PARP Inhibitors Center Stage for Ovarian Cancer

This transcript has been edited for clarity.

Hello. My name is Dr Susana Banerjee, and I'm a consultant medical oncologist at the Royal Marsden Hospital in London and a reader at the Institute of Cancer Research. It is my pleasure to be talking to you from the European Society for Medical Oncology (ESMO) 2019 Congress. I have been a member of the scientific committee for the gynecologic cancer track, and we have heard some very exciting data here on gynecologic cancer.

At ESMO 2018, the practice-changing results of the SOLO-1 trial were presented and later published in the New England Journal of Medicine.^[1] That study looked at olaparib maintenance therapy after chemotherapy in women with advanced ovarian cancer. Women with a BRCA mutation did very well, with substantial improvement in progression-free survival (PFS). That led to the approval of olaparib in many countries across the world.

Key questions came from that. Can more women benefit from poly(ADP)-ribose polymerase (PARP) inhibitors? Would combinations further improve outcomes? The three studies presented at the presidential session of ESMO 2019 help address some of those questions.

PRIMA Trial

Professor Antonio Gonzalez-Martin presented data on PRIMA.^[2] This was an international randomized study from European and US groups that looked at over 700 women with advanced ovarian cancer in the first-line setting, particularly those at high risk for stage IV disease or with cancer left behind at the end of surgery. Following chemotherapy, these patients received maintenance niraparib or placebo.

In women with homologous-recombination deficiency (HRD), there was a substantial 57% improvement in PFS time (hazard ratio [HR], 0.43). What does the HR of 0.43 mean in practice? Median PFS increased from around 10 months to just over 21 months, so a doubling of PFS time. There was also a statistically significant improvement in PFS of 38% in all-comers (HR, 0.62). When the investigators drilled down further into subgroups looking at homologous-recombination deficient or proficient patients, it was very interesting to see a statistically significant improvement in women who had homologous-recombination-proficient tumors (HR, 0.68).

The implications of this study could be that potentially all women with advanced ovarian cancer—high-grade serous and endometrioid cancers—could benefit from maintenance niraparib.

PAOLA-1 Trial

PAOLA-1^[3] was a large phase 3 randomized academic trial of over 800 women. The question was whether olaparib could add [benefit] to bevacizumab maintenance therapy. Presenter Isabelle Ray-Coquard summarized that there was a substantial improvement in PFS (HR, 0.59) for all-comers who received bevacizumab with olaparib compared to bevacizumab alone as maintenance therapy. What was very well done in this study were the further analyses looking at patients with or without BRCA mutations and then drilling down further according to HRD. The take-home message here is that patients with BRCA mutations had the most benefit and then patients with HRD. There was no substantial improvement in patients who had HRD proficiency (HR, 0.92).

VELIA Trial

The final trial I'd like to mention is the VELIA study, presented by Robert Coleman.^[4] This was a US-led study with international collaboration that looked at the efficacy of the PARP inhibitor veliparib in combination with chemotherapy and then continued as maintenance therapy. The results shown were the comparisons between chemotherapy with veliparib and veliparib maintenance versus chemotherapy with placebo and placebo maintenance. We saw an improvement in the patients who received veliparib in terms of PFS. This had a similar message: that patients with BRCA mutations did better than those with HRD, but substantial improvements were seen in both groups.

Putting It All Together

How do we put this all together? What do these three studies add to the information we know about PARP inhibitors in the first-line setting?

I think the main message is that more women can benefit from having a PARP inhibitor in the first-line setting as maintenance treatment beyond those women with the BRCA mutation. This is key for [improving] access to drugs for more women that could help delay the time before cancer progression. This is an opportunity where we could increase overall survival and increase cure rates because, to date, when patients relapse and then access a PARP inhibitor, the outcomes are not curable, although there is an increased benefit in terms of PFS.

The next main question is: Can some patients receive a PARP inhibitor alone, or would they benefit from a combination with bevacizumab? We really need to drill down and absorb the data that we heard, and work out as an oncology community which patients would benefit most from the PARP inhibitor alone. Would patients with BRCA mutations benefit from olaparib, or would those beyond BRCA mutations benefit with niraparib? Who may benefit from a combination with bevacizumab?

A key question for me as a clinician in practice is how we can best support our patients in terms of the side effects related to these combinations and single-agent PARP inhibitors. It's important to understand how to manage the toxicities, dose interruptions, and dose reductions so that we can have as many patients as possible stay on treatment for longer.

I think these trials have shown us that through well-designed clinical trials and international collaborations we will hopefully improve outcomes for women with ovarian cancer. For example, it would be great to see what the addition of bevacizumab can do to olaparib alone. We saw in PAOLA-1 that all patients had bevacizumab and olaparib was added—what about the other way around? It would also be very interesting when looking at the combination in the VELIA study [to find out whether] patients really need that chemotherapy combination or if they could benefit from the maintenance approach alone. These were all very complex but exciting results.

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