PARP Inhibitors Continue to Lead Progress in Ovarian Cancer

Elisabeth Diver, MD

PARP inhibitors have made a significant impact on the field of ovarian cancer, especially in patients with germline BRCA mutations, explained Elisabeth Diver, MD. Their influence is poised to grow in combination with other drugs, she said, such as checkpoint inhibitors and antiangiogenic agents.

In November 2018, the FDA granted a priority review designation to a supplemental new drug application for olaparib (Lynparza), which was based on data from the phase III SOLO-1 trial. The application was submitted for use as a maintenance therapy in patients with newly diagnosed BRCA-positive advanced ovarian cancer who achieved a complete or partial response to standard frontline platinum-based chemotherapy.

At 41 months of follow-up, the median progression-free survival (PFS) by independent central review had not yet been reached in patients who received frontline maintenance with olaparib versus 14.1 months in those who received placebo. The median PFS in the investigator-assessed PFS was not reached in the olaparib arm versus 13.8 months in the placebo arm (HR, 0.30; 95% CI, 0.23-0.41; P <.0001). The FDA is scheduled to make its decision on the application by the end of the first quarter of 2019.

“This is going to be the beginning of practice-changing care for us in ovarian cancer management,” explained Diver. “We're going to see that women with germline BRCA mutations are going to start receiving maintenance therapy after upfront chemotherapy.”

OncLive: Please provide an overview of your presentation.

Could you elaborate on the data we have seen with each PARP inhibitor?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma, Diver, a clinical assistant professor of obstetrics and gynecology, gynecologic oncology at Stanford Medicine, discussed ongoing advances with PARP inhibitors in ovarian cancer.Diver: I discussed the role of PARP inhibitors in ovarian cancer by focusing on the 3 FDA approved PARP inhibitors: olaparib, rucaparib (Rubraca), and niraparib (Zejula). I spoke about their various FDA-approved and non-FDA approved indications for the treatment of women with ovarian cancer.For niraparib, we spoke about the FDA-approved indication for women with platinum-sensitive ovarian cancer as maintenance therapy after platinum-containing chemotherapy. The approval was based on the NOVA trial. This trial was important for ovarian cancer management as it showed benefit in all women with ovarian cancer, regardless of BRCA germline or somatic status.

For olaparib, the most exciting update we have is the new data that just came out with the SOLO-1 trial. We reviewed the new findings, which demonstrated a dramatic PFS benefit after upfront chemotherapy for women with germline BRCA mutations.

Could you highlight the data from the phase III SOLO-1 trial?

What was the impact of the QUADRA trial?

What are some ongoing trials in the space that you’re excited about?

What novel therapies are coming down the pike?

For rucaparib, we reviewed the ARIEL2 and ARIEL3 trials to discuss the maintenance and treatment indications.At the 2018 ESMO Congress, we saw the first PFS curves come from SOLO-1. In this trial, we showed that the median PFS for women with germline BRCA 1/2 after upfront treatment with olaparib was not yet reached. Sixty percent of patients were disease-free at 3 years.QUADRA shows us that we can potentially use PARP inhibitors for treatment in all-comers regardless of BRCA status, though outcomes were certainly better in women with BRCA mutations than those without them.From here, we're excited to see the results of some of the other ongoing PARP inhibitors trials, including GOG-3005 with veliparib. Additionally, [we are waiting to see] some of the upfront niraparib data that we anticipate coming out soon.We spoke a little bit about some of the combination therapy data with PARP inhibitors. None of these combinations are FDA approved, but we looked at the data with cediranib and olaparib from Joyce F. Liu, MD, MPH, in platinum-sensitive ovarian cancer as well as some of the new TOPACIO data.

Does every PARP inhibitor have a role to play in ovarian cancer?

What are the common adverse events (AEs) associated with PARP inhibitors?

What are other patient selection criteria for these therapies?

What do PARP inhibitors have the highest chance of synergizing with?

Specifically, the cediranib and olaparib data looked at the combination of these 2 agents in women with platinum-sensitive ovarian cancer as treatment. The most exciting outcome from that study was that the combination therapy in the non-BRCA women showed great benefit. The combination allowed those women to have the benefit that PARP inhibitors have provided for women with germline BRCA mutations.That's a really good question. We don't have any head-to-head trials, and we don't anticipate having any head-to-head trials. As such, choosing a PARP inhibitor relates to the indication of the therapy as well as some of the side effects and mechanisms of action of the drug.The most common AEs of PARP inhibitors are nausea and vomiting, fatigue, and issues with counts, such as anemia. Specifically, thrombocytopenia is an AE associated with niraparib.There aren’t many differences other than the thrombocytopenia that I think about when choosing one or the other. Niraparib has once-daily dosing, which can be convenient for a lot of women. Sometimes, with liver function issues, I worry about the rise in liver function tests you can see with rucaparib, though those do tend to normalize.We're looking forward to some of the combinations of immunotherapy with PARP inhibitors. I still think we're looking forward to the combination therapy with the VEGF inhibitors that the cediranib data hinted at [when] looking at bevacizumab (Avastin).

We're going to see a bunch of trials coming soon looking at PARP with chemotherapy, particularly as upfront therapy. PARP inhibitors are being introduced in clinical trials in ovarian cancer at all stages of the game—frontline, platinum-sensitive, platinum-resistant recurrence, and for maintenance.

What should physicians know about the use of PARP inhibitors in this space?

At Stanford Medicine, we're going to be opening the OPAL trial, which will look at the combination of niraparib and bevacizumab, and their immunotherapy, TSR-042.The important thing to emphasize is the role that PARP inhibitors have in the maintenance setting after platinum-sensitive recurrence. General population data show that there are still more women who are eligible for these drugs who aren't yet receiving them. While these drugs aren't appropriate for everyone, it's important to consider their use.

Moore K, Colombo N, Scambia G, et al. Olaparib maintenance therapy following first-line platinum-based chemotherapy in patients with FIGO stage III—IV ovarian cancer (OC) with a BRCA1/2 mutation (BRCAm): phase III SOLO1 trial. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA7_PR.