Molecular Markers and Prior Treatment Inform Maintenance PARP Inhibition in Ovarian Cancer

Bradley J. Monk, MD, FACOG, FACS

Homologous recombination deficiency (HRD) status, BRCA mutational status, and prior bevacizumab (Avastin) treatment should be used to inform which PARP inhibitor—olaparib (Lynparza), rucaparib (Rubraca), or niraparib (Zejula)—a patient with ovarian cancer should receive in the frontline or recurrent maintenance settings, said Bradley J. Monk, MD, FACOG, FACS, who added that, ultimately, the goal is for every eligible patient to receive PARP inhibition in the frontline maintenance setting alone or in combination with bevacizumab.

“The standard treatment for ovarian cancer is global. Whether you are a medical oncologist or a gynecologic oncologist, and whether you are in Phoenix, Arizona; or Berlin, Germany, [the standard of care] is the same: chemotherapy, maximum cytoreductive surgical effort, and maintenance, either with a PARP inhibitor alone or in combination [with bevacizumab],” said Monk, a professor in the Division of Gynecologic Oncology at Arizona Oncology (The US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine at St. Joseph’s Hospital, medical director of the Gynecologic Program at The US Oncology Research Network, and codirector of GOG Partners.

“It is important for us to understand the benefit [of PARP inhibitors in the maintenance setting, even though the period the patient receives maintenance therapy] is supposed to be a [treatment-free] holiday,” Monk added. “If managed correctly, [adding a PARP inhibitor doesn’t] reduce quality of life; the patient can remain not only symptom free from a PARP inhibitor but also progression free from cancer.”

The Institutional Perspectives in Cancer webinar on ovarian cancer was a spotlight on frontline and second-line maintenance approaches in ovarian cancer, as well as on immunotherapies. In an interview with OncLive^®, Monk discussed data that solidified the role of maintenance PARP inhibition in patients with ovarian cancer as well as guidelines for selecting PARP inhibitors alone or in combination with bevacizumab.

OncLive^®: What about the patient population made the SOLO-1 trial (NCT01844986) unique?

Monk: SOLO-1 was the first randomized, phase 3 trial to show the efficacy of [frontline] PARP maintenance therapy in newly diagnosed advanced ovarian cancer. The unique aspect of SOLO-1 was [that it was] limited to patients who had a BRCA-associated tumor, either germline or somatic. Having said that, [the data from SOLO-1] were transformational [when they were] presented during the 2018 ESMO Congress. [Olaparib] was FDA approved [for this indication] in 2019. 

[The data from SOLO-1] changed the landscape [of ovarian cancer] by showing that a PARP inhibitor could be given as frontline maintenance [therapy], as well as that biomarkers matter.

What key goals were reached in the PRIMA trial (NCT02655016) with niraparib?

PRIMA had 3 goals. [The first goal was] to go beyond what SOLO-1 showed and show that [frontline] PARP inhibitor maintenance therapy could [extend] beyond BRCA to allcomers. [PRIMA] did that. The second goal was to look at the highest-risk patients, such as those with gross residual disease [after] neoadjuvant [therapy] or stage IV cancer and bring relief to those patients suffering the most. [PRIMA] did that. The third goal was to personalize the dose of niraparib [for patients]. Niraparib is the only frontline, once-daily PARP inhibitor [for] all-comers [given in an] individualized dose. All of that is a result of the PRIMA trial.

The beauty of [the PRIMA study] is that between the collaboration with ENGOT [The European Network for Gynaecological Oncological Trial groups] and GOG Partners, we were able to get [niraparib] FDA approved 37 months from the time that the first patient was enrolled [on the study]. This was a transformational study [with regard to] the agent, the opportunity, the dosing, and the speed [in which it led to an FDA approval].

How had the addition of bevacizumab to PARP inhibitor therapy affected the treatment landscape? Is toxicity a concern with this type of combination?

In 2011, we published GOG-0218 [NCT00262847] in the New England Journal of Medicine, which led to almost immediate global approval [of bevacizumab], except in the United States, where it was not FDA approved until June 2018. [The 7-year delay] was because we needed to show the value [of bevacizumab] to the regulatory agency in prolonging progression-free survival [PFS]. Therefore, while the Europeans were utilizing bevacizumab routinely, the United States did not have an FDA approval. The European Network, led by the French group, decided to take what they were already doing with bevacizumab and add olaparib in the [frontline] maintenance phase to create the first randomized trial of a combination with a PARP inhibitor and, in this case, bevacizumab. [The results of that study] were positive, meaning that it met its primary end point of PFS, but the [results] were impactful only in those patients who were homologous recombination deficient.

[Bevacizumab plus olaparib] is a wonderful combination, but giving 2 agents together obviously increases toxicity. It’s not really fair to compare [the combination] with single-agent olaparib from the SOLO-1 trial or single-agent niraparib from the PRIMA study because [the PAOLA-1 trial (NCT02477644)] did not have a PARP inhibitor–alone arm.

Generally, particularly in Europe, if [patients receive] both [bevacizumab and olaparib] in the beginning, there is not reimbursement [by] the time of recurrence. The comparator is not the PAOLA-1 regimen vs the PRIMA or SOLO-1 regimens; rather it is the PAOLA-1 regimen followed by chemotherapy alone vs the SOLO-1 or PRIMA regimens followed by chemotherapy and bevacizumab. [One caveat of the combination regimen is that] when we utilize both opportunities in the frontline setting, we increase toxicity and perhaps eliminate options moving forward.

If [the] PAOLA-1 [regimen] cures more patients, it is definitely the best opportunity, but we don’t know that answer yet. [We don’t know] whether there will be an improvement in overall survival [OS] in PAOLA-1 or, for that matter, in SOLO-1 or PRIMA. There was no survival advantage with bevacizumab alone in GOG-0218.

What does treatment selection look like for patients with platinum-sensitive ovarian cancer?

We have 9 FDA approvals for PARP inhibitors [in ovarian cancer]: 3 frontline [indications] and 6 recurrent [indications]. Three of those [approvals] in the recurrent setting are for platinum-sensitive maintenance therapy. That is unique because in platinumsensitive maintenance treatment, patients have to respond to platinum[-based therapy] to qualify for the indication because that was the eligibility for the 4 studies: Study 19 [NCT00753545], SOLO2 [NCT01874353], ENGOT-OV16/NOVA [NCT01847274], and ARIEL3 [NCT01968213]. We don’t use HRD or even BRCA [testing] that much at the time of [recurrent] platinum-sensitive maintenance therapy because the biomarker here is platinum sensitivity. Regardless of the biomarker, if the patient does respond to a platinum doublet, they are very likely to respond to PARP inhibitor maintenance treatment [in the recurrent setting].

The interesting component, though, is that because [PARP inhibition] is such a no-brainer, all 3 PARP inhibitors are approved in [the recurrent maintenance] setting. It creates a situation where we have identical approvals, and we have to make a decision [as to] which of the 3 PARP inhibitors— olaparib, niraparib, or rucaparib—is the best option for a patient. It’s a particularly challenging question and, frankly, [requires] a shared and personalized decision with the patient and provider. There is really no right answer.

Should PARP inhibitors be utilized in the frontline maintenance setting for patients with platinum-sensitive ovarian cancer? How does that affect the data from recurrent maintenance trials?

NOVA was the first randomized, phase 3 trial to specifically address the utilization of a PARP inhibitor in platinum-sensitive [disease as] maintenance treatment [for patients with] BRCA and non-BRCA[–mutant disease].

Study 19 and ARIEL3 [evaluated PARP inhibitors in this setting], but Study 19 was a complicated, small study. NOVA [evaluated PARP inhibition] in a systematic way and set the paradigm. [The data were] published in the New England Journal of Medicine.

My goal with patients who [are eligible for] platinum-sensitive maintenance therapy is to use it in the first-line setting. Therefore, these platinum-sensitive maintenance trials are almost historical, but there are still patients who didn’t have the opportunity [to receive frontline maintenance therapy] because [olaparib from] PRIMA was FDA approved in April 2020 and [olaparib plus bevacizumab] from PAOLA-1 was FDA approved in May 2020. There are patients who [have] recurring [disease] who didn’t receive a frontline PARP inhibitor.

Over time, my goal is to have every patient, if eligible, have the potential benefit of a PARP inhibitor, ideally in the frontline maintenance setting. If a patient missed [the] opportunity for [frontline] platinum-sensitive maintenance therapy, there are 3 treatment opportunities [in the recurrent maintenance setting] based on BRCA or HRD [status].

How have the ASCO guidelines incorporated PARP inhibitors as maintenance therapy?

In October 2020, the ASCO guidelines for PARP inhibition were published in the Journal of Clinical Oncology; the first author was [William P. Tew, MD, of Memorial Sloan Kettering Cancer Center]. [This publication] was really transformational because it basically said that every patient should be considered for niraparib and every patient should be considered for olaparib if they have a BRCA tumor mutation. The other indications in [the setting of recurrent,] platinum-sensitive maintenance [therapy] are listed as “may,” which is a lower level [of recommendation compared with “should”].

These [guidelines] provide clinical guidance for [what] providers and payers should utilize in [the setting of] frontline maintenance treatment, either niraparib in all-comers or olaparib in molecularly defined subsets.

Do the National Comprehensive Cancer Network (NCCN) guidelines mirror the ASCO guidelines with respect to the incorporation of PARP inhibitors?

As published in February 2021, the NCCN guidelines provide clear direction on the utilization of PARP inhibitors in the frontline maintenance treatment of [patients with] ovarian cancer. In fact, [the NCCN guidelines] closely mirror what John K. Chan, MD, [of the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center] and I published in Gynecologic Oncology in December 2020.

[That publication] basically [stated] that there are 3 key decisions [that need to be made when selecting an up-front treatment for patients with advanced ovarian cancer]. Even before the first decision is made, everyone needs to agree to do germline testing, generally with a panel. If [the patient has] a germline BRCA mutation, we’re done [considering options]. If [the patient doesn’t have] a germline BRCA mutation, we have to pivot to tumor testing because you can identify not only the family [members who] need risk-reducing surgery or screening but also patients who are most likely to benefit from a PARP inhibitor.

How do you go about determining whether a patient should receive a PARP inhibitor alone or in combination with bevacizumab?

If there is no germline mutation, we look for the opportunity to use a PARP inhibitor [via] tumor testing, which is basically an HRD test. There are 2 FDA-approved HRD tests [available] in the clinic.

After we’ve done [HRD testing], we are able to make the f irst hard decision: Do we give neoadjuvant chemotherapy? Remember, there is no such thing as optimal debulking [surgery] because we can either cut it out or we can’t. If we can cut [the tumor] out [and the patient is R0], it is good. If we can’t, we begin neoadjuvant chemotherapy with interval debulking between the third and fourth cycles.

The second decision is that after [either giving or not giving] neoadjuvant chemotherapy: [Do we give bevacizumab]? The indication for bevacizumab is for all-comers with stage III or IV ovarian cancer. A 10-month OS advantage was suggested [with bevacizumab] even in the highest-risk population with stage IV disease. When or whether bevacizumab is utilized has a lot of controversy. Personally, having first reported bevacizumab’s activity in ovarian cancer in the current setting, I used to utilize bevacizumab commonly up front.

After we’ve made the first and second decisions, we have to make the third decision, which is what this conversation about PARP inhibitors [comprises]. That [decision] is informed by bevacizumab because if we are [giving] bevacizumab, we are not going to stop it if it is effective and tolerable. However, if the patient has an HRD molecular signature, we are going to add olaparib as per the PAOLA-1 trial. If we are not using bevacizumab, there are 2 buckets: [patients with] BRCA [mutations] and [patients with] HRD without BRCA [mutations]. In the BRCA-mutant cohort not on bevacizumab, the options are olaparib per SOLO-1 or niraparib per PRIMA. That’s a tough decision, but it is most important that patients with BRCA mutations get a PARP inhibitor as [frontline] maintenance treatment. If we are not using bevacizumab, the only PARP inhibitor that is utilized in the HRD non–BRCA-mutant cohort is niraparib per PRIMA. If we don’t use bevacizumab in the non-HRD [cohort], we can use niraparib in the homologous recombination–proficient group.