PARP Inhibitors Potentially Broaden Utility in Gynecologic Cancers With Data from SGO 2020

Elizabeth M. Swisher, MD

In the phase III VELIA trial, patients with high-grade serous ovarian cancer demonstrated promising responses with the addition of veliparib to frontline induction chemotherapy compared with chemotherapy alone. Significant benefit was observed in terms of progression-free survival (PFS) particularly among patients who received the veliparib/chemotherapy induction followed by veliparib maintenance therapy compared with the control arm, indicating a potential role for PARP inhibitor maintenance in this setting, according to the findings presented at the 2020 Society of Gynecologic Oncology (SGO) Annual Meeting.

Exploratory analyses suggested the addition of this PARP inhibitor to chemotherapy may improve the antitumor activity of the chemotherapy regimen, carboplatin plus paclitaxel. However, the PFS benefit was more pronounced in patients harboring a BRCA mutation, as well as those who tested positive for homologous recombination deficiency (HRD).

Rucaparib (Rubraca) also demonstrated improvement in PFS as maintenance therapy as treatment of patients with platinum-sensitive recurrent ovarian cancer in the phase III ARIEL3 clinical trial. Based on these findings, the FDA granted approval to rucaparib tablets in April 2018 as maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Updated long-term data from the ARIEL3 study were also presented virtually at the 2020 SGO Annual Meeting.

While veliparib lacks approval from the FDA, the agent appears to benefit all comers as opposed to the PARP inhibitor rucaparib, which shows benefit only in those who have received benefit with platinum-based chemotherapy previously. Results from the VELIA study appear promising for the treatment of all comers with high-grade serous ovarian cancer.

In an interview with Targeted Oncology, Elizabeth M. Swisher, MD, a co-leader of the Breast and Ovarian Cancer Research Program at Seattle Cancer Care Alliance, a professor in the Division of Gynecologic Oncology at the University of Washington School of Medicine, director of the Division of Gynecologic Oncology at UW Medicine, and affiliate investigator in the Clinical Research Division at Fred Hutchinson Cancer Research Center, discussed data for PARP inhibitor maintenance therapy in patients with ovarian cancer, including the VELIA study of veliparib and the ARIEL3 trial of rucaparib.

TARGETED ONCOLOGY: What was unique about the VELIA study in comparison to other trials of PARP inhibitor maintenance therapy in ovarian cancer?

Swisher: The VELIA trial showed that there was an advantage to using veliparib as upfront therapy in combination with chemotherapy followed by maintenance for patients with high-grade serous ovarian cancer at first diagnosis. What makes VELIA different than other trials that have looked at upfront maintenance therapy for ovarian cancer is that there was a phase where the PARP inhibitor was combined with chemotherapy. Not only is that different in terms of the treatment, but it also means the way patients were enrolled was different.

All patients were enrolled at their diagnosis without any knowledge of whether or not they were sensitive to platinum. It makes for a little different of a patient population than the others where patients were enrolled after they had already responded to platinum. VELIA patients will include a small fraction of patients who have primary platinum-refractory disease, which would never be enrolled in the other trials. In addition, the other trials had some other requirements, such as greater than 90% reduction of CA125 for PRIMA. The selection is quite different for the trials, and although they all show a benefit for a PARP inhibitor, they cannot really be compared to each other.

TARGETED ONCOLOGY: What were the results of the VELIA study?

Swisher: The trial showed an improvement in PFS for patients that have BRCA mutations; patients that have HRD, which includes BRCA mutations; patients that have no HRD on the testing; and patients in the intention-to-treat population, which means the entire population. It was a stepwise analysis, and there was benefit in all groups.

I should also say that the benefit was really limited to the patients where they got maintenance because there was a third arm where patients got veliparib during chemotherapy but no maintenance therapy, and they did not have an advantage in PFS over the patients that got just placebo.

TARGETED ONCOLOGY: How do you expect these findings to impact the treatment landscape in ovarian cancer?

Swisher: It provides another regimen for maintenance therapy upfront using a PARP inhibitor for ovarian cancer. What is different about it is that you can treat all patients as opposed to only the patients who have a really good response to platinum, so it is a very different regimen, and I think it is hard to line it up versus the other regimens to say in which patients should you do or not do 1 way or another.

We have to figure out how to best utilize it, but it was a well-tolerated regimen. All patients benefited, and that I find that encouraging because there is a fraction of patients in there that are platinum-refractory or platinum-resistant that may have never gone on to a different type of maintenance therapy. Those patients still appeared to be getting benefit from this regimen.

TARGETED ONCOLOGY: How do you determine eligibility for this therapy compared with other maintenance regimens?

Swisher: The study was for patients who had high-grade serous ovarian cancer, and it was used in both patients who had received neoadjuvant chemotherapy and those who had primary debulking chemotherapy. I think anyone with advanced disease who had high-grade serous ovarian cancer would be a candidate for this regimen.

TARGETED ONCOLOGY: What should physicians take away from the VELIA trial?

Swisher: I think it broadens the potential utilization of PARP inhibitors. If you have a patient, for instance, that you decided to consider PARP inhibitor maintenance therapy for but with 1 of the other regimens that begins after chemotherapy, you can maybe give the patient 3 cycles of chemotherapy, and they are not responding that well. Those patients are probably never going to be eligible for the PARP inhibitor maintenance therapy, but you could potentially add veliparib to utilize this regimen, which was really more for all comers. I could see it being utilized in that way. Of course, it is not FDA approved yet, so we do have to wait on that. However, I can see that it might have a bit of a broader applicability.

TARGETED ONCOLOGY: Is there anything else you would like to note on the antitumor activity of veliparib combined with chemotherapy?

Swisher: It is very interesting that the HRD testing is not a predictor for response, even though it seems to be more of a predictor in the other regimens. That may be because, in the VELIA study where the PARP inhibitor was combined with chemotherapy, it may be functioning in a different way than as a pure PARP inhibitor. It may be potentiating the chemotherapy, which is why it seems to work just as well for the non-HRD patients. This is somewhat speculative, but again, the biomarkers behave differently, and patients appear to be doing equally well regardless of their HRD status, so maybe it has to do with the PARP inhibitor functioning a little differently when it is combined with chemotherapy.

TARGETED ONCOLOGY: Is there a predictive biomarker to determine the patient’s reaction to this regimen?

Swisher: At present, there is not. We are working on other biomarkers that may or may not be better predictors, and that is definitely something for future work. When the pandemic is over and we can return to our proper research, we hope to be able to answer that question.

TARGETED ONCOLOGY: Rucaparib is already FDA approved as maintenance therapy in a subset of patients with ovarian cancer, and updated long-term data were presented at the 2020 SGO Annual Meeting. What was observed in this update?

Swisher: ARIEL3 was a trial of maintenance therapy with the PARP inhibitor rucaparib following response to platinum chemotherapy in platinum-sensitive recurrent ovarian cancers. Patients had to have high-grade serous or endometroid ovarian cancer, have either their first or second recurrence, and be sensitive to platinum both on their interval since their previous platinum treatment and during that specific treatment to which they have responded well to the platinum. They could then be randomized to either placebo or rucaparib maintenance therapy, which was continued indefinitely until progression.

The trial showed that maintenance therapy was of significant benefit for patients with either germline or somatic BRCA mutations or those with HRD, including cancers that had BRCA mutations, and also for the overall population of these cancers.

TARGETED ONCOLOGY: What is the key takeaway from the ARIEL3 study?

This trial has been published before, and I think those data are well known. Rucaparib received an FDA approval for that indication. What was presented specifically at SGO was the long-term follow-up of that and if that improvement in outcomes persists even after the patient progresses.

There were some theories that if you treat with a PARP inhibitor until the patient progresses, patients could be more resistant when the do recur rather than if they had just recurred initially. To figure that out, we have to evaluate how long it takes to get to the next regimen after that. There was still an improvement for patients in ARIEL3, even when you were looking out beyond recurrences happening after maintenance therapy. Patients still did better than patients that were on placebo, so that is very encouraging to see you are not driving resistance by using these maintenance therapies.

TARGETED ONCOLOGY: Would you say rucaparib has found its place in the ovarian cancer sequencing?

In the setting of the recurrent population, rucaparib is an excellent agent to use for maintenance therapy in platinum-sensitive recurrent ovarian cancer. Other trials are ongoing in the upfront setting with rucaparib, and given that other PARP inhibitors have functioned, if anything, better up front than in the recurrent setting, I expect that rucaparib will as well, but those data are pending.