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 early stages of DNA damage.

The drug, being developed by Clovis, is currently under investigation as a treatment of metastatic castration-resistant prostate cancer (mCRPC). It has already been approved by the U.S. Food and Drug Administration (FDA), under the brand name Rubraca, as a therapy for patients with BRCA-mutated advanced ovarian cancer who have been treated with two or more chemotherapy regimens. (BRCA is a protein that helps repair damaged DNA). Recent data suggest that the PARP inhibitor could also treat metastatic prostate cancers with BRCA or ATM mutations (ATM is another protein that helps repair damaged DNA), or other mutations in DNA damage-repair genes.

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 drugs like alkylating agents or platinums. 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, killing them. BRCA is also involved in DNA repair, so the 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.

The TRITON2 study (NCT02952534) is a multicenter, open-label Phase 2 clinical trial to evaluate the effects of rucaparib in about 160 patients with mCRPC who have a deleterious mutation in BRCA1BRCA2, ATM, or another pre-specified DNA repair gene. Eligible patients must have progressed 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 drug, both objective response and prostate specific antigen response. The study is currently open for enrollment at sites across the U.S. and in Liverpool, U.K.

  1. The TRITON3 study (NCT02975934) is a randomized and open-label Phase 3 trial to evaluate the effects of rucaparib compared to a physician’s choice of therapy — Zytiga (abiraterone acetate), Xandi (enzalutamide) or Taxotere (docetaxel) —  in some 400 patients with mCRPC who have a deleterious 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 mCRP. The study’s primary endpoint is progression-free survival. This study also is enrolling patients at sites across the U.S.

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