Rucaparib Approved for Ovarian Cancer Free

The FDA greenlighted Boulder, CO–based Clovis Oncology's rucaparib (Rubraca) to treat women with advanced ovarian cancer who have already received at least two chemotherapies and have a somatic or germline BRCA1 or BRCA2 mutation as identified by an approved companion diagnostic test. Up to 20% of high-grade serous ovarian cancers have a deleterious BRCA gene mutation.

To detect the BRCA alterations—and thus determine which patients are eligible to receive rucaparib—the agency also gave a nod to the FoundationFocus CDxBRCA test on December 19. Marketed by Foundation Medicine of Cambridge, MA, the test is the first next-generation sequencing–based companion diagnostic to receive FDA approval.

Rucaparib belongs to a class of anticancer agents called PARP inhibitors, which induce synthetic lethality in cancer cells with defective homologous repair, such as those harboring deleterious BRCA mutations.

Approval of the drug and the companion diagnostic was based on data from two multicenter, single-arm trials evaluating their efficacy and safety. Studies of efficacy involved 106 women with BRCA-mutated advanced ovarian cancer who had already been treated with at least two chemotherapy regimens. At trial enrollment, BRCA status was determined with either local germline test results or a Foundation Medicine clinical trial assay. Mutation status was later verified by the FoundationFocus CDxBRCA test in 96% of the patients for whom a tumor sample was available.

Among all 106 patients, the objective response rate to rucaparib was 54%, with a median duration of response of 9.2 months. Among patients sensitive to platinum-containing regimens, the response rate was 66%. For patients with platinum-resistant and platinum-refractory disease, the response rates were 25% and 0%, respectively. There was no significant difference in response rates between patients with a BRCA1 mutation and those with a BRCA2 mutation.

The safety of rucaparib was assessed in a trial involving 377 patients. The most common side effects were nausea, fatigue, vomiting, anemia, abdominal pain, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. Two cases of acute myeloid leukemia were reported.

Another PARP inhibitor, olaparib (Lynparza; AstraZeneca), was approved in 2014 to treat women with germline BRCA-mutated advanced ovarian cancer who had received at least three prior chemotherapies. In the trial that led to its approval, 34% of 137 such patients responded to olaparib. Head-to-head comparisons of PARP inhibitors have not been done, but the efficacy of olaparib and rucaparib seems comparable based on published data.

In addition, although the toxicities of PARP inhibitors are generally similar, “there will be some innate and unique side effects among the different PARP inhibitors,” says Ursula Matulonis, MD, of Dana-Farber Cancer Institute in Boston, MA. For example, she notes that rucaparib is more likely to cause liver enzyme abnormalities as well as grade 3 anemia, potentially complicating prescribing decisions and making personalized treatment plans and follow-up essential for patients taking the drugs.

Because many patients don't benefit from PARP inhibitors, or may not benefit for very long, physicians want to test the drugs in combination with other therapies, such as antiangiogenic agents or PI3K inhibitors. “Can we make the cancer cell more homologous repair–deficient?” asks Matulonis. Also, “after there's evidence of cancer growth, could we add something to a PARP inhibitor to continue to make it work? These are good questions, but they're not answered yet,” she says. –Suzanne Rose

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.