Carol Aghajanian, MD, Chief of the Gynecologic Medical Oncology Service at Memorial Sloan Kettering Cancer Center, New York, commented on the final analysis of NOVA for The ASCO Post. She highlighted the difficulty in truly measuring overall survival in recurrent ovarian cancer. Dr. Aghajanian also noted that as PARP inhibitors are now used more in earlier disease, the new restrictions for their use in recurrent disease should not be particularly disruptive in clinical practice.

It is difficult to measure overall survival in ovarian cancer, largely because patients typically cycle through multiple lines of therapy across various stages of disease. In NOVA, as in most clinical trials, placebo recipients who experience disease progression may naturally go on to receive the experimental treatment. Postprogression therapy in NOVA was not determined, just one of several reasons why determining overall survival was clearly challenging, she said. 

The lack of an overall survival benefit in NOVA resulted in niraparib’s restriction to patients with germline BRCA–mutated disease in the second line and later. A similar restriction is expected for rucaparib, based on ARIEL3. Although the progression-free survival benefits for these drugs in this setting were clear, Dr. Aghajanian said, “I do recognize the FDA’s concerns.”

Carol Aghajanian, MD

“Despite the challenge of measuring overall survival, there are trials in the recurrent disease setting that have shown hazard ratios going over 1.0, essentially showing reduced overall survival in certain subgroups of patients treated with PARP inhibitors (ie, those with non–BRCA-mutated disease). It’s one thing not to be able to measure overall survival, or to have overall survival look similar [between the arms], but it’s another when you see the hazard ratio surpass 1.0. I think the FDA’s withdrawal of the indication [in patients with non–germline BRCA–mutated disease] is appropriate,” she said.

More restricted use of PARP inhibitors may also make their use safer, she added, referring to accumulating evidence of increased risk for acute myeloid leukemia and myelodysplastic syndrome. The incidence of these second cancers is clearly higher in the recurrent disease population, exceeding 7% in a subset of patients in NOVA. The indefinite treatment duration of maintenance therapy for recurrent disease would no doubt contribute to this risk, she suggested.

Dr. Aghajanian pointed out that the trials of PARP inhibition for maintenance after two or more treatment lines were designed before the value of these agents in earlier disease was appreciated. As PARP inhibitors are now used earlier, NOVA’s findings and the FDA’s restrictions “are almost a moot point,” she said.

“We are using PARP inhibitors more in the upfront setting. That’s where the biggest advantage is and where our focus should be. I think that’s the bottom line,” Dr. Aghajanian emphasized.

Meanwhile, for patients with non–germline BRCA–mutated recurrent disease who have been doing well, approaches to care vary, she said. “Some patients continue treatment, whereas others decide to stop after, say, 2 or 3 years. Still others decide to stop earlier. That’s a conversation between the patient and her oncologist.” 

DISCLOSURE: Dr. Aghajanian has served as a principal investigator for trials funded by AbbVie, AstraZeneca, Clovis, and Genentech/Roche.