PARP Inhibitors – Effective in Men with BRCA-Mutant Prostate Cancer

Men with prostate cancer have genomic defects that can be targeted with PARP Inhibitors – should undergo genomic testing

Charles H. Weaver, MD
7–11 minutes
Home » Prostate Cancer » PARP Inhibitors – Effective in Men with BRCA-Mutant Prostate Cancer

by Dr. C.H. Weaver M.D. updated 8/2023

Precision cancer medicines known as poly ADP-ribose polymerase (PARP) Inhibitors should be considered for use early in the management of advanced prostate. PARP inhibitors were developed treat women with ovarian or breast cancers caused by specific genomic defects that prevent them from repairing DNA which results in cancer. Approximately 1 in 4 men with prostate cancer have similar defects in DNA repair and can benefit from treatment with a PARP Inhibitor.

The PARP Inhibitors Rubraca® (rucaparib), Lynparza (olaparib) and Zejula (nirapanib) have all been demonstrated to delay the progression of prostate cancer in men with advanced prostate cancer and the most recent studies have demonstrated that combining PARP inhibitors with other drugs can further improve outcomes.16-18 All men should should undergo genomic testing to determine whether PARP inhibitors play a role in the management of their cancer.

About PARP Inhibitors

The PARP enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy and are called PARP inhibitors. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth. Blocking the DNA damage response is most impactful in cancers that already have a deficiency in repairing their DNA. Deficient homologous recombination repair (HRR) is most common when mutations in BRCA1 and/or BRCA2 are present.

Lynparza was the world’s first drug to reach the market targeted against inherited cancer mutations, and was found to benefit as many as a third of patients with prostate cancer, including many who did not inherit cancer genes but whose cancers had acquired defects in DNA repair according to initial study results released in the New England Journal of Medicine in 2015. 

Understanding HRR gene mutations

Homologous recombination repair (HRR) mutations occur in approximately 20-30% of patients with mCRPC.4 HRR genes allow for accurate repair of damaged DNA in normal cells.5,6 HRR deficiency (HRD) means the DNA damage cannot be repaired, and can result in normal cell death. This is different in cancer cells, where a mutation in HRR pathways leads to abnormal cell growth and therefore cancer. HRD is a well-documented target for PARP inhibitors. PARP inhibitors block a rescue DNA damage repair mechanism by trapping PARP bound to DNA single-strand breaks which leads to replication fork stalling causing their collapse and the generation of DNA double-strand breaks, which in turn lead to cancer cell death.6 There are several genes in the HRR pathway that when mutated might benefit from PARP inhibitor treatment. These include ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C.

Rubraca (rucaparib)

Rubraca is the first PARP inhibitor approved for the treatment of prostate. The U.S. Food and Drug Administration (FDA) approved Rubraca® for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy.7,8 The FDA approval for for Rubraca is based on data from patients with mCRPC and a deleterious BRCA mutation enrolled in the multi-center, single arm TRITON2 clinical trial. Rubraca…

  • Produced a 44% overall response rate – rates were similar for patients with germline and somatic BRCAm.
  • Achieved a 55% PSA response rate.
  • The median duration of response had not been reached at the time of reporting with responses ranging from 2 to > 24 months

Lynparza (olaparib)

On May 31, 2023, the Food and Drug Administration approved Lynparza in combination with Zytiga (abiraterone) and prednisone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).

In the initial trial evaluating Lynparza 16 of 49 men with mCRPC responded to treatment with Lynparza.  The results of the trial led to the TOPARP-B clinical trial in which only men whose prostate cancers had detectable DNA repair mutations were treated with Lynparza. All men enrolled in the trial had mCRPC, 99% had received Taxotere, 90% Zytiga, Xtandi (enzalutamide), and 38% Jevtana.

The overall response rate to treatment was 54% in 98 men with DNA repair mutations. Among 30 men with confirmed mutations in BRCA 1/2 alterations, 83% responded to treatment, and 57% with PALB2 alterations responded to the treatment. Lynparza delayed cancer progression an average of 5.5 months

PARP Inhibitors Superior to Xtandi & Zytiga

The PROfound clinical trial evaluated the effectiveness and safety of Lynparza compared with Xtandi or Zytiga in men mCRPC who had progressed on prior treatment with new hormonal anticancer treatments and had a qualifying genetic mutation in one of 15 genes involved in the HRR pathway, including among BRCA1/2, ATM and CDK12.3,11

Results from the trial showed that Lynparza delayed cancer progression compared to Xtandi or Zytiga in men with mCRPC selected for BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations.  Updated trial results published in September 2020 revealed that the Lynparza associated delay in cancer progression also led to improved overall survival which and this resulted in FDA approval for patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic mCRPC, who have progressed following prior treatment with Xtandi or Zytiga.11

  • Lynparza reduced the risk of death by 31% versus Xtandi or Zytiga.
  • Median survival duration was 19.1 months for Lynparza versus 14.7 months for Xtandi or Zytiga.

Approximately 1 in 3 men with advanced prostate cancer have alterations in one or more genes linked to repairing damaged DNA. BRCA mutations are the most common DNA repair mutations but ATM, CDK12, CHEK2 and PALB2 mutations were also detected.

Results from the trial showed a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival with Lynparza versus Xtandi, or Zytiga in men with mCRPC selected for BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations.9

In another study of 155 patients with metastatic castration-resistant prostate cancer and deleterious BRCA alterations the overall response rate to Rubraca was reported to be 50%.10

PARP Combinations Further Improve Outcomes

In patients with mCRPC the addition of Lynparza to Zytiga delays PSA progression compared to treatment with Zytiga alone.17 The benefit is most pronounced in men with BRCA-mutated disease. The median delay in time to PSA progression was 41 months for the combination compared to 6 months for treatment with Zytiga alone. According to the study author “The PSA results are consistent with the primary and secondary results of PROpel, and support Lynparza plus Zytiga as an important new first-line treatment option for patients with mCRPC.”  

Adding the PARP inhibitor Zejula to the anti-androgen drug Zytiga may be a new first-line treatment for patients with mCRPC and homologous recombination deficiency. The phase 3 MAGNITUDE clinical trial directly compared the Zejula-Zytiga combination to Zytiga alone in 423 men with mCRPC and biomarkers for HRR. The combination significantly reduced the risk of radiographic progression or death by 27% and the median time to cancer progression was 16.5 months for Zejula treated patients compared to 13.7 months for Zytiga alone. The combination was most effective in patients with BRCA1/2 alterations. Among these high-risk patients, the treatment combination reduced the risk of progression or death by 47% (16.6 months versus 10.9 months).

Results are similar the PROpel clinical trial that  combined the PARP inhibitor Lynparza with Zytiga as 1st-line treatment for men with mCRPC with or without HRR gene mutations.12  In the PROpel study, researchers randomly assigned 796 to treatment with Zytiga with our without Lynparza.  The interim analysis showed that the combination therapy significantly delayed cancer progression regardless of patients’ HRR mutational status.13 Final analysis demonstrated survival time was 42 months for the combination compared with 35 months for Zytiga alone, and let to FDA approval. The greatest benefit was seen in patients with mutations in BRCA genes.

Another Phase 3 clinical trial, TALAPRO-2 had led to FDA approval of a third PARP inhibitor Talzenna® (talazoparib). When used in combination with Xtandi® in men with metastatic castration-resistant prostate cancer (mCRPC) the combination also delays cancer progression compared to treatment with Xtandi alone.15 Participants in the trial needed to have a mutation in at least 1 of the following 12 genes involved in the HRR pathway: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C.

Connect With Others for Support and information

Cancer Connect was the first social network created for people with cancer. Founded by oncologists to support prostate cancer patients and their caregivers, over 40 million individuals have accessed Cancer Connect programs since 1997. Cancer Connect is used by leading cancer centers like Dana Farber, Roswell Park and The James at Ohio State to support their patients. Join the conversation, ask questions, share your experience, and learn how the best cancer centers are treating prostate cancer from others. Share your experience, ask a question, or start a conversation by posting on Cancer Connect.

References:

  1. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. The New England Journal of Medicine. 373:1697-1708. October 29, 2015,
  2. abstracts.asco.org/239/AbstView_239_254043.html
  3. Lynparza Phase III PROfound trial in HRR* mutation-selected metastatic castration-resistant prostate cancer met primary endpoint
  4. Mateo, J, et al (2015). DNA-repair defects and olaparib in metastatic prostate cancer. New England Journal of Medicine, 373(18), pp.1697 – 1708.
  5. Li et al. (2008). Homologous recombination in DNA repair and DNA damage tolerance. Cell Research, 18(1), pp.99-113.
  6. Ledermann et al. (2016). Homologous recombination deficiency and ovarian cancer. European Journal of Cancer, 60, pp.49-58.
  7. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer
  8. ESMO 2019: Preliminary Results from the TRITON2 Study of Rucaparib in Patients with DNA Damage Repair-deficient mCRPC: Updated Analyses
  9. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer
  10. J Clin Oncol. 2020 Aug 14. Epub ahead of print.
  11. Saad F, Shore N, Feyerabend S, et al. Efficacy of physician’s choice of enzalutamide or abiraterone in the control arm of PROfound. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. PD34-09.
  12. https://www.astrazeneca.com/media-centre/press-releases/2021/lynparza-propel-trial-meets-primary-endpoint.html
  13. https://meetings.asco.org/abstracts-presentations/205332
  14. https://meetings.asco.org/abstracts-presentations/205328
  15. businesswire.com: https://www.businesswire.com/news/home/20221004005291/en/

  16. Saad F, Armstrong AJ, Oya M, et al. Prostate-specific antigen analyses in PROpel: abiraterone and olaparib versus abiraterone and placebo as first-line therapy for metastatic castration-resistant prostate cancer. Presented at: 2023 AUA Annual Meeting; April 28-May 1, 2023; Chicago, IL. Abstract MP11-16.

  17. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9). doi:10.1056/EVIDoa2200043

  18. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-and-abiraterone-acetate-plus-prednisone-brca-mutated-metastatic-castration#:~:text=On%20August%2011%2C%202023%2C%20the,as%20determined%20by%20an%20FDA%2D

, , , , , , , , , , , , , , ,

You May Be Interested In