Thomas J. Herzog, MD, Deputy Director, University of Cincinnati Cancer Center, who presented a distillation of the PRIMA trial data along with updated results of the phase III PAOLA-1 trial of olaparib plus bevacizumab maintenance, called the data “practice-changing.”

Thomas J. Herzog, MD

“We’ve suspected for a while that patients with BRCA1 mutations do not do as well as those with BRCA2, even with PARP inhibitors, but these data challenge that premise,” said Dr. Herzog. “The hazard ratios are very close, and [niraparib] is highly effective for both subgroups.”

Clinical Implications

According to Dr. Herzog, these findings “usher in the precision medicine era” for ovarian cancer, considering the benefit in HRD cohorts, but the addition of a niraparib-plus-bevacizumab arm in PRIMA and an olaparib-only arm in PAOLA-1 would have been ideal. Instead, clinicians will have to wait to see those data from the phase II OVARIO trial, he noted. In addition, significant barriers to cross-trial comparisons between PRIMA and PAOLA-1 and an overreliance on unpowered subgroups make it challenging to apply these data in clinical practice, in terms of PARP inhibitor selection.

“There are thought leaders who have spent countless hours studying and comparing data from subgroup analyses from these phase III trials, but as others have pointed out, because they are underpowered subgroups, they are hypothesis-generating at best,” explained Dr. Herzog. “Whether or not one uses bevacizumab—about 40% to 50% in the United States and 60% or higher in Europe do—may ultimately influence how these data are interpreted and clinically implemented by your individual practice.”

FDA Approval: ‘All That Matters’

During the question-and-answer session that followed the discussion, presenter of the PRIMA data, Bradley J. Monk, MD, of the University of Arizona College of Medicine, Phoenix, attempted to simplify the debate. “This isn’t anywhere near as complicated as you make it sound,” he said. “The only thing that matters is the approval of the U.S. Food and Drug Administration (FDA): a biomarker nonrestricted approval. An FDA-approved companion diagnostic is not required to initiate treatment.”

Dr. Monk continued: “It’s all about speed. When you do things efficiently, you get to a label faster, and 37 months after PRIMA started, you have a label, and the flexibility to use the medication as you see fit.”

Although a companion diagnostic is not required, Dr. Monk still recommended clinicians use it for prognostic and predictive purposes. “Niraparib works in homologous recombination–proficient patients, but just not quite as well,” he explained. “For patients who are negative for homologous recombination deficiency (HRD) and undergo observation, the median time to disease progression is 5.4 months. With niraparib, it’s just a few months longer, but there are some exceptional responders.”

Although off label, patients who are HRD-negative may also opt to add bevacizumab, he suggested, as early OVARIO data support the combination. 

DISCLOSURE: Dr. Herzog is on the scientific advisory board of AbbVie, AZ, Caris, Clovis, Genentech, GSK, Johnson & Johnson, Merck, and Myriad.