Including a PI3-Kinase Inhibitor with an PARP Inhibitor Improves Tumor Shrinkage in Patients with Resistant Ovarian Cancer
Researchers found that the addition of PI3-kinase caused tumor cells to become sensitive to the effects of the PARP inhibitor.
The combination of olaparib, a PARP inhibitor, with BYL719, an alpha-specific PI3-kinase inhibitor, resulted in tumor shrinkage in patients with resistant ovarian cancer, according to researchers at the Dana-Farber Cancer Institute. Their study results were presented during a clinical trials mini-symposium at the American Association for Cancer Research Annual Meeting 2017.
PARP inhibitor causes tumor shrinkage by impairing the ability of tumor cells to repair DNA damage. However, the response of patients with platinum-resistant ovarian cancer to PARP inhibitor is only approximately 4%. Researchers found in preclinical studies that the addition of PI3-kinase caused tumor cells to become sensitive to the effects of the PARP inhibitor.
The combination treatment was taken to a phase 1 clinical trial that consisted of 28 patients with high-grade serous ovarian cancer, 26 of whom had platinum-resistant cancer. Patients received olaparib, a PARP inhibitor, along with the investigational alpha-specific PI3-kinase inhibitor, BYL719.
"When we combined the 2 drugs, we obtained a very good response rate — as high as 36% in patients with ovarian cancer that was resistant to platinum-based chemotherapy," said Panagiotis Konstantinopoulos, MD, PhD, a medical oncologist with the Susan F. Smith Center for Women's Cancers at Dana-Farber and lead investigator.The median duration of the response in patients with ovarian cancer to the combined treatment was approximately 5.5 months, which is “a good duration of response in this patient population," said Dr Konstantinopoulos. Olaparib is currently approved for the treatment of platinum-resistant ovarian cancer in women with germline BRCA mutation. The response rate of women in this study without germline BRCA mutations was 29%, which is comparable to the 33% response rate of women with germline BRCA mutations. "The activity of this combination in ovarian cancer patients without germline BRCA mutations and with platinum-resistant disease was higher than expected from olaparib monotherapy and warrants further investigation," said Dr Konstantinopoulos.
1. Konstantinopoulos PA, Barry WT, Birrer M, et al. Phase I study of the alpha specific PI3-Kinase inhibitor BYL719 and the poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib in recurrent ovarian and breast cancer: analysis of the dose escalation and ovarian cancer expansion cohort. Presented at: American Association for Cancer Research Annual Meeting 2017; April 1-5, 2017; Washington, DC. Abstract CT008.