A combination of an immunotherapy drug and a DNA repair-blocking agent can be significantly more effective than either drug alone in women with hard-to-treat ovarian cancer, a phase I/II clinical trial led by Dana-Farber Cancer Institute researchers demonstrates. The investigators will present their findings on Tuesday, March 27th at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women's Cancer being held here this week.
The trial tested a tandem of pembrolizumab – which targets the checkpoint protein PD-1 on immune system T cells – and the PARP inhibitor niraparib – which interferes with cancer cells' ability to repair damaged DNA – in 60 patients with ovarian cancer that was resistant to platinum chemotherapy. The investigators found that the drug pair produced complete or partial responses – total or limited shrinkage of ovarian tumors – in 25 percent of patients. That compares to response rates of less than 5 percent in similar patients treated with PARP inhibitors alone, and 11 percent in patients with ovarian cancer treated with pembrolizumab alone.
The results are especially impressive in light of the fact that study participants had received multiple earlier treatments for ovarian cancer, and therefore represented an especially hard-to-treat group, trial leaders say. Some participants had undergone up to five previous treatments, and more than half had already been treated with bevacizumab, a drug that closes off cancers' access to the bloodstream.
"These results are extremely promising for this set of patients, who have had several previous treatments and don't respond to platinum chemotherapy, and therefore have few other treatment options available," said Dana-Farber's Panos Konstantinopoulos, MD, PhD, who led the trial and will present the finding at the SGO Annual Meeting. "Some participants are continuing to benefit from the therapy, more than 18 months after starting it."
PARP inhibitors such as niraparib have been approved by the Food and Drug Administration for patients with ovarian cancer that carries mutations in the BRCA genes, but PARP inhibitors alone produce a response in less than 5 percent of patients whose ovarian cancer is platinum-resistant and free of BRCA mutations. In the new trial, niraparib plus pembrolizumab sparked remissions in 26 percent of patients with platinum-resistant ovarian cancer and normal BRCA. Also encouraging, the combination didn't produce severe or unexpected side effects in patients.
The combination of niraparib with pembrolizumab in the trial follows laboratory research by Dana-Farber scientists suggesting that PARP inhibitors and immunotherapy would make a synergistic pair, Konstantinopoulos says. PARP inhibitors allow cancer cells to accumulate DNA damage, which makes the cells more visible – and vulnerable – to the immune system.
The results of the new trial set the stage for further studies of combinations of PARP inhibitors and immune checkpoint inhibitors in ovarian cancer as well as other solid cancers, Konstantinopoulos remarks. Furthermore, the correlative work for this study is supported by the Dana-Farber SU2C Ovarian Cancer Dream Team.