Pursuing PARP Beyond HRD+ Ovarian Cancer

Hye Sook Chon, MD

Single-agent olaparib (Lynparza) and niraparib (Zejula) have shown a significant extension in progression-free survival (PFS) as frontline maintenance therapy in patients with homologous recombination deficient (HRD)–positive ovarian cancer, explained Hye Sook Chon, MD, who added that although the addition of bevacizumab (Avastin) to niraparib demonstrated a numerical improvement in PFS in homologous recombination proficient tumors, the combination may not be the optimal treatment strategy in this patient population.

“[Patients with] homologous recombination proficient [tumors] need to have more study. For those patients, ongoing clinical trials are looking at immunotherapy or immunotherapy with a PARP inhibitor with or without bevacizumab. We’d like to see whether we can [make some progress for] those patients with unmet need. We may be able to use biomarkers as a starting point for more biomarker-driven treatment options in this patient population,” said Chon.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on ovarian cancer, Chon, a gynecologic oncologist at Moffitt Cancer Center, teased out some of the differences between the data with PARP inhibitors in the frontline maintenance setting and shed light on ongoing research with combinations that could broaden their utility in patients with advanced ovarian cancer.

OncLive®: How has the use of bevacizumab changed since the FDA approved it for use in combination with a PARP inhibitor as frontline maintenance treatment?

Chon: The indication for bevacizumab as a maintenance treatment has been a roller coaster until it got approval back in 2017, even though the first publication came in many years prior to that FDA approval. Even though there is a benefit in PFS with bevacizumab maintenance that is clearly more beneficial in a certain patient population who has suboptimal debulking or patients with stage IV ovarian cancer.

I usually use bevacizumab as a maintenance treatment in not all my patients with ovarian cancer, but rather those with the high-risk features I just described. Using bevacizumab in the era of PARP inhibitors as maintenance treatment is based on the PAOLA-1 study. [The study showed that] using bevacizumab in combination with a PARP inhibitor in the HRD-positive [population is associated with] a benefit in PFS. I use bevacizumab with a PARP inhibitor in those patients.

Have PARP inhibitors shown benefit in all patients, irrespective of HRD status?

It is an exciting time for us as gynecologic oncologists that treat patients with ovarian cancer because of the benefit we’ve observed from multiple phase 3 randomized trials with maintenance treatment. However, we are aware that not everybody will benefit from bevacizumab or a PARP inhibitor in the maintenance setting.

The PRIMA trial, even though the benefit [was seen in] all-comers, regardless of BRCA mutation or HRD [status], the true gain from the maintenance treatment compared with the [PAOLA-1 trial], albeit a different patient population and eligibility criteria, was not as robust.

I’m so grateful that we identified those patients who can benefit [from frontline PARP maintenance].

What role could checkpoint inhibitors play in frontline maintenance therapy? Could they be combined with PARP inhibitors?

Immunotherapy does not appear to be as [effective in ovarian cancer as in] other solid tumors such as lung cancer and melanoma based on the data that have been presented so far. There are multiple clinical trials, especially in lung cancer, using combination treatment with chemotherapy [and immunotherapy]. In ovarian cancer, combination approaches rather than single-agent approaches may be more beneficial. We also are aware that there can be more of a synergistic effect between bevacizumab, PARP inhibitors, and checkpoint inhibitors. We will continue to work on defining patient populations who can benefit [from these approaches].

However, we thought that there would be a synergistic effect between bevacizumab and a PARP inhibitor, but the PAOLA-1 study showed modest activity with a more additive benefit rather than a synergistic benefit. We are hoping for more treatment options in that patient population, but caution needs to be taken based on what we learned from the PAOLA-1 study.

What is the importance of not generalizing these study results for application in practice?

We are very excited to have multiple, large, randomized clinical trials in the setting of frontline maintenance treatment. However, we need to be cautious when we interpret or bring these data into clinical practice that we cannot compare [these studies] head-to-head. We need to understand the patient population of each study, and also the primary objective from that study.

When you dig into each study, you will see different patient populations between SOLO-1, PAOLA-1, PRIMA, and GOG-218. You can’t generalize PFS when you apply these data in your clinical practice. Moreover, the patient population you’re dealing with may be different from other colleagues. It is our job as gynecologic oncologists and clinicians sitting across the table with patients to know your patients more than anyone else. From those phase 3 clinical trials, it is your job to interpret those data and apply them to your patient population.