June 2015, Vol 4, No 3
PARP Inhibitor and PI3K Inhibitor Combo in Breast and Ovarian Cancers
Now that a number of targeted therapies are available for the treatment of cancer, one of the big questions is how best to combine them, especially for patients with few other treatment options. Preliminary study shows that combining the PARP inhibitor olaparib with the investigational PI3K inhibitor BKM120 achieves responses in 2 aggressive cancer types that share a genomic landscape: high-grade serous ovarian cancer and triple-negative breast cancer. This preliminary study 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, Director and Program Leader of Medical Gynecologic Oncology at Dana-Farber Cancer Institute, Boston, MA.
“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,” she continued.
This study, presented at the 2015 Annual Meeting of the American Association for Cancer Research, follows on the heels of preclinical data suggesting that the combination is more effective than either drug alone; both the preclinical studies and the phase 1 study are funded by the Stand Up to Cancer (SU2C) initiative.
“We could not have done these studies without SU2C,” she emphasized.
The first part of the study was a dose-escalation phase that included 46 patients (12 with breast cancer and 34 with ovarian cancer [90% with serous ovarian cancer]). Seventy-seven percent of patients had germline BRCA mutations. Median age of ovarian cancer patients was 60 years, and median age of breast cancer patients was 47.5 years. Of the breast cancer patients, 63% had triple-negative disease.
Of 10 dose levels tested in the dose-escalation phase, the maximum tolerated dose was 50 mg once daily of BKM120 and 300 mg/bid of olaparib. Overall, the combination was well tolerated. Dose-limiting toxicities of concern were grade 3 depression in 1 patient and grade 4 liver function test abnormality in another patient.
In the dose-expansion phase, nausea (79%) and fatigue (66%) were the most common adverse events. Hyperglycemia occurred in 40%, depression in 22%, and anxiety in 19%.
“These central nervous system effects occur because BMK120 crosses the blood-brain barrier,” Matulonis 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,” she said.
Tumor shrinkage of greater than 30% according to RECIST was observed in about one-third of patients with either triple-negative breast cancer or high-grade serous ovarian cancer. In the ovarian cancer patients, partial response was seen in 26% of patients, and stable disease in 48%. In the breast cancer cohort, 5 patients achieved a partial response.
The next step is to study the PI3K inhibitor BYL719, which does not cross the blood-brain barrier, and determine whether this drug can be more safely combined with olaparib.
“Moving forward, combination of biologics will require understanding the genomic landscape and to figure out where these combinations fit,” Matulonis said.
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