Navigating the Molecular Landscape: PARP Inhibitors in Gynecologic Cancers

In the rapidly evolving landscape of gynecologic oncology, molecular profiling has shifted from a retrospective academic exercise to an essential cornerstone of frontline management. For the community oncologist, navigating the nuances of homologous recombination deficiency (HRD) and mismatch repair (MMR) status is critical for tailoring maintenance strategies in ovarian and fallopian tube cancers.

In an interview with Targeted Oncology, Erin Crane, MD, MPH, a gynecological oncologist at the Atrium Health Levine Cancer Institute in Charlotte, North Carolina, explores the clinical decision-making process for maintenance therapy, specifically comparing the roles of PARP inhibitors such as niraparib (Zejula) and olaparib (Lynparza). By examining pivotal data from the PRIMA trial (NCT02655016)¹ and the implications of HRD-negative status, Crane provides a practical framework for choosing between active maintenance and a watch-and-wait approach based on a patient’s unique mutational signature.

Targeted Oncology: For the community oncologist, the choice between niraparib and olaparib often comes down to the patient's molecular profile. In a mismatch repair proficient (pMMR)/homologous recombination deficient (HRD)–negative patient, what clinical markers lead you to choose maintenance niraparib vs a watch-and-wait approach?

Erin Crane, MD, MPH: I think there's a lot of different terminology that's come to light lately with the advent of molecular profiling, and now, with our patients with ovarian and fallopian tube cancers, we're getting this at the very outset of their diagnosis so that we can start having those early conversations about maintenance therapy.

I think it's important that we all understand the terminology, because when we talk about [pMMR], that has to do with recognition of DNA damage and repair, just like [HRD] does as well. For [pMMR], typically we see that more in our patients with endometrial cancer, and that really speaks to whether we talk about using maintenance therapy with immunotherapy in that patient population. [HRD] is more applicable to the ovarian cancer population. So, while we do see some patients with ovarian cancer with [MMR] deficiency, specifically if they have something like Lynch syndrome, in general, we're not really using immunotherapy in the maintenance setting for patients with ovarian cancer. So really, it's the [HRD] we're looking at. We know that about 50% of patients with ovarian cancer will have HRD. For the other 50%, they will not. And so, we really home in on the patients with [HRD], which of course, encompasses patients with BRCA germline or somatic mutations that comprise about 20% of the HRD component. In those patients, the choice between olaparib and niraparib really depends on what their mutational profiling looks like. Niraparib is basically approved for all patients with [HRD], regardless of BRCA mutation status. The convenience of that is that it's given once daily, and the PRIMA trial showed a definitive advantage in patients with [HRD] tumors.

What we know from the PRIMA trial was that patients who had [HRD] definitely benefited from the addition of niraparib maintenance after completion of chemotherapy. Olaparib is indicated for patients who are BRCA positive alone or in combination with bevacizumab [Avastin] for patients who are HRD positive, which also encompasses the BRCA mutation population. It is not indicated alone as a single agent for patients who are only HRD positive just yet. 

That's really a large choice that we have to make as oncologists, whether we're going to use olaparib in combination with bevacizumab vs niraparib alone in the [HRD] population. All those things really come into play, and a lot of it has to do with the culture of maintenance therapy use within the institution and its providers. You can certainly make an argument to use bevacizumab in the upfront setting based on multiple studies that have demonstrated an improvement in [progression-free survival]. You can make an argument to use it in the recurrent setting when patients have platinum-sensitive disease, and so some providers prefer to save it for later. So, the molecular profiling, basically any patient who has [HRD] should be offered a PARP inhibitor, either olaparib with bevacizumab or niraparib alone. The harder part is counseling patients with homologous recombination proficiency, or what we call HRD-negative patients, because for those patients, PARP inhibitors really are not an option. Maintenance really boils down to whether you want to offer those patients maintenance bevacizumab, which again, largely depends on their tumor factors, their tumor biology, and then cultural preferences within the practice and within the region.

With the recent manufacturer restrictions on PARP inhibitors in later lines of therapy, how should community practices adjust their long-term treatment sequencing for recurrent disease?

I think a lot of us were surprised by some of the changes that came out. Specifically, PARP maintenance in the recurrent platinum-sensitive setting was found to shorten life expectancy. I think the more that we've drilled down into the data, the more that we realize that's really secondary to the increased risk of treatment-related [acute myeloid leukemia; AML] and [myelodysplastic syndrome; MDS]. I think as practitioners, to be honest, it's not really changed our practice patterns a lot and has not had that much of an impact, because by the time that data had come out, we'd all pretty much shifted PARP maintenance use into the frontline setting. At that point, the PRIMA data, the SOLO-1 data [NCT01844986],³ and the PAOLA-1 data [NCT02477644]⁴ were all out or were evolving. We already knew that probably the best time for patients to be on PARP maintenance was in the upfront setting rather than the recurrent setting. In the recurrent setting for patients who have had prior PARP therapy, that really has to be approached with the utmost caution, due to the increased risk of treatment-related AML and [MDS]. Almost all of those indications have been removed, except for patients who have BRCA mutations. But, even so, most of us at this point are not rechallenging patients with PARP inhibitors in the maintenance setting after recurrence if they have platinum-sensitive disease. There are a few patients every now and then who have BRCA mutations who did not receive it in the frontline setting, and I would say in the maintenance setting, in that context, it's reasonable, but otherwise, the utility of PARP inhibitors and recurrent platinum-sensitive disease is really limited, and most of the time we're using it for appropriate patients in the frontline setting.

In the community setting, where access to “ultraradical" surgical teams may be limited, how do you determine which patients are better served by neoadjuvant chemotherapy vs an immediate referral for primary surgery?

Of course, our hope is that everyone has access to the care that they need, but in certain communities, that may not be the reality. I think a lot of us are using neoadjuvant chemotherapy, not so much secondary to access, but because now several large randomized trials have shown that in many ways, it's not inferior to upfront radical debulking, and may save patients from an ultraradical surgery where they wind up with a colostomy, multiple blood transfusions, [intensive care unit] admissions or prolonged hospitalization.

I'd say neoadjuvant chemotherapy in this context has become much more acceptable for patients with a large disease burden, or with multiple medical comorbidities who may not be able to sustain a large surgery, which often complicates their picture when they come in already somewhat debilitated from disease. Unless someone has disease that's clearly [able to undergo debulking] and very limited in the upfront setting, neoadjuvant chemotherapy in the community, where patients may not have access to ultraradical surgery, is perfectly acceptable.

However, in any scenario, if radical surgery is indicated, then it is really important that those patients have access to it, because we do know that getting patients to R0, or complete macroscopic resection of disease, does portend a much better prognosis than for patients in whom we have to leave disease behind. Neoadjuvant chemotherapy is perfectly acceptable, but shouldn’t take the place of a much-needed or indicated surgery.

You've contributed to Society of Gynecologic Oncology surveys regarding clinician wellness. What is one practical change community clinics can make to reduce the administrative burden while maintaining high-level evidence-based care?

That's the million-dollar question, right? I think all of us love our jobs and the crux of what we do, but it's always the administrative tasks in the background that sometimes make our wellness scores not what they should be. I'd say really ensuring that you have good support staff to eliminate some of that work burden that we take on that can be delegated to others. In our clinic, for example, we have 2 chemotherapy nurses who are just dedicated to coordinating chemotherapy, triaging patient [adverse] effects, and educating patients. And then along those lines, we have several [advanced practice providers] and midlevel providers who are able to assist with day-to-day needs, including getting patients in for needed visits, answering questions, fielding some of the results that really fill up our administrative inboxes…. The other thing that's been helpful are some of the dictation services that we have, like DAX Copilot and some of the other methods that we have helping with charting and notes, so we’re really cutting down on the amount of time we're having to take work home with us at night or spending in the clinic when we could be doing other more productive things.

REFERENCES

1. A study of niraparib (GSK3985771) maintenance treatment in participants with advanced ovarian cancer following response on front-line platinum-based chemotherapy. ClinicalTrials.gov. Updated February 2, 2026. Accessed February 11, 2026. https://clinicaltrials.gov/study/NCT02655016

2. Relacorilant in combination with different treatment regimens in patients with gynecological cancers. ClinicalTrials.gov. Updated October 22, 2025. Accessed February 11, 2026. https://clinicaltrials.gov/study/NCT06906341

3. Olaparib maintenance monotherapy in patients with BRCA mutated ovarian cancer following first line platinum based chemotherapy. (SOLO-1). ClinicalTrials.gov. Updated December 10, 2025. Accessed February 11, 2026. https://clinicaltrials.gov/study/NCT01844986

4. Platine, Avastin, OLAparib in 1st line (PAOLA-1). ClinicalTrials.gov. Updated August 2, 2022. Accessed February 11, 2026. https://clinicaltrials.gov/study/NCT02477644