Combination of PARP inhibitor and targeted therapy significantly outperforms PARP inhibitor alone in patients with chemotherapy-resistant ovarian cancer

About a third of patients with ovarian cancer who wouldn’t be expected to respond to drugs known as PARP inhibitors had partial shrinkage of their tumors when a second, targeted drug was added to treatment, Dana-Farber Cancer Institute investigators found in a clinical trial.

The results of the phase I trial, which combined the PARP inhibitor olaparib with alpelisib, an investigational drug that targets the cell protein PI3-Kinase alpha, are reported online in the journal The Lancet Oncology.

“When we combined the two drugs, we obtained a very good response rate – as high as 36 percent in some patients with ovarian cancer that was resistant to platinum-based chemotherapy,” said Dana-Farber’s Panagiotis Konstantinopoulos, MD, PhD, the first author of the paper.

In the trial, 28 patients with high-grade serous ovarian cancer received the drug combination. Ten percent achieved a partial response – measurable shrinkage of their tumors – and 50 percent had stable disease. That compares with just four percent of such patients who, according to previous research, would be likely to respond to a PARP inhibitor alone. The side effects of the combined treatment were easily manageable, for the most part, and in line with expectations for the two drugs.

The trial grew out of research at Dana-Farber that indicated that a PI3K inhibitor could sensitize cancer cells to the effects of a PARP inhibitor, which hamstrings tumor cells’ ability to repair damage to their DNA. The median length of the response to the two-drug treatment was 5.5 months, which is “a good duration of response in this patient population,” said Konstantinopoulos.

Olaparib is approved for the treatment of platinum-resistant ovarian cancer in women with inherited BRCA gene mutations. However, in the current trial, 31 percent of women without such mutations responded to the combination therapy – not much lower than the 33 percent response rate in women who did have the 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 therapy alone and warrants further investigation,” said Konstantinopoulos.

The senior author of the paper is Ursula A. Matulonis, MD, of Dana-Farber. Co-authors are: William T. Barry, PhD, Geoffrey I. Shapiro, MD, Erica L. Mayer, MD, Bose Kochupurakkal, PhD, Christin Whalen, Jennifer Curtis, MS, Sarah Farooq, MPH, Weixiu, Luo, MS, Sangeetha Palakurthi, PhD, Paul Kirschmeier, PhD, Joyce Liu, MD, Alan D. D’Andrea, MD, and Eric Winer, MD, of Dana-Farber; Michael Birrer, MD, of Massachusetts General Hospital; Shannon N. Westin, MD, Robert L. Coleman, MD, and Gordon B. Mills, MD, of University of Texas MD Anderson Cancer Center; Karen A. Cadoo, MD, Roisin E. O’Cearbhaill, MD, and Carol Aghajanian, MD, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College; Lewis C. Cantley, PhD, of Weill Cornell Medical College; Julia Eismann, MD, Mary K. Buss, MD, and Gerburg M. Wulf, MD, of Beth Israel Deaconess Medical Center; Scott H. Kaufmann, MD, of Mayo Clinic; and Elizabeth M. Swisher, MD, of the University of Washington.

The trial was supported by the Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Ovarian Cancer Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT16-15) led by Dana-Farber’s Alan D’Andrea, MD, and by the Breast Cancer Research Foundation.