Exploration of BRCA1/2 as precision medicine targets in mCRPC began more recently than in breast and ovarian cancers, with the discovery that somatic and germline mutations in DNA repair genes are frequent in advanced prostate tumors.3,5,6

“The importance and prevalence of BRCA1/2 and other DNA repair gene mutations in prostate cancer was not appreciated until about 5 years ago,” Dr Antonarakis noted. “Understanding the prostate cancer genome was a prerequisite first step before beginning to design genomically targeted therapies.”

TRITON2 patients took rucaparib (600 mg orally twice daily), and concomitant gonadotropin-releasing hormone analog unless they had prior bilateral orchiectomy.2

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At a median treatment duration of 8.1 months and a median follow-up of 17 months, radiographically confirmed ORR among 62 patients with measurable disease was 43.5% and median duration of response was not evaluable at the time of analysis, ranging from 1.7 to 24 months; 8 patients (6%) experienced complete response (CR), 44.6% had partial response, and 38.5% had stable disease.2 ORR was similar among patients with germline or somatic BRCA mutations and between those with BRCA1 or BRCA2 mutations. The PSA response rate was 54.8%, and patients with BRCA2 mutations had a higher PSA response rate.2

“TRITON2 suggested that prostate cancer patients with BRCA2 mutations responded better than those with BRCA1, that biallelic BRCA1/2 mutations responded better than monoallelic mutations, and that homozygous deletions responded better than other pathogenic BRCA1/2 mutations,” noted Dr Antonarakis. “The most likely explanation for the apparent enhanced efficacy of rucaparib against BRCA2 compared to BRCA1 is that BRCA2 alterations in prostate cancer are more often biallelic mutations, and that BRCA2-related cancers are less likely (than BRCA1-related cancers) to harbor additional concurrent genomic mutations, like TP53.”

Co-occurring mutations in TP53 and PTEN are associated with worse prognosis, and PARP inhibitors generally prove less effective in cancers with ATM, CDK12, and CHEK2 mutations, Dr Yang said.

The incidence of BRCA mutations in early-stage prostate cancers is low; early-stage prostate cancers remain “very curable and treatable” for most patients, noted Dr Yang, so PARP inhibition (PARPi) will most likely be relegated to treatment of mCRPC, he hypothesized.

“That being said, PARP inhibition is being tested in clinical trials in earlier lines of treatment for metastatic disease and in combination with androgen suppression,” Dr Yang said. “Also, PARPi is a very potent radiation sensitizer, and there are trials testing that in combination with androgen suppression and radiation in patients with early-stage, but high-risk, disease.”

Dr Antonarakis was more hopeful that PARP inhibition will be useful in non-mCRPC disease.

“I believe that PARP inhibitors should now be tested in hormone-sensitive metastatic (and even nonmetastatic) prostate cancer,” he said. “At Johns Hopkins, for example, we are currently conducting a trial [phase 2 TRIUMPH study; ClinicalTrials.gov Identifier: NCT03413995] using rucaparib monotherapy without androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer harboring germline DNA repair gene mutations.”

Disclosures: The TRITON2 and TRITON3 studies were funded by Clovis Oncology, the US National Cancer Institute (NCI), and Department of Defense Prostate Cancer Research Program. Clovis Oncology staff were involved in manuscript preparation for the TRITON2 report published in the Journal of Clinical Oncology.2 For a full list of disclosures, please refer to the original study.

References

  1. US Food and Drug Administration. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer [press release]. Published online May 15, 2020. Accessed September 21, 2020.
  2. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. Published August 14, 2020.doi:10.1200/JCO.20.01035
  3. Markowski MC, Antonarakis ES. BRCA1 versus BRCA2 and PARP inhibitor sensitivity in prostate cancer: more different than alike? J Clin Oncol. Published August 14, 2020. doi:10.1200/JCO.20.02246
  4. US Food and Drug Administration. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer [press release]. Published May 20, 2020. Accessed September 21, 2020.
  5. Taylor RA, Fraser M, Rebello RJ, et al. The influence of BRCA2 mutation on localized prostate cancer. Nature Rev Urol. 2019;16(5):281-290. doi:10.1038/s41585-019-0164-8
  6. Tripathi A, Balakrishna P, Agarwal N. PARP inhibitors in castration-resistant prostate cancer. Cancer Treat Res Commun. 2020;24:100199. doi:10.1016/j.ctarc.2020.100199

Topics:

Prostate Cancer