In some patients with advanced ovarian cancer, the combination of programmed cell death protein 1 (PD-1) and poly (ADP-ribose) polymerase (PARP) inhibitors can produce responses, but up until now, investigators have been unable to predict which patients would not benefit from the treatment and should explore other options. A new study by Färkkilä et al in Nature Communications showed that it now may be possible to identify such patients in advance.
Researchers found that two factors—a specific pattern of gene mutations in the tumor cells, and evidence of a vigorous immune response to the cancer—are markers of whether patients will respond to the combination. Patients whose tumor tissue had either of these features were more likely to respond, whereas those whose tissue lacked either feature showed no benefit from the drug combination.
Panagiotis Konstantinopoulos, MD, PhD
“By taking these factors into account, researchers leading trials of this combination in patients with advanced chemotherapy-resistant ovarian cancer may select individuals who may respond to this combination of drugs,” said co–senior study author Panagiotis Konstantinopoulos, MD, PhD, Director of Translational Research, Gynecologic Oncology, at Dana-Farber Cancer Institute.
PD-1 and PARP Inhibition in Ovarian Cancer
Although checkpoint inhibitors work exceptionally well in many types of cancer, ovarian cancer has been an exception. The PD-1 checkpoint inhibitor pembrolizumab, for example, produces responses in less than 5% of patients with PD-L1–negative cancers. The same is true of PARP inhibitors; as a single agent, the PARP inhibitor niraparib has a beneficial effect in just 3% of patients with ovarian cancer that is resistant to platinum-based chemotherapy and is not BRCA-mutated.
When checkpoint and PARP inhibitors are used together, however, those benefits multiply. The TOPACIO/Keynote-162 clinical trial found that pembrolizumab and niraparib in combination produced complete or partial responses in 18% of patients with platinum-resistant ovarian cancer. Furthermore, 65% of the study participants had their disease kept under control. For some of those who responded, the benefits lasted for well over a year. The results were especially impressive because all the participants had received multiple previous treatments for ovarian cancer, making them especially hard to treat.
However, study leaders had no way to determine, in advance, which participants wouldn’t be helped by the therapy.
Methods
To see if they could be identified, Dr. Konstantinopoulos his colleagues conducted two analyses of participants’ tumor samples: a letter-by-letter search of the tumor cells’ genome for abnormalities and a census of “exhausted” T cells within the tumor tissue. The researchers then correlated their findings with information on whether and how extensively patients responded to the combination therapy.
Results
“By taking these factors into account, researchers leading trials of this combination in patients with advanced chemotherapy-resistant ovarian cancer may select individuals who may respond to this combination of drugs."— Panagiotis Konstantinopoulos, MD, PhD
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They found that patients whose tumor cells carried either mutational signature 3 (a pattern of gene mutations associated with an inability to repair certain kinds of DNA damage) or a positive immune score (a measure of signaling activity between tumor cells and the immune system) may derive a benefit from treatment with pembrolizumab/niraparib. Patients whose cells lacked either of these features received no such benefit.
“Patients with advanced or metastatic ovarian cancer who are resistant to standard platinum-based chemotherapy agents often have few further options for treatment,” concluded Dr. Konstantinopoulos. “Our findings will help ensure that patients for whom a PARP inhibitor-checkpoint inhibitor combination won’t be beneficial can focus on other clinical trials of treatments that may be more effective for them.”
Disclosure: The study was supported by a grant from Stand Up To Cancer, the Ovarian Cancer Research Fund, TESARO, GSK Company, and Merck & Co. For full disclosures of the study authors, visit nature.com.
