PARP Inhibitors and Recurrent Platinum-Sensitive Ovarian Cancer

Treating Recurrence after PARP Therapy

• Maintenance therapy with PARP inhibitors is still relatively new
• There are no clear guidelines yet for how to treat women with platinum-sensitive tumors when they recur after PARP maintenance therapy
• New trials, such as MEDIOLA, suggest a triplet option

Four years ago the FDA approved the first PARP inhibitor (niraparib) for maintenance treatment of platinum-sensitive, recurrent epithelial ovarian (or fallopian tube or primary peritoneal) cancer. More PARPs have been approved since. According to Dr. John Nakayama, a gynecologic oncologist with Allegheny Health Network in Pittsburgh, many big questions remained unanswered.

“Everybody is getting PARP inhibitors in the first line, so what do we do with someone who had a BRCA mutation in the frontline, had a great response to it?” he asks. “Those people are still on PARP inhibitors right now, just because of the timing of the FDA indication. But what happens two, three, four years from now when they come back and they’re platinum sensitive, they have this huge progression-free survival?” What treatment should these women receive when they recur? Right now, says Dr. Nakayama, we don’t know.

The SOLO1 trial of maintenance therapy with olaparib (brand name: Lynparza) stopped the drug after two years, but found that more than half the women who were in complete response at baseline who received maintenance olaparib for 2 years remained free of relapse 5 years later. So, asks Dr. Nakayama, what happens to women who stop after two years, go another two or three years free of relapse, and then recur?

Some questions that need answering before deciding how to proceed, says Dr. Nakayama, are:

• How did the patient respond to PARP inhibitors?
• Was it a complete or partial response?
• Is the patient still platinum sensitive?
• When was the last time the patient took a PARP inhibitor?

Women who went years without relapse while on PARP inhibitor maintenance are clearly different than those who progressed while on a PARP inhibitor. “So that’s a big unanswered question that a lot of people are asking: Do you add something else? Do you add an ATR or Wee1 inhibitor?” These drugs, he continues, aren’t FDA-approved in this setting yet, but favorable evidence is emerging.

Data from the MEDIOLA trial is also pointing the way forward. The trial looked at responses in ovarian cancer treated with olaparib plus durvalumab (brand name: Imfinzi) plus bevacizumab (brand name: Avastin). “The data shows very exciting progression-free survival in platinum-sensitive recurrence. They were all part naive mind you, but the fact that you’re seeing such impressive PFS changes in that triplet is very encouraging.”