Long-term Data for Niraparib Support Continued Use of PARP Inhibitors in HRD+ Ovarian Cancer

Dario R. Roque, MD

Updated long-term data from the phase 3 PRIMA trial (NCT02655016) of niraparib (Zejula) in patients with homologous recombination–deficient (HRD) ovarian cancer and the phase 3 SOLO-1 trial (NCT01844986) of olaparib (Lynparza) in patients with BRCA-mutated ovarian cancer demonstrated progression-free survival (PFS) benefits vs placebo, adding more data to support the use of PARP inhibitors as frontline maintenance therapy for select patient populations in ovarian cancer, according to Dario R. Roque, MD.

“The evidence is very clear from long-term data presented at the [2022] ESMO Congress, both from the PRIMA trial and the SOLO-1 trial, that PARP inhibitors should absolutely be a part of standard of care for patients with tumors that are HRD[-positive],” Roque explained in an interview with OncLive^® following a State of the Science Summit™ on gynecologic cancers, which he chaired.

In the interview, Roque discussed the importance of incorporating the use of PARP inhibitors into practice for patients with HRD-positive ovarian cancer, the role of PARP inhibitors for patients with homologous recombination–proficient (HRP) ovarian cancer and the unmet needs for that patient population, and the expanding investigation of the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (Elahere) in ovarian cancer.

Roque is an assistant professor of Obstetrics and Gynecology (Gynecologic Oncology) at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern Medicine, Feinberg School of Medicine in Evanston, Illinois.

OncLive^®: Regarding the role of PARP inhibitors in frontline maintenance therapy, what was observed in the updated long-term PFS data from the PRIMA trial?

Roque: One of the things that I wanted to highlight were the data that was presented at the 2022 ESMO Congress in [September]. Investigators presented the updated long-term PFS data [from PRIMA] with a median follow-up of 3.5 years. They confirmed a sustained benefit of niraparib in terms of reducing the risk of progression [or] death for patients that were in the experimental arm.

In those patients who had [HRD-positive] tumors, the [risk] of progression or death was reduced by 48%. The median PFS was more than doubled in that patient population from 11.2 months to 24.5 months in the placebo arm vs the niraparib arm, respectively.

They also confirmed the PFS benefit in the overall population, with patients in the niraparib arm demonstrating [a 5.6-month] improvement in their PFS. This essentially consolidates the role of niraparib in this frontline [maintenance] setting in the management of ovarian cancer.

The benefit is much more pronounced in women who have HRD[-positive] tumors. I believe that this benefit is significant enough that niraparib, and PARP inhibitors in general, should be standard of care for patients with HRD [positivity].

How do updated data from the SOLO-1 trial add to the support for PARP inhibitors as frontline maintenance in ovarian cancer?

[What] I reviewed about the PRIMA trial applies in the sense that [updated data from SOLO-1] consolidates the benefit of olaparib…in patients with BRCA mutations, which were the patients that were included in the SOLO-1 trial. That update that was presented at the 2022 ESMO Congress is essentially the longest follow-up for any PARP inhibitor in the frontline setting. It supports the use of maintenance olaparib to achieve long remissions. It has the potential for cure when considering how many patients had very prolonged benefit, despite having stopped therapy at the 2-year end point [in accordance with] the study design.

What unmet needs still need to be addressed for patients with ovarian cancer with HRP-positive tumors?

These patients account for about 50% of patients with ovarian cancer. There are approved treatments for those patients in the maintenance setting, including niraparib—which is FDA approved even for patients who are HRP[-positive]—and bevacizumab [Avastin]. Although the PFS benefits [for these agents] were statistically significant in the trials [that supported the] approvals, that benefit remains quite small in comparison with the benefit that we see in patients with HRD[-positive] tumors.

[Niraparib or bevacizumab maintenance] is something that is worth discussing with [HRP-positive] patients as an option, but [the benefit] is not significant enough that we have met that clinical need. Patients [with HRP-positive ovarian cancer] have this significant need that must be met in order to achieve similar benefits as those with HRD[-positive] tumors.

Thomas J. Herzog, MD, of the University of Cincinnati Cancer Center, discussed the role of ADCs in ovarian cancer. What other research is being conducted with mirvetuximab soravtansine following its approval in folate receptor α (Frα)–positive, platinum-resistant ovarian cancer?

It is exciting that mirvetuximab soravtansine was approved because it fills an unmet clinical need in those patients with platinum-resistant ovarian cancer. The approval was based on the results from the [phase 3] SORAYA trial [NCT04296890], which was a single-arm trial that demonstrated a [31.7%] overall response rate and durable duration of response of 6.9 months among those patients who had platinum-resistant ovarian cancer. All those patients were pretreated with bevacizumab and had been exposed to 1 to 3 prior lines of therapy.

In terms of other trials that are looking at mirvetuximab soravtansine, I should start by mentioning the [phase 3] MIRASOL trial [NCT04209855], which is a confirmatory trial for mirvetuximab soravtansine. It is a phase 3 trial that is [randomly assigning] patients with similar inclusion criteria to those patients in the SORAYA trial to either mirvetuximab soravtansine or investigator’s choice of chemotherapy in that platinum-resistant cohort.

One difference between the MIRASOL and SORAYA trials is that [for] MIRASOL, patients do not have to have been exposed to bevacizumab previously. Again, this is a confirmatory trial to see if the benefits of mirvetuximab soravtansine in this patient population are better than the benefit derived from standard-of-care chemotherapy as decided by the provider.

Another trial that is also being done with mirvetuximab soravtansin is in the platinum-sensitive setting. The [phase 3] GLORIOSA trial [NCT05445778] is evaluating the role of mirvetuximab soravtansine in combination with bevacizumab vs bevacizumab alone in the maintenance setting for patients with Frα-high disease who have just completed a run of platinum-based chemotherapy.

There is also the [phase 2] PICCOLO trial [NCT05041257], which is looking at mirvetuximab soravtansine [as a single agent] in patients with Frα-high expression [and] platinum-sensitive disease. Notably, this is a single-arm trial, so there is not a comparator arm. [However], it is an interesting trial because it’s using mirvetuximab soravtansin as a single agent, which is a unique possibility in those patients who have Frα-high expression.

Emma Barber, MD, of Robert H. Lurie Comprehensive Cancer Center, Northwestern University, discussed the importance of biomarker testing in endometrial cancer. What are the limitations of treating patients based on disease histology? How does biomarker testing in this population lead to more accurate and effective therapies?

As we differentiate molecular subtypes of endometrial cancer, the more we are going to be targeting therapy based on molecular subtypes. The prime example of this is the use of pembrolizumab [Keytruda] and immune checkpoint inhibitors in general. Pembrolizumab and dostarlimab-gxly [(Jemperli) are both FDA approved] in patients who have microsatellite instability–high or mismatch repair–deficient [dMMR] endometrial cancer.

The testing of these tumors for molecular markers is helping us currently, based on FDA approvals, to decide which patients will derive benefit from checkpoint inhibitors by themselves, or if we need to combine them with lenvatinib [Lenvima], based on the results from [phase 3] KEYNOTE-775 [NCT03517449].

[Testing for molecular markers] is something that we should be doing more consistently. We’re starting to get data on whether testing for P53 will be helpful. There were some data presented at the 2022 ASCO Annual Meeting, based on the phase 3 SIENDO trial [NCT03555422], where there was a benefit of using selinexor [Xpovio] in patients with P53 wild-type endometrial cancer. [These data] highlight the importance of being able to better identify these molecular subtypes so we can adequately target these patients with the most effective systemic agents.

We are getting closer to offering more targeted therapies to patients with endometrial cancer based on molecular subtypes. Although we have made some progress in those [patients] that have dMMR, there is a still a lot of work to be done. [However, these are] exciting times, and I would encourage all my colleagues to routinely send for next-generation sequencing for endometrial cancer so that we can better treat these patients.

Are there any clinical trials ongoing at Robert H. Lurie Comprehensive Cancer Center that you would like to highlight?

One of the studies that we’re really excited about being able to offer patients [in the near future] is the [phase 2] IMGN853-0420 trial [NCT05456685], where we will look at mirvetuximab soravtansine in patients with high expression of Frα in the platinum-sensitive setting. It is a phase 2 trial, where mirvetuximab soravtansine will be used in combination with carboplatin.

The reason this is exciting is because now we’re looking at different combinations, rather than carboplatin plus paclitaxel, which has been the standard in this space for many years. [We are replacing] paclitaxel with mirvetuximab soravtansine to see if we can get similar or improved responses in this patient population [and potentially] avoid some of the adverse effects that come with paclitaxel, such as neuropathy, which can be bothersome for these patients. We’re in the process of opening the study at our institution.