Ursula A. Matulonis, MD
A two-pronged strategy combining the PARP inhibitor olaparib and the PI3K inhibitor BKM120 proved to be a safe and clinically beneficial regimen for women with triple-negative breast cancer (TNBC) and for patients with high-grade serous ovarian cancer, according to early clinical trial results presented at the 2015 AACR Annual Meeting.
The oral regimen demonstrated partial response (PR) rates of 21% among patients with breast cancer and 26% among women with ovarian cancer who participated in the phase I dose-escalation trial.1
The findings show that dual inhibition of the pathways is a valid approach that should be pursued with further research for patients with these malignancies, lead author Ursula A. Matulonis, MD, said in presenting the findings at a press conference. Matulonis is director and program leader of Medical Gynecologic Oncology in the Susan F. Smith Center for Women’s Cancers at the Dana-Farber Cancer Institute in Boston.
Additionally, researchers found that the combination showed activity in certain patients regardless of whether their tumors tested positive for germline BRCA
) mutations, which currently is required under the FDA’s approval for administering olaparib as a treatment for women with advanced, recurrent ovarian cancer.
“It is important that we saw responses against both BRCA
-mutant and BRCA
wild-type cancers,” Matulonis, who also is an associate professor of Medicine at Harvard Medical School, said in a statement. “We need to do further analysis to identify biomarkers that we can use to more effectively identify the patient population that will be most positively affected by the olaparib/BKM120 combination.”Maximum Dose Established
The clinical trial was designed to test the maximally tolerated dose (MTD) of the combination of olaparib and BKM120 given orally on a continuous daily basis.2
The trial also will evaluate the combination of olaparib and another PI3K inhibitor, BYL719, and those findings will be reported at a later date.
Patients were eligible for the trial if they had a confirmed diagnosis of TNBC or high-grade serous ovarian cancer, or a documented gBRCA
mutation in either of those tumor types regardless of tumor histology.
The olaparib/BKM120 segment enrolled 46 patients with ovarian cancer and 24 patients with breast cancer. Participants in the ovarian cancer cohort were a median age of 60 years, 90% had high-grade serous tumors, and 77% had a gBRCA
mutation. In the breast cancer cohort, the median age was 47.5 years, 63% had TNBC, and 58% had a gBRCA
Among the patients with ovarian cancer, the overall response rates (ORRs) were 26% (12 patients) with a PR, 48% (22 patients) with stable disease (SD), and 15% (7 patients) with progressive disease (PD). Five patients (11%) were not evaluable.
For patients with breast cancer, the ORRs were 21% (5 patients) with a PR, 50% (12 patients) with SD, and 17% (4 patients) with PD. Three patients (13%) were not evaluable. Among the responders in the breast cancer group, four patients had triple-negative tumors, including three individuals with gBRCA1
mutations and one with gBRCA
wild-type. The fifth responder’s tumor was positive for estrogen and progesterone receptors and harbored a gBRCA2
In all, the study tested 10 different dose level combinations of olaparib and BKM120. Once the MTD was determined, 10 patients each with breast cancer or high-grade serous ovarian cancer entered the expansion phase.
The MTD was found to be 50 mg once per day of BKM120 plus 300-mg tablets twice per day of olaparib. There were three instances of dose-limiting toxicities (DLTs) of hyperglycemia, transaminitis, and depression, and a grade 4 instance of transaminitis; four patients who each had one toxicity experienced these DLTs.
Overall, the combination was well tolerated, with toxicities primarily of grades 1/2 severity, Matulonis said. The most common nonhematologic toxicities of all grades were nausea (79.4%), fatigue (66%), and hyperglycemia (40%). Anemia (23.5%) and neutropenia (12%) were the most common hematologic toxicities of all grades.Rationale for Combination
Matulonis said the trial illustrates that, in order to develop combinations of biologic agents, researchers will have to establish biomarkers to target appropriate patient populations so that sensitivity to novel agents can be predicted and mechanisms of action can be clarified.
“The combinations of these biologics moving forward will point to us understanding the genomic landscape of that particular patient’s tumor and try to decide, as different combinations are developed, where these combinations fit in,” she said.