Evolution of PARP Inhibitors in Advanced Ovarian Cancer



Michael Birrer, MD: PARP [poly (ADP-ribose) polymerase] inhibitors are a great story of bench-to-bedside transition. The initial work was done primarily in the United Kingdom but also some in the United States, which focused on mechanisms of DNA repair. And it was discovered that the PARP protein is important for the repair of single-stranded DNA breaks. If you inhibit PARP with a PARP inhibitor, then those single stranded breaks become double-stranded breaks. And double-stranded breaks are very important. They are lethal to cells unless the cell can repair them. And the way the cell repairs double-stranded breaks is through a mechanism that involves BRCA1 and BRCA2.

Hence, it was hypothesized that using PARP inhibitors would create what’s known as synthetic lethality within cells that have mutations in BRCA1 and BRCA2. That hypothesis panned out beautifully in the laboratory. These are published in high-level publications, in Nature and Science. And then over a relatively short period of time, these molecules, these PARP inhibitors, found their way into the clinic. And in the clinic the toxicity profile was remarkably tolerable, and the activity of these agents in tumors that had BRCA1 mutations as their origin was simply remarkable. And that’s the history of it.

There were some starts and stops along the way, but we’re here, and it has led to 3 separate agents from 3 separate companies being approved, 2 of them being approved for the treatment and all 3 of them being approved for the maintenance of high-grade serous ovarian cancer.

The names of the three PARP inhibitors include olaparib, niraparib, and rucaparib. The dosing for olaparib was actually 400 mg po bid—orally twice a day—when it was a capsule. It is now in the tablet form, and that is administered as 300 mg po bid. I emphasize that because the capsules actually involved taking 16 capsules a day, and they were very difficult. So the tablet form has been a big move forward. Niraparib is 300 mg once a day, and that may be perceived as an advantage. It’s in 100-mg tablets, and there are 3 of them. The drug can be given at night before the patient goes to sleep. Rucaparib is 600 mg twice a day, and that is somewhat similar to olaparib.

The approval for these drugs first came in this country as treatment. Olaparib was approved as fourth-line treatment, or greater than third-line. And then rucaparib right after that was 3 lines, or 2 lines or greater. So both of them were approved very rapidly for treatment of BRCA1 or BRCA2-mutated ovarian cancer.

At the same time, the randomized phase III trials were performed looking at the value of these drugs for maintenance therapy. And SOLO2, NOVA, and ARIEL3 all got approval for all 3 agents for basically second-line maintenance. And just recently, olaparib got approval through SOLO-1 as first-line maintenance. So it’s complicated, but the take-home message is that we have these drugs for maintenance therapy, including first remission for BRCA1 or BRCA2 patients. And we also have 2 of them for treatment.

Transcript Edited for Clarity.

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