, 2023. Accessed November 30, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-and-abirateroneacetate-plus-prednisone-brca-mutated-metastatic-castration

4. Lynparza. Prescribing information. AstraZeneca Pharmaceuticals; 2023. Accessed November 30, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s014lbl.pdf

5. Talzenna. Prescribing information. Pfizer; 2023. Accessed November 30, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211651s010lbl.pdf

6. Akeega. Prescribing information. Janssen Biotech; 2023. Accessed November 30, 2023. https://www.janssenlabels. com/package-insert/product-monograph/prescribinginformation/AKEEGA-pi.pdf

7. Xtandi. Prescribing information. Astellas Pharma; 2021. Accessed November 30, 2023. https://www.astellas.us/docs/12a005-enz-wpi.pdf

8. Zytiga. Prescribing information. Janssen Biotech; 2021. Accessed November 30, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202379s035lbl.pdf

9. Tarish FL, Schultz N, Tanoglidi A, et al. Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair. Sci Transl Med. 2015;7(312):312re11. doi:10.1126/scitranslmed.aac5671

10. Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2(12):1134-1149. doi:10.1158/2159-8290.CD-12-0120

11. Polkinghorn WR, Parker JS, Lee MX, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3(11):1245-1253. doi:10.1158/2159-8290.CD-13-0172

12. Taylor AK, Kosoff D, Emamekhoo H, Lang JM, Kyriakopoulos CE. PARP inhibitors in metastatic prostate cancer. Front Oncol. 2023;13:1159557. doi:10.3389/fonc.2023.1159557

13. Szmulewitz RZ, Peer CJ, Ibraheem A, et al. Prospective international randomized phase II study of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer. J Clin Oncol. 2018;36(14):1389-1395. doi:10.1200/JCO.2017.76.4381

14. Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(10):1094-1108. doi:10.1016/S1470-2045(23)00382-0

15. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10398):291-303.

16. Chi KN, Rathkopf D, Smith MR, et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(18):3339-3351. doi:10.1200/JCO.22.01649

17. Marchetti A, Rosellini M, Nuvola G, et al. PARP inhibitors and radiometabolic Approaches in metastatic castration-resistant prostate cancer: what’s now, what’s new, and what’s coming?. Cancers (Basel). 2022;14(4):907. doi:10.3390/ cancers14040907