Perspectives on ARIEL4 were provided for The ASCO Post by the invited discussant Ursula Matulonis, MD, Professor of Medicine, Harvard Medical School, and Chief of Gynecologic Oncology and the Brock Wilson Family Chair at Dana-Farber Cancer Institute, Boston, and by Konstantin Zakashansky, MD, Director of Gynecologic Oncology at Mount Sinai West, Director of the Division of Minimally Invasive Gynecologic Surgery for the Mount Sinai Health System, and Associate Professor of Obstetrics and Gynecology, Icahn School of Medicine at Mount Sinai.
“My key takeaway from this presentation is that the ARIEL4 data fits the paradigm that single-agent PARP inhibitors in BRCA-mutant recurrent ovarian cancer are comparable to chemotherapy and may at times be superior, depending on the study population, trial design, and control treatment,” Dr. Matulonis said.
Ursula Matulonis, MD
Konstantin Zakashansky, MD
In the ARIEL4 efficacy population—which excluded patients with BRCA reversion mutations—progression-free survival was improved with rucaparib vs chemotherapy (hazard ratio = 0.64) but response rates were similar. Since nearly one-third of patients were partially platinum-sensitive, she questioned whether weekly paclitaxel is the best control treatment for this subgroup.
“Compiled data in BRCA-mutant patients show that the response rate with olaparib drops with increasing platinum resistance and increasing number of prior therapies,” Dr. Matulonis said. “How PARP inhibitor activity compares against chemotherapy in randomized trials such as ARIEL4 will depend on history, degree of platinum sensitivity, and choice of the control-arm chemotherapy.”
But Are the Findings Already Irrelevant?
Although the findings of ARIEL4 are “exciting and encouraging,” they may be of less practical importance, Dr. Zakashansky commented. He noted that early on in the development of PARP inhibitors, their noninferiority to standard chemotherapy was welcome news, as patients could be offered a better-tolerated treatment. “Now, we have randomized data showing they are superior…. That’s encouraging. But with overwhelming data showing the superiority of maintenance PARP inhibitors for BRCA-mutated patients early in their treatment, there are going to be very few patients who have not received a PARP inhibitor by the second or third line of therapy,” he pointed out.
“Unfortunately, it’s a problem with this trial and others like it that it takes years to conduct. This study only included patients who were BRCA1/2 germline mutation or somatic mutation carriers and were PARP inhibitor–naive, and already received two or more prior treatments. Where are we going to find those patients? They are important data…, but from the trenches, it’s not of tremendous practical importance,” Dr. Zakashansky maintained.
What he viewed as perhaps more interesting and important were the results of the exploratory analysis in the subgroup with BRCA reversion mutations—who derived more benefit from chemotherapy than rucaparib. “These are novel data on BRCA reversion mutations,” he said. “We know some patients are going to be resistant to PARP inhibitors, but the data allowing us to understand the mechanism behind this resistance were lacking. Knowing more about these reversion mutations can help us differentiate potential responders from nonresponders and identify patients who perhaps should go on an alternative treatment.”
DISCLOSURE: Dr. Matulonis has received honoraria from Advaxis; has served as a consultant or advisor to Merck, NextCure, and Novartis; has received research funding from Fujifilm, Immunogen, Leap Therapeutics, Merck, Mersana, Novartis, SQZ Biotechnologies, Syndax, and Tesaro; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca. Dr. Zakashansky has served as a consultant or advisor for Ethicon and Verb (Johnson & Johnson).
