Rubraca (Rucaparib) Shrank Tumors in Nearly Half of Advanced Prostate Cancer Patients with BRCA Mutations.

Rubraca (rucaparib), Clovis Oncology‘s oral PARP inhibitor, shrank tumors in 44% of metastatic hormone-resistant prostate cancer (mCRPC) patients with BRCA mutations included in the Phase 2 TRITON2 clinical trial. The treatment, which is already approved for ovarian cancer, also reduced PSA levels — a biomarker of prostate cancer — in 51.1% of patients with BRCA mutations. The findings were presented recently at the European Society of Medical Oncology (ESMO) 2018 Congress  and other meetings by Wassim Abida, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, and principal investigator for the Phase 2 study.

About a quarter of advanced prostate cancers show mutations in BRCA1BRCA2 or other genes encoding proteins that repair damaged DNA. These tumors are more sensitive to further DNA damage, and often respond well to treatments that block other proteins involved in aiding DNA repair. The PARP enzymes are more involved when BRCA proteins are not functioning properly, and PARP inhibitors have shown great promise in breast and ovarian cancer patients with BRCA mutations. Now, data from the TRITON2 Phase 2 trial (NCT02952534) shows that Rubraca also is effective in prostate cancer patients with such mutations.

The Phase 2 trial is testing the efficacy and safety of Rubraca (600 mg twice a day) in 85 mCRPC patients who have inherited or acquired BRCA mutations, or in one of the 13 DNA repair genes known to increase susceptibility to PARP inhibitors, and who were already treated with androgen receptor-directed therapy (e.g. Xtandi or Zytiga) and taxane-based chemotherapy (e.g. taxotere). Depending on their disease and mutation status, patients were divided in three groups: those with BRCA or ATM mutations and with measurable disease; those with BRCA or ATM mutations without measurable disease; and, those with mutations in other DNA repair genes, with or without measurable disease. The primary goal of the study is to determine the proportion of patients with measureable disease who respond to Rubraca, and those without measureable disease who achieve a significant lowering of their PSA levels. Secondary measures include duration of response, time to disease progression or death, overall survival and safety measures.

After a median follow-up of 5.7 months, 46 out of 85 patients were evaluable for responses. Among the 25 patients with BRCA mutations, 44% had seen their tumor shrink, after only a median of 3.7 months on treatment. At the time of the analysis, more than half of patients were still responding to Rubraca. The results also showed that 51.1% of patients with BRCA  mutations saw a reduction in their PSA levels. The most common adverse events were fatigue, nausea, anemia, and constipation. Five patients discontinued Rubraca due to a treatment-related adverse effect, and one patient died of disease progression.

Enrollment in TRITON2 is ongoing. The trial expects to evaluate about 160 patients from at least 100 worldwide locations, and to study other mutations besides BRCA1/2.

Findings from the trial have led the U.S. Food and Drug Administration to grant breakthrough therapy designation to Rubraca as a treatment for mCRPC patients with BRCA mutations, earlier this month.This FDA designation is given to speed the development of medications that might treat serious conditions and potentially provide an improvement on available therapies.  It has now been shown that PARP inhibitors are a validated therapeutic class in oncology in multiple tumor types, and these new data underscore the benefit that Rubraca may provide for men with advanced, BRCA-mutant castration-resistant prostate cancer.

This information represents a compilation of two articles published in the 10/24/18 Prostate Cancer News Today.

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