The U.S. Food and Drug Administration (FDA) has granted conditional approval to Rubraca (rucaparib) for treating patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA mutations who have previously received an androgen receptor inhibitor and taxane-based chemotherapy.
The agency’s decision was made under an accelerated approval process after previously granting the therapy breakthrough therapy designation and priority review status for the same indication. It was based on promising response rates and duration of responses seen in patients receiving the therapy in the Phase 2 TRITON2 trial (NCT02952534).
Accelerated approval is given to a medication that addresses an unmet need in a serious medical condition, providing it has shown benefits in a clinical trial. The continued use, and full approval, of Rubraca will require further verification of clinical benefit in the confirmatory Phase 3 TRITON3 trial (NCT02975934), which is still enrolling.
Rubraca became the first PARP inhibitor approved for prostate cancer patients in the U.S., followed just five days later by Lynparza (olaparib), which received the FDA’s nod for mCRPC patients with mutations in DNA repair genes.
“Rubraca is the first in a class of drugs to become newly available to patients with mCRPC who harbor a deleterious BRCA mutation,” Wassim Abida, MD, principal investigator in TRITON2, said in a press release. “Given the level and duration of responses observed with Rubraca in men with mCRPC and these mutations, it represents an important and timely new treatment option for this patient population.”
Rubraca, by Clovis Oncology, is an oral treatment that was initially approved for ovarian cancer. It works by blocking the activity of PARP enzymes, which are responsible for repairing DNA in cells. By blocking the activity of these enzymes, Rubraca prevents cancer cells from fixing their DNA, ultimately causing their death.
PARP inhibitors are particularly effective in cancer cells carrying defects in other DNA repair mechanisms, including those with mutations in the BRCA genes, due to their reliance on PARP to survive and grow.
TRITON2 is investigating the safety and efficacy of Rubraca in 209 metastatic CRPC patients who carry mutations in genes involved in a mechanism of DNA repair called homologous recombination repair (HRR) — which includes BRCA genes. Among them, 62 had inherited or acquired mutations in BRCA and their cancer could be measured at the time of treatment initiation.
Before entering the study, patients had received one to two next-generation androgen receptor inhibitors — which include Xtandi (enzalutamide) and Erleada (apalutamide) — and one taxane-based chemotherapy.
In TRITON2, they are receiving 600 mg Rubraca, given twice daily for up to approximately three years. The trial’s main goals are to assess overall response rates in men with measurable disease, and the proportion of men who experienced a reduction in the levels of prostate-specific antigen (PSA) — a biomarker of prostate cancer — after treatment.
Secondary goals included duration of response, time to disease progression, overall survival, and safety measures.
Results showed that 44% of patients with BRCA mutations and measurable disease responded to Rubraca and that 56% of such responses lasted six months or more. Response duration ranged from 1.7 months to more than two years, and more than half of patients were still responding to treatment at the time of the analysis.
Addiitonally, 63 of the 115 men with BRCA mutations with or without measurable disease had a confirmed PSA response, deemed as a 50% or higher reduction in PSA levels.
The most common adverse reactions seen in at least 20% of BRCA-mutated patients included fatigue, nausea, anemia, transient increase in liver enzymes, decreased appetite, and constipation.
“The data from the TRITON2 clinical trial supporting the FDA approval of Rubraca in mCRPC have been highly consistent over time, and we are pleased that the FDA has granted an accelerated approval for Rubraca,” said Patrick J. Mahaffy, president and CEO of Clovis Oncology. “We are proud to offer Rubraca as a new treatment option to physicians and eligible prostate cancer patients with a deleterious BRCA mutation.”
The confirmatory TRITON3 study is now investigating whether Rubraca is better than standard care treatment for metastatic CRPC patients with mutations in the most common HRR mutated genes, BRCA and ATM.
The trial is recruiting approximately 400 participants across 149 clinical sites in the U.S., Europe, Canada, Australia, and Israel. Patients must have received one prior therapy with second-generation androgen receptor inhibitors, and will be randomly assigned to either Rubraca or the investigators’ choice of either Xtandi, Zytiga (abiraterone acetate), or the chemotherapy Taxotere (docetaxel).
Pending positive results from TRITON3, the FDA may grant full approval to Rubraca for this indication.
“The FDA approval of Rubraca is a significant milestone for patients with metastatic castration-resistant prostate cancer and a deleterious BRCA mutation,” said Howard Soule, PhD, executive vice president and chief science officer of the Prostate Cancer Foundation.
“Although new treatments for prostate cancer have been approved in recent years, most men living with advanced stages of this disease continue to face a difficult journey with few treatment options,” he added.
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