Combination of PARP and PI3K Inhibitors Share a Genomic Landscape in Breast and Ovarian Cancers

August 2015, Vol 6, No 7

Philadelphia, PA—Now that a number of targeted therapies are available for the treatment of cancer, one of the big questions is how to best combine them, especially for patients with few other good treatment options. A preliminary study showed that combining the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) with the investigational phosphatidylinositol 3-kinase (PI3K) inhibitor BKM120 achieved responses in 2 aggressive cancer types that share a genomic landscape—high-grade serous ovarian cancer and triple-negative breast cancer.

This preliminary study was presented at the 2015 American Association for Cancer Research meeting and showed the feasibility of combining these 2 therapies, and further studies are ongoing.

“From a genomic commonality standpoint, there are similarities between high-grade serous ovarian cancer and triple-negative breast cancer. They share a common genomic landscape, with the presence of a high number of copy alterations. Preclinical studies suggested the synergy of these 2 drugs in cell lines, which led to the present study,” explained Ursula A. Matulonis, MD, Medical Director and Program Leader of Medical Gynecologic Oncology, Dana-­Farber Cancer Institute, Boston.

“The phase 1 study reassures us that it is possible to combine olaparib and BKM120, and that we have seen responses in women with triple-negative breast cancer, as well as in women with high-grade serous ovarian cancer,” Dr Matulonis said.

Preclinical data suggested that the combination was more effective than either drug alone.

The first part of the study was a dose-escalation phase that included 46 patients, 12 with breast cancer and 34 with ovarian cancer. Of 10 dose levels tested, the maximally tolerated dose was 50 mg once daily of BKM120 and 300 mg twice daily of olaparib.

In the dose-expansion phase, nausea (80%) and fatigue (66%) were the most common adverse events. Hyperglycemia occurred in 40% of patients, an on-target effect, Dr Matulonis noted. Depression was reported in 22% of patients, and 19% of patients experienced anxiety.

“These central nervous system effects occur because BKM120 crosses the blood–brain barrier,” she said.

“An important finding of this study ­is that we saw responses in both BRCA-mutant and BRCA wild-type cancers. Further study is ongoing to identify biomarkers to select patients most likely to benefit from this combination,” Dr Matulonis said.

Tumor shrinkage of >30%, according to Response Evaluation Criteria in Solid Tumors, was observed in approximately 33% of patients with triple-negative breast cancer or with high-grade serous ovarian cancer. In the latter population, partial response was seen in 26% and stable disease in 48%. In the breast cancer cohort, 5 patients had a partial response.

“Moving forward, combinations of biologics will require understanding the genomic landscape and to figure out where these combinations fit,” Dr Matulonis said.

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