Rubraca (rucaparib) is an oral small-molecule inhibitor conditionally approved by the U.S. Food and Drug Administration (FDA) to treat men with metastatic castration-resistant prostate cancer (mCRPC) who carry BRCA mutations. It was developed by Clovis Oncology.

The approval, specifically for men who previously received an androgen receptor inhibitor and taxane-based chemotherapy, was based on the promising response rates and duration of responses seen in the TRITON2 Phase 2 trial (NCT02952534).

The FDA also approved the therapy, which blocks PARP enzymes, for patients with BRCA-mutated advanced ovarian cancer who previously received two or more chemotherapy regimens.

Clovis also is exploring rucaparib in other solid tumors with BRCA or other DNA-repair gene mutations.

How does it work?

Cancer treatment requires killing the cancer cells. This can be achieved by using agents that damage DNA, which can be radiation or DNA-binding molecules like alkylating agents or platinum. However, DNA repair mechanisms within the cells can offset the effectiveness of these treatments.

PARP is an important enzyme that plays a role in DNA repair during initial damage. Therefore, Rubraca-mediated PARP inhibition can make the cancer cells more sensitive to DNA damage when exposed to radiation or DNA-alkylating agents. This can ultimately result in their death. BRCA also plays a role in DNA repair. Thus, tumors defective in BRCA are particularly prone to DNA damage.

Rubraca inhibits PARP-1, PARP-2, and PARP-3 and therefore has an enhanced ability to prevent DNA repair in tumor cells, particularly those with a defective BRCA gene.

Rubraca in clinical trials

The TRITON program — featuring clinical trials of rucaparib for prostate indications — is an integrated translational-clinical development program. It was designed by researchers to accurately and prospectively identify prostate cancer patients with metastatic and castration-resistant disease who also have tumor genotypes that may lead them to benefit from Rubraca therapy.

TRITON2 is an ongoing, multicenter, open-label Phase 2 clinical trial (NCT02952534) that is evaluating the effects of oral Rubraca in about 360 patients with mCRPC who have a harmful mutation in the BRCA1BRCA2, or ATM genes, or another pre-specified DNA repair gene. Eligible patients must have progressed, or worsened, on at least one, but no more than two previous androgen-receptor targeted therapies and one prior taxane-based chemotherapy.

The study’s primary outcome is the response rate to the treatment, in terms of both an objective response — changes in the size of the tumor — and a prostate-specific antigen (PSA) response. Enrollment in the study has finished and researchers expect to complete the trial in February 2021.

Clovis presented preliminary results from TRITON2 at the European Society for Medical Oncology (ESMO) Congress in 2019. Those results showed that 43.9% of patients with BRCA mutations and measurable disease achieved an objective response rate (ORR), or a predetermined decrease in tumor size, and 52% of participants showed a significant reduction in PSA levels.

TRITON3 is a confirmatory, randomized, and open-label Phase 3 clinical trial (NCT02975934) that is evaluating the effects of Rubraca compared with a physician’s choice of therapy — Zytiga (abiraterone acetate), Xandi (enzalutamide), or Taxotere (docetaxel).

The trial is enrolling an estimated 400 participants with mCRPC who have a harmful germline or somatic mutation in BRCA1, BRCA2, or ATM. Eligible patients must have progressed on at least one, but no more than two prior androgen-receptor targeted therapies and must not have received chemotherapy for mCRPC. The primary endpoint for TRITON3 is progression-free survival.

Participants are currently being recruited at 150 sites across the U.S., Canada, Australia, Europe, and Israel. More information is available here.

The projected completion date for the trial is April 2022.


Last updated: Sept. 1, 2020


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