Frontline Maintenance Therapy Transforms Advanced Ovarian Cancer With PARP Inhibitors

Mae Zakhour, MD

Frontline maintenance therapy options of niraparib (Zejula) and olaparib (Lynparza) alone or in combination with bevacizumab (Avastin) for patients with advanced ovarian cancer continue to shape the field, but the future focuses on defining which regimens are best suited for individual patients and what to do for patients with homologous recombination deficient (HRD)–negative tumors, explained Mae Zakhour, MD.

“Prior to the regulatory approval of PARP inhibitors, there was an unmet need in terms of frontline maintenance therapy in advanced ovarian cancer because there were very few options. As displayed in past data, chemotherapy has been unsuccessful, and, it wasn’t until bevacizumab gained a role in the space that there was a ray of hope,” said Zakhour. “Ultimately, these past few years have been very exciting times for the treatment of advanced ovarian cancer.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on ovarian cancer, Zakhour, a gynecologic oncologist, and associate fellowship program director for the Gynecologic Oncology fellowship at University of California, Los Angeles Health, discussed the rise of PARP inhibitors as frontline maintenance therapy in advanced ovarian cancer and the key data that supported these regulatory decisions.

OncLive^®: What were the biggest takeaways from the SOLO1, PAOLO-1, and PRIMA trials? 

Zakhour: There have been 3 trials that supported the regulatory approvals of PARP inhibitors in the frontline maintenance setting. These trials are SOLO1, which evaluated olaparib as frontline maintenance, PAOLA, which evaluated olaparib and bevacizumab (Avastin) in this setting, and the PRIMA trial, which evaluated frontline maintenance niraparib. Notably, niraparib is an interesting indication because it’s the first frontline maintenance PARP inhibitor for patients with ovarian cancer, regardless of BRCA or HRD status.

SOLO1 was the first trial to come out; it evaluated about 400 patients. All patients had to have either a confirmed or suspected BRCA mutation. Notably, the risk of disease progression or death was 70% lower in patients who received maintenance olaparib compared with those who received placebo. If you look at the progression-free survival (PFS) curve, there is a clear delineation [between the 2 arms]. However, at 3 years, the overall survival rates were not significantly different. 

PAOLO-1 is another randomized, phase 3 trial that evaluated the combination of bevacizumab and olaparib in about 800 patients with advanced ovarian cancer in the frontline maintenance setting. Patients were randomized 2:1 and were stratified based on HRD status. There was a statistically significant difference in PFS for the entire cohort, but there was a particularly significant difference in those who had HRD-positive tumors.

PRIMA evaluated maintenance niraparib in all-comers so, in patients regardless of HRD or BRCA status. The median PFS was found to be statistically significant in the entire cohort. However, if you look again at patients with HRD-positive disease, you see a more significant difference in PFS [with olaparib/bevacizumab].

When applying these data to clinical practice, how do you decide what the optimal therapy is for BRCA- and/or HRD-positive patients?

PARP inhibition, in the frontline maintenance setting, makes a lot of sense for patients who harbor a BRCA mutation, along with those who are HRD-positive. This is not only for patients with germline mutations, but also for those with somatic alterations. 

Although the data are not as strong, we do have an FDA approval for niraparib in the frontline setting, regardless of HRD status. I don't believe the data are as strong to support the use of PARP inhibitors in HRD-negative patients. In terms of specific PARP inhibitors, we avoid cross-trial comparisons, [and try not to compare] hazard ratios from one drug to another. From what we know, olaparib and niraparib seem to be effective in patients who are HRD-positive. 

What is the controversy around HRD testing? 

Interestingly, along with the FDA approval of olaparib plus bevacizumab in the frontline maintenance setting, came the FDA approval for the companion diagnostic test [myChoice CDx to examine if patients are eligible to receive the combination], which was created by Myriad Genetics. 

However, there are several other somatic testing options available, and they all have their own ways of calculating HRD. In practice, there's a variation in terms of what each institution uses for somatic testing. However, I don't believe this assay is being used across the board. 

Does prior treatment with bevacizumab impact whether you would treat patients with the combination of olaparib and bevacizumab?

Prior data have shown that bevacizumab maintenance is not effective in all patients. This therapy mostly benefits patients who have stage IV disease or suboptimal cytoreduction.

For patients who meet the criteria, and also received prior lines of bevacizumab, we do have good data for adding olaparib in the frontline maintenance setting. For patients who have not received prior bevacizumab, I believe we have a good indication for using PARP inhibitor maintenance if they have HRD-positive tumors.

How do the safety profiles of these PARP inhibitors compare with one another?

We know that there's a different adverse effect [AE] profile for each of the PARP inhibitors. We don't have a frontline maintenance approval for rucaparib (Rubraca), but we do use that often in the recurrent setting. For those patients, we're keeping a closer eye on their liver function tests.

With niraparib, we see a lot more thrombocytopenia than with the other agents. There are some patient factors as well in terms of nausea, vomiting, fatigue, that may have us change from one drug to the other. But they do have all slightly different AE profiles so we must consider the patient's comorbidities and their lab values before heading into PARP inhibitor maintenance.

How would you define the current status of veliparib in ovarian cancer?

Consistent with what we're seeing in the other PARP inhibitor trials, veliparib has a similar mechanism of action. It’s showing a statistically significant difference in PFS for patients who receive it upfront and have HRD-positive tumors. Similar to what we know about olaparib and niraparib, veliparib seems to be a potential option for the future.

What key challenges need to be addressed in this space? 

We are still seeking a satisfactory maintenance therapy that has acceptable toxicities in patients who are not BRCA- or HRD-positive. For about 50% of these patients, we still don’t have a great treatment option after they finish chemotherapy. 

Looking forward, what therapies could be used in combination with PARP inhibitors? 

Some ongoing trials are evaluating combinations of immunotherapy and PARP inhibitors, along with the combination of VEGF inhibitors and PARP inhibitors. The field is highly anticipating these data.