Novel olaparib combination shows activity in ovarian, breast cancers

PHILADELPHIA — A combination treatment composed of the PARP inhibitor olaparib and the investigational PI3K inhibitor BKM120 demonstrated activity in women with triple-negative breast cancer or high-grade serous ovarian cancer, according to study results presented at the American Association for Cancer Research Annual Meeting. The regimen also appeared safe, researchers said.

High-grade serous ovarian cancer and triple-negative breast cancer are similar in that they often have germline BRCA mutations, have a sensitivity to platinum agents and have high copy number alterations based on The Cancer Genome Atlas, according to study background. Further, preclinical data have suggested olaparib (Lynparza, AstraZeneca) is synergistic with BKM120 (Novartis) and BYL719 (Novartis) in both cancers.

Ursula A. Matulonis, MD, medical director of gynecologic oncology at the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute and associate professor of medicine at Harvard University Medical School, and colleagues evaluated olaparib plus BKM120 in 12 patients with triple-negative breast cancer and 34 patients with high-grade serous ovarian cancer. Thirty-five patients had germline BRCA mutations.

“This is one area where we in ovarian cancer are in the forefront,” Matulonis said during a press conference. “We are using an FDA-approved biomarker through germline BRCA status to basically say when a patient is eligible to receive olaparib.”

The researchers tested 10 dose-level combinations of olaparib and BKM120, starting at 60 mg daily BKM120 with 100 mg twice daily olaparib. Researchers determined the maximum tolerated dose was 50 mg BKM120 once daily with 300 mg olaparib twice daily.

Dose-limiting toxicities included grade 3 depression in one patient and a grade 4 liver function test in another patient. These outcomes caused the researchers to limit the dosage of BKM120 to only half of the single-agent dose, even though the eventual maximum combination dosage was higher than that which brought about the toxicities.

The patient who experienced depression had well-controlled diabetes when enrolled into the trial, but she discontinued the trial when her diabetes was no longer manageable, Matulonis said. The patient with liver functionality adversity had liver metastases that elevated during the initial cycle and the investigators could not rule out the combination dose as a cause for the elevation.

Still, the investigators concluded that the combination is feasible, and there was evidence of clinical benefit at all dose levels in both the germline BRCA-positive and germline BRCA wild-type patients with triple-negative breast cancer and high-grade serous ovarian cancer.

A second dose escalation trial combining olaparib with BYL719 — which Matulonis said is better tolerated — in the treatment of both cancers is ongoing.

“The combination of these biologics moving forward will point to us understanding the genomic landscape of a patient’s tumor and help us to decide, as different combinations are developed, where each combination fits,” Matulonis said. – by Anthony SanFilippo

Reference:

Matulonis UA, et al. Abstract 8972. Presented at: American Association for Cancer Research Annual Meeting; April 18-22, 2015; Philadelphia.

Disclosure: The investigational agent BKM120 was provided by Novartis. Matulonis reported research funding and speakers bureau remuneration from AstraZeneca. HemOnc Today was unable to obtain a list of relevant disclosures for the other researchers.