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 indicates. The trial, known as TOPACIO/Keynote-162, offers compelling evidence that immunotherapies, which rarely have an impact against ovarian cancer as single agents, can produce a powerful anti-cancer response in tandem with other drugs. A report on the trial is published in today’s issue of JAMA Oncology.
The trial tested a combination 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 62 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 18 percent of patients. Sixty-five percent of participants had their disease kept under control, including three patients with complete responses, eight with partial responses, and 28 with stable disease. That compares to response rates of less than 5 percent in similar patients treated with PARP inhibitors alone, and 9% percent in patients with ovarian cancer treated with pembrolizumab alone.
The results are especially impressive given 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 Panagiotis Konstantinopoulos, MD, PhD, the lead author of the study. "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 complete or partial responses in 19 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.
In several cases, the benefits of the two-drug therapy were quite durable, even among patients whose cancers did not shrink, including nine patients with stable disease that lasted for more than 6 months and 2 patients with stable disease for more than 1 year.
The combination of niraparib with pembrolizumab in the trial follows laboratory research by Dana-Farber scientists, including Drs. Zhao, Matulonis and Konstantinopoulos 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.
Co-authors of the study are: Steven Waggoner, MD, of Case Western Reserve University School of Medicine, University Hospitals of Cleveland; Gregory A. Vidal, MD, of West Cancer Center, Memphis, Tenn.; Monica Mita, MD, of Cedars-Sinai Medical Center, Los Angeles, Calif.; John W. Moroney, MD, of University of Chicago Medicine; Robert Holloway, MD, of Florida Hospital Cancer Institute and Global Robotics Institute; Linda Van Le, MD, of University of North Carolina Lineberger Comprehensive Cancer Center; Jasgit C. Sachdev, MD, of HonorHealth Research Institute and Translational Genomics Research Institute, Scottsdale, Ariz. Eloise Chapman-Davis, MD, of Weill Cornell Medicine, Cornell University; Gerardo Colon-Otero, MD, of Mayo Clinic, Jacksonville, Fla.; Richard T. Penson, MD, of Massachusetts General 56 Hospital; Ursula A. Matulonis, MD, and Alan D’Andrea, MD, of Dana-Farber; Young Bae Kim, MD, of Tufts Medical Center; Kathleen N. Moore, MD, of the University of Oklahoma; Elizabeth M. Swisher, MD, of the University of Washington; Anniina Färkkilä, MD, of Helsinki University Hospital and University Helsinki, Helsinki, Finland; Erica Stringer-Reasor, MD, of the University of Alabama at Birmingham; Jing Wang, PhD, Nathan Buerstatte, MPH, Sujata Arora, MS, Julie R. Graham, PhD, Dmitri Bobilev, MD, and Bruce J. Dezube, MD, of TESARO, Inc., Waltham, Mass.; and Pamela Munster, MD, of UCSF Medical Center at Mount Zion.
The study was supported in part by a Stand Up to Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT16-15) which is led by Dr. Alan D’Andrea.