Rucaparib is a drug being developed by Clovis Oncology as a treatment for metastatic castration-resistant prostate cancer (mCRPC). Rucaparib is an oral, small-molecule inhibitor of PARP1, PARP2, and PARP3, which all belong to a family of enzymes called poly-ADP-ribose polymerases (PARP). PARP enzymes play an important role in the DNA repair process during the early stages of DNA damage.
Rucaparib has already been approved by the U.S. Food and Drug Administration (FDA), under the brand name Rubraca, as a treatment for patients with BRCA-mutated advanced ovarian cancer who have been treated with two or more chemotherapy regimens (BRCA is a gene encoding for a protein that helps repair damaged DNA).
Clovis is also exploring rucaparib in other solid tumors with BRCA or other DNA-repair gene mutations, including breast, pancreatic, gastroesophageal, bladder, and lung cancers.
How rucaparib works
Cancer treatment requires killing the cancer cells. This can be achieved using agents that damage DNA, such as radiation or DNA-binding molecules like alkylating agents or platinum. However, their effectiveness can be offset by DNA repair mechanisms within the cells. Since PARP is an important enzyme involved in DNA repair during initial damage, rucaparib-mediated inhibition of PARP can make the cancer cells unusually sensitive to DNA damage when exposed to radiation or DNA-alkylating agents, thereby killing them. BRCA is also involved in DNA repair, so tumors defective in BRCA are particularly prone to DNA damage.
Since rucaparib inhibits PARP-1, PARP-2, and PARP-3, it has an enhanced ability to prevent DNA repair in tumor cells, particularly those with a defective BRCA gene.
Rucaparib in clinical trials
The TRITON (trial of rucaparIb in prostate indications) program is an integrated translational-clinical development program that is designed 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 rucaparib therapy.
TRITON2 is a multicenter, open-label Phase 2 clinical trial (NCT02952534) to evaluate the effects of oral rucaparib in about 360 patients with mCRPC who have a deleterious mutation in BRCA1, BRCA2, ATM, 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 response rate to the treatment, both objective response (the size of the tumor) and prostate-specific antigen (PSA) response. The study has finished enrollment at sites across the U.S. and in Liverpool, U.K and is expected to be completed in February 2021.
Clovis presented preliminary results from the TRITON2 study at the European Society for Medical Oncology (ESMO) congress in 2019. They showed that 43.9% of patients achieved an objective response rate (ORR), or a predetermined decrease in tumor size, and 52% of patients showed a change in PSA levels.
TRITON3 is a randomized and open-label Phase 3 clinical trial (NCT02975934) to evaluate the effects of rucaparib compared to a physician’s choice of therapy — Zytiga (abiraterone acetate), Xandi (enzalutamide) or Taxotere (docetaxel) — in an estimated 400 patients with mCRPC who have a harmful germline (found in all cells of the body) or somatic (only found in localized cells of the body) 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 study’s primary endpoint is progression-free survival. This study is currently recruiting patients at sites across the U.S., Canada, Australia, and Europe and has a projected completion date of April 2022.
Based on the preliminary results from the TRITON2 trial, Clovis filed a supplemental new drug application (sNDA), which was granted priority review designation. Priority review shortens application review times from 10 months to six months. A decision from the FDA is expected in the summer of 2020.
Last updated: Jan. 16, 2020
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