PARP Inhibition Presses Forward With the Possibility of Retreatment and Combo Approaches in Ovarian Cancer

Patients with recurrent platinum-sensitive ovarian cancer should receive PARP inhibitors as maintenance therapy, irrespective of whether they harbor BRCA mutations or are homologous recombination deficient (HRD), said Jing-Yi Chern, MD, ScM. Data from the phase 3 NOVA (NCT01847274) and SOLO-2 (NCT01874353) trials have solidified the role of maintenance PARP inhibition in this setting, she added.

“If patients with platinum-sensitive recurrent ovarian cancer have an appropriate response [to frontline therapy], it is very important that we consider PARP inhibitors in [the maintenance] setting,” said Chern. “We see that even patients without BRCA mutations gain benefit [from PARP inhibitors in this setting]. This may be the only opportunity that patients get [for effective treatment] until more trials are available for them, so it is important to consider putting these patients on PARP inhibitors.”

However, clinical studies, such as the phase 3b OReO (NCT03106987) trial, are actively enrolling patients to evaluate whether retreatment with PARP inhibitors is beneficial, explained Chern. Other clinical trials are addressing whether combination regimens with PARP inhibitors and immunotherapy or chemotherapy are clinically relevant in improving responses for this patient population, she said.

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on ovarian cancer, Chern, a gynecologic oncologist at Moffitt Cancer Center, discussed the role of maintenance PARP inhibition in patients with recurrent platinum-sensitive ovarian cancer, as well as remaining questions with PARP inhibitors in this setting.

OncLive^®: Are there any data to suggest that PARP inhibitors can be used sequentially in ovarian cancer? 

Chern: PARP inhibitors have been in use for quite some time in the [recurrent] setting, [and] it is now almost common practice that [they are used as] maintenance therapy in the [frontline] setting. The question that we are going to have to answer is: What is the utility of PARP inhibition after previous PARP [inhibitor therapy]? I don’t think we have that answer yet. When these studies were done, they were kind of done in reverse. We used [PARP inhibitors] in the recurrent setting, but we have data that support the use of PARP inhibitors in the frontline [maintenance] setting. Now we are going to see a change in practice. What are we going to do in [patients with] platinum-sensitive or platinum-resistant recurrences? [Will] PARP inhibition have a role in that group of patients?

Are there specific research efforts ongoing that may answer this question? 

The OReO trial is looking at PARP after PARP. Hopefully, once those data are complete, we will have a better idea of what role PARP [reexposure has] in the recurrent setting.

How are you selecting between the available PARP inhibitors in practice?

Three PARP inhibitors are on the market: niraparib [Zejula], olaparib [Lynparza], and rucaparib [Rubraca]. Generally, they are all very well-tolerated agents, and they are probably similar. I don’t think one is superior to another.

How did the data from the NOVA and SOLO-2 trials contribute to our understanding of the activity of PARP inhibitors in recurrent ovarian cancer?

The NOVA and SOLO-2 trials [focused on] platinum- sensitive recurrent ovarian cancer. In these [trials], patients most likely had not had PARP inhibition in the frontline setting. Our goal is to increase that platinum-free interval because we know that a long [platinum-free] interval can improve overall outcomes, including survival. Both of these studies showed that PARP inhibition allows that improvement [in outcome]. Particularly in patients who [had] a germline BRCA mutation in the NOVA study, we saw a 21-month [median] progression-free survival [(PFS) with niraparib] compared with a 5-month [median] PFS with placebo; that alone is a 16-month improvement [in PFS]. That allows for patients who have progression or recurrence to go back on a [platinum-containing] regimen. We see benefit even in those patients who don’t have a germline [BRCA] mutation but are HRD [positive]. That is significant at about 9 months. Those patients who do not have any mutations, including [patients who are] HRD [negative], gain a 5-month benefit [from PARP inhibition]. 

The NOVA study demonstrated that niraparib has a role in improving that platinum-free interval. The SOLO-2 study looked at olaparib and [reported] that the placebo group had a 5-month median PFS [vs] 19.1 months in the olaparib group. That is a 14.1-month advantage using a PARP inhibitor [in the maintenance setting].

[Although] PFS was the primary end point, the overall survival [OS] end point [was met as well] in the SOLO-2 study. There was still a 13-month [improvement in] OS [with olaparib, according to updated] data that were presented at the [2020 American Society of Clinical Oncology Virtual Scientific Program]. These 2 studies highlight how we can use maintenance therapy in patients who have platinum-sensitive recurrences to increase the platinum-free interval.

Are combination strategies with PARP inhibitors and immunotherapy or chemotherapy worth exploring? What factors might inform which patients are suited for that type of regimen?

Those questions will be answered [with the] studies [that are] coming out. Chemotherapy is the old way of treating patients with ovarian cancer because now we have new targeted therapies, including PARP inhibitors and immunotherapy.

Our institution participated in one particular study that [evaluated] chemotherapy plus a PARP inhibitor plus immunotherapy in the frontline setting. [The study also] allows for maintenance therapy after that. Combinations will have a role, and adding these targeted therapies will help drive that platinum-free interval; that is what we are aiming for.

In the recurrent setting, [the type of approach we use] is going to be a little different. Again, chemotherapy will always be a standard of care [in the recurrent setting], but we know that recurrences are likely to occur in shorter intervals. We have to look for other opportunities, including PARP inhibition [plus] immunotherapy. Trials such as JAVELIN Ovarian 100 [NCT02718417] used immunotherapy in the recurrent setting. [That study] did not meet its end point.

[Treatment in that setting is going to consist of a] combination, but what is that combination? Ongoing studies have looked at this [question, as well as] some studies that just looked at PARP inhibitors in the recurrent setting and showed benefit. For example, the QUADRA trial [NCT02354586] demonstrated [benefit with niraparib in the recurrent setting]. We are going to have to create more trials to compare [these regimens] and see what the [optimal] combination is to give the greatest benefit [to patients].

What other ongoing research at Moffitt Cancer Center would you like to highlight?

We are looking at ways to identify patients early on to ensure that they receive a maintenance therapy [regimen] if appropriate. We’ve developed these pathways to identify patients and ensure they get tested early in their treatment so that they are ready for maintenance therapy. These pathways have also allowed us to identify other mutations that allow [patients] easier access onto other clinical trials. Some of those trials include [those evaluating] PARP inhibitors, as well as antibody-drug conjugates and immunotherapy. [Those trials are] ongoing at our cancer center. [Through this research], we are able to find or ensure opportunities for our patients to [receive] these other agents that they otherwise could not.