BMN 673 monotherapy makes splash in BRCA-mutated ovarian, breast cancer



AMSTERDAM – The experimental PARP inhibitor BMN 673 had impressive single-agent activity in pretreated breast and ovarian cancer patients carrying BRCA 1 and 2 mutations, based on results from a small, ongoing phase I/II trial.

The objective response rate by RECIST (Response Evaluation Criteria in Solid Tumors) criteria was 44% for both the breast (8/18) and ovarian (11/25) cancer patients.

Patrice Wendling/IMNG Medical Media

Dr. Ramesh Ramanathan

Responses were durable in both groups at a median of about 8 months, leading to a median progression-free survival of 32.3 weeks in ovarian cancer patients and 33.1 weeks in breast cancer patients, Dr. Ramesh Ramanathan reported in a late-breaking abstract at the multidisciplinary European cancer congresses.

"There’s very little to discuss here. This is a flat-out, very successful phase 1 trial," said Dr. Peter Dubsky, a surgeon with the Medical University of Vienna, who was invited to discuss the results.

He observed that toxicity with BMN 673, described in the abstract as the most potent and specific inhibitor of poly-ADP ribose polymerase (PARP) in clinical development, was lower than would be expected from a PARP inhibitor. In addition, "responses were seen starting at 100 mcg, but the maximum tolerated dose is 10 times that," Dr. Dubsky said.

The maximum tolerated dose of 1 mg/day is being used in a newly launched, open-label, 429-patient phase III trial, said Dr. Ramanathan, medical director of the Scottsdale (Ariz.) Healthcare Research Institute. The multicenter trial is evaluating BMN 673 against the physician’s choice of capecitabine (Xeloda), eribulin (Halaven), gemcitabine (Gemzar), or vinorelbine (Navelbine) in germline BRCA-mutation patients with locally advanced or metastatic breast cancer treated with no more than two prior chemotherapy regimens for metastatic disease.

The dose-escalation portion of the phase I study involved 80 patients dosed at 25-1,100 mcg/day. The study was then expanded and included 18 patients with germline BRCA-mutant breast cancer and 28 patients with germline BRCA-mutant ovarian cancer. Patients were dosed once daily at 100 mcg and above.

The heavily pretreated expansion cohort had received a median of three prior chemotherapy regimens (range, 0-8). BRCA 1 mutations were more common in ovarian cancer patients (20/28), and BRCA 2 mutations were more frequent in the breast group (11/18). Their median age was 58 years and 42 years, respectively.

Among 25 ovarian cancer patients evaluable by RECIST, 1 patient had a complete response, 10 had partial responses, and 4 had stable disease lasting 24 weeks or more, Dr. Ramanathan reported.

Responses were seen in 17 of 22 platinum-sensitive patients. "Platinum sensitivity may be important in identifying patients sensitive to BMN 673," he said.

Cancer antigen 125 levels evaluable in 27 ovarian cancer patients dropped by more than 50% in 19 (70%) and returned to the normal range in 9.

All 18 breast cancer patients were evaluable by RECIST, with a complete response in 1, partial responses in 7, and stable disease in 5. The clinical benefit response rate (complete response, partial response, or stable disease for at least 24 weeks) was 72% (13/18).

At the 1-mg/day phase III dose, however, the RECIST response rate reached 50% (7/14), and the clinical benefit response rate, 86% (12/14), Dr. Ramanathan said.

He noted that BMN 673 was generally well tolerated, with the most common drug-related toxicities being myelosuppression, fatigue, nausea, and alopecia occurring in less than 30% of patients. In the phase I portion of the trial, thrombocytopenia was dose limiting, occurring as a grade 3 event in 14 patients (17.5%) and a grade 4 event in 1 patient (1.3%). Grade 3 anemia was seen in 12 patients (15%).

BioMarin Pharmaceuticals funded the trial. Dr. Ramanathan reported clinical research and travel support for the presentation. His coauthors reported similar relationships as well as employment with BioMarin.

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