Questions Remain Regarding PARP Inhibition in Recurrent Platinum-Sensitive Ovarian Cancer

Joshua G. Cohen, MD, FACOG, FACS

Although PARP inhibitors have demonstrated significant benefit when used in the first-line maintenance setting for patients with ovarian cancer, it is still unclear whether repeat inhibition in the second line will serve to improve outcomes for those with recurrent disease, according to Joshua G. Cohen, MD, FACOG, FACS, who added that duration of treatment is another area in need of further exploration.

“As more patients with ovarian cancer receive a PARP inhibitor as initial treatment, it's a question of whether those patients will benefit from a PARP inhibitor in the recurrent setting,” Cohen, an assistant professor in the Division of Gynecologic Oncology at University of California, Los Angeles (UCLA), said. “We don't know the answer to that; very limited data are available. One of the next fields of study will be to better understand this.”

Due to the lack of definitive data, Cohen recommended the use of a platinum chemotherapy doublet if the patient has platinum-sensitive disease. The addition of another maintenance therapy, such as bevacizumab (Avastin), could also potentially provide benefit, as was observed in the phase 3 PAOLA-1 trial (NCT02477644), although these data still need to be confirmed within the relapsed setting, Cohen explained.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Ovarian Cancer, Cohen, who is also a gynecologic oncologist at Ronald Reagan UCLA Medical Center, further discussed the efficacy of PARP inhibitors in ovarian cancer, remaining questions regarding repeat inhibition and treatment duration, and the potential for combinations.

OncLive®: What recent developments have been reported with PARP inhibitors in recurrent ovarian cancer?

Cohen: Several trials are examining the efficacy of PARP inhibitors in the recurrent setting. We have good data to suggest that patient populations who have platinum-sensitive disease do benefit from PARP inhibitors. [In these patients], the goal is to prolong their disease-free interval and give them more time off of chemotherapy.

SOLO2 was a recent trial presented during the 2020 ASCO Virtual Scientific Program. Results showed a benefit in overall survival [OS] in patients with platinum-sensitive disease who received a PARP inhibitor. This is a very big development given that we've really been looking for other options beyond standard chemotherapy to impact OS in certain populations.

However, given the available data for PARP inhibitors, we also know that certain patients will not benefit from PARP inhibitors in the maintenance setting, or at least not as significantly [as others]; these patients are those who do not have a BRCA germline or somatic mutation and those who do not have homologous recombination deficiency (HRD) or loss of heterozygosity on their tumor testing. It is likely that patients who have BRCA wild-type disease are not going to benefit nearly as much with a maintenance PARP inhibitor. For those patients, we need to explore other options.

What lessons have been learned about PARP inhibition from recent trials? Based on available data, how do you approach the use of these agents in practice?

If you look at the hazard ratios, [they’re] off the charts. We've really never seen anything like this, with regard to response rates and the benefit that has been seen in patients with ovarian cancer. If you have a patient who has a germline mutation in BRCA1/2 based on testing or a somatic mutation, the benefit we’re seeing is anywhere from 12 to 24 months with regard to progression-free survival [PFS], which is really almost unheard of in the current paradigm of platinum-based chemotherapy.

For instance, in the NOVA trial, when we looked at patients who had a germline BRCA mutation and received niraparib [Zejula] maintenance, we saw a PFS of 21 months compared with 5 months in those who did not receive a PARP inhibitor. Clearly, [this is] a benefit of 16 months with just an oral pill. When we compare that with a different patient population in the same study, those who had a non-germline BRCA mutation, meaning that they had a somatic mutation, there was still a benefit of 6 months with the use of niraparib compared with placebo. Again, is a major win for an oral pill, and it’s usually well tolerated.

Patients who had BRCA wild-type disease and a positive HRD score also had a benefit of approximately 5 months. In patients who we know may not benefit, specifically those who have both BRCA wild-type disease and are negative for HRD, their benefit was approximately 3 months or less. In that setting, while it certainly would be reasonable to put someone on a PARP inhibitor, we have to weigh the toxicity and the cost [and the benefit of the agent] in that setting with the patient to determine what seems feasible.

Now that 3 PARP inhibitors have been approved for use in the first-line maintenance setting, how do you approach second-line treatment?

If someone has previously received a PARP inhibitor in the maintenance setting and experiences disease recurrence, I would still go back to chemotherapy based on the best available data, assuming they are platinum sensitive. If the recurrence occurs within 6 months of receiving a platinum [agent] and they were on a PARP inhibitor during that time, they’re likely not going to benefit from a platinum agent or another PARP inhibitor. We know that platinum sensitivity is a surrogate marker for response in PARP inhibitors. However, if they previously experienced prolonged benefit on a PARP inhibitor, and perhaps they had a disease-free interval of 6 months to 1 year, I would treat that patient with a platinum-based chemotherapy and then discuss various maintenance strategies.

Available data are limited with regard to giving PARP after PARP. We don't have data to necessarily indicate that there's true benefit [with this approach]. I would discuss the addition of another maintenance strategy such as bevacizumab, which has demonstrated benefit based on PAOLA-1. In the recurrent setting, we really can't extrapolate these data. However, I would treat someone who is platinum sensitive with a platinum doublet and put them on bevacizumab based on the available data in the recurrent setting, particularly if they previously received a PARP inhibitor maintenance after their first recurrence.

You mentioned that it remains unclear whether repeat PARP inhibition will be beneficial in patients with recurrent disease. Where do efforts need to focus going forward?

The biggest unmet need right now is [understanding] PARP after PARP. Now that PARP inhibitors are moving into the up-front setting and several patients are going to receive these agents after initial platinum treatment, we need to better understand whether there is going to be benefit with PARP inhibitors after prior exposure.

We also need better options for our patients with platinum-resistant or platinum-refractory disease. Trials have begun to look at immunotherapy in this population, but this still an area of unmet need. Unfortunately, the PARP inhibitors that we do have available do not seem to have significant benefit, at least when used as single agents. If there's a role for PARP inhibitors in the setting of platinum resistance, it's likely going to have to be in the combination setting.

What is known thus far regarding duration of treatment with these agents?

We know that overall, PARP inhibitors are well tolerated. Based on the SOLO2 data, 22% of patients were on olaparib [Lynparza] for more than 5 years. While that's extremely exciting, we still don't quite know the toxicity or the long-term complications associated with prolonged use of a PARP inhibitor. We did see an 8% occurrence rate of acute myeloid leukemia or myelodysplastic syndrome in the group of patients who are on the PARP arm of SOLO2 versus 4% in the placebo arm; granted, there was crossover.

Although it's amazing that we're helping our patients live longer, we need to know how to counsel them. For instance, if you have someone who's responding to a PARP [inhibitor] and they've been on it for 3 years, do you keep them on it another 2 years? Do you stop it? We don't quite know the answer [to that question]. The optimal length of treatment and the toxicity profile once you get past a certain number of years of treatment [is unclear]. However, that’s a good problem to have, and that's something that we're going to continue to look into.

What emerging agents and approaches are under investigation in maintenance therapy?

The next step is seeing whether PARP inhibitors and immunotherapy combinations will be beneficial. It's very intriguing idea although we didn’t see a synergistic effect with bevacizumab plus PARP inhibitors in PAOLA-1, at least in the up-front setting. We still don’t quite understand the interaction between PARP inhibitors and immunotherapy.

In the next 2 to 3 years, we're going to see more of these trials and preliminary results will help us to better understand whether immunotherapy is going to be synergistic with PARP inhibition. We do know that immunotherapy is fairly well tolerated in patients, although to date, we have not seen the response rates with single-agent immunotherapy that we wanted to see in recurrent ovarian cancer. However, based on the science that we now know, PARP inhibitors may improve response rates to immunotherapy. These are the next exciting combinations that we're going to see in clinical trials.