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Combining the poly(ADP-ribose) polymerase inhibitor olaparib and the investigational P13K inhibitor BKM 120 was safe and active in triple-negative breast cancer and ovarian cancer in a phase I trial.
Patients with both BRCA-mutant and BRCA-wildtype breast cancer responded to the combination. One patient with germline BRCA-wildtype triple-negative breast cancer (TNBC) and lung metastases had a partial response and remained on treatment for 20 cycles, or nearly 2 years, study author Dr. Ursula Matulonis reported at the annual meeting of the American Association for Cancer Research.
Rationale for the study lay in data from mouse models showing that combination olaparib and BKM120 was more effective than either drug alone in BRCA-mutant breast cancer and BRCA-wildtype TNBC. Similarities also exist between high-grade serous ovarian cancer and TNBC, including an association with germline BRCA mutations, sensitivity to platinum agents, and high copy number alteration rates, she said in a press briefing at the meeting.
Olaparib (Lynparza), a PARP (poly [ADP-ribose] polymerase) inhibitor, was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.
The phase I, dose-escalation study enrolled 70 patients with a diagnosis of recurrent high-grade serous ovarian cancer or TNBC but also allowed documented germline BRCA mutation carriers regardless of histology.
The histology was high-grade serous in 90% of the 46 ovarian cancer patients, while 2% had high-grade endometrioid disease, 4% carcinosarcoma, and 4% poorly differentiated carcinoma. Most of the 24 breast cancer patients (63%) had TNBC, while 29% had estrogen receptor–positive/progesterone receptor–positive disease and 8% had ER+/PR– breast cancer.
Germline BRCA mutations were present in 77% of ovarian and 58% of breast cancer patients. The median age in the two groups was 60 years and 47.5 years, respectively. Prior PARP or P13kinase pathway inhibitors were allowed during dose escalation.
Among ovarian cancer patients, 12 (26%) had a partial response and 22 (48%) had stable disease. Responses were similar in the breast cancer group, with 5 (21%) partial responses and 12 (50%) patients with stable disease, said Dr. Matulonis of the Dana-Farber Cancer Center and Harvard Medical School, both in Boston.
Ten dosing regimens were evaluated in the study, beginning with an initial dose of BKM120 60 mg once daily and olaparib 100 mg twice daily, both given orally on a continuous basis. This elicited two dose-limiting toxicities (DLTs) – grade 3 hyperglycemia and grade 3 transaminitis – and prompted the investigators to back down to dose levels of 40 mg and 50 mg, respectively.
No DLTs occurred until dosing reached BKM120 60 mg and olaparib 300 mg, at which point one grade-4 transaminitis and one grade-3 depression were reported in cycle 2, she said. Dose levels of 50 mg and 300 mg, respectively, were selected for the expansion cohort.
As for why the two DLTs occurred at the initial dose but the same doses were later used without incident, Dr. Matulonis said that one of the patients with a DLT fell out of well-controlled diabetes and the other had liver metastases that accelerated during treatment.
Overall, the most common nonhematologic toxicities of any grade were nausea (79.4%), fatigue (66%), and hyperglycemia (40%). Related hematologic toxicities of any grade were anemia in 23.5%, neutropenia in 12%, and thrombocytopenia and leukopenia, both in 10% of patients.
“Combinations of biologic agents will require establishment of target patient populations using biomarkers in order to predict sensitivity as well as determine mechanisms of resistance,” Dr. Matulonis concluded.
Next-generation sequencing is ongoing for BKM120/olaparib patients and mechanisms of response and resistance are being studied in human ovarian mouse models, she added.
The study was funded by Stand Up to Cancer, the Kathryn Fox Samway Foundation, and participating centers. Olaparib was provided by AstraZeneca and BKM120 by Novartis. Dr. Matulonis reported research funding from AstraZeneca, as well as renumeration for attending a speaker’s bureau.
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