PARP inhibitors are changing the way ovarian cancer is treated.
Bhavana Pothuri, M.D.
Three PARP inhibitors, Rubraca (rucaparib), Lynparza (olaparib) and Zejula (niraparib), are expanding treatment options for patients with ovarian cancer who progress on chemotherapy.
The recent FDA approvals of Lynparza and Zejula in the maintenance settings, specifically, have opened a new door where previously there were no such therapies available.
Now, clinical trials are testing PARP inhibitors in combination with immunotherapy to increase antitumor activity. Rubraca is currently being explored in combination with Tecentriq (atezolizumab) in a phase 1b open-label study, with dose-finding and dose-expansion phases (NCT03101280). For the dose-expansion phase, patients must have a deleterious germline or somatic BRCA 1/2 mutation or tumors that are BRCA wild-type, but show high levels of loss of heterozygosity.
The ongoing confirmatory study for Rubraca’s approval, ARIEL4, is comparing Rubraca with chemotherapy in patients with BRCA-positive ovarian, fallopian tube, or primary peritoneal cancer, who have received at least two prior platinum-based chemotherapy regimens (NCT02855944).
“Understanding that [PARP inhibitors are] another therapy in our armamentarium for the treatment of ovarian cancer is really important,” explained Bhavana Pothuri, M.D., an associate professor in the Department of Obstetrics and Gynecology at NYU Langone's Perlmutter Cancer Center.
In an interview with CURE, Pothuri discussed the available PARP inhibitors and ongoing trials further investigating these agents in ovarian cancer.It is a very exciting time for PARP inhibitors. The PARP inhibitors are a class of targeted agents that are utilized in ovarian cancer, and this is important because ovarian cancer accounts for only about 20 percent of gynecologic malignancies, but it accounts for over 50 percent of gynecologic cancer deaths. There is a real need for new agents, and the PARP inhibitors are a class of new agents for which we now have approvals with multiple different drugs.
It’s an exciting time. The first PARP inhibitor that has been approved was Lynparza in December 2014. Lynparza was approved in patients with recurrent ovarian cancer who have had three or more prior lines of therapy, and were BRCA-mutation carriers.
This was very exciting. About two years later, Rubraca, another PARP inhibitor, was also approved for two or more lines of prior treatment, and it was approved in patients with either a somatic or a germline mutation—so either a mutation in the tumor or in the blood. Again, that expanded the access a little bit and allowed us to use PARP inhibitors earlier in a patient’s disease course. Again, this is more progress for our patients with ovarian cancer.
The recent approvals for maintenance [therapy] are also very exciting. The first PARP inhibitor to be approved was Zejula for maintenance therapy, and this was approved in patients with two or more lines of platinum therapy. Patients who responded had either a complete response or a partial response to prior platinum therapy. The data were impressive, and it looked like there was a benefit among all patients, regardless of BRCA mutation status. This led to approval in all patients with recurrent ovarian cancer who responded to prior platinum therapy.
Most recently, Lynparza also received this indication. Again, this is a very exciting time; we now have several PARP inhibitors—two approved as therapy for recurrent disease and two approved for maintenance in ovarian cancer. That is a great question. Currently, there are studies looking at that question. We are awaiting data looking at PARP inhibitor maintenance therapy after completion of primary chemotherapy, and we’re looking at it for different drugs. These studies are pending and we’re excited to see what they show. Chemotherapy will have a role in ovarian cancer, it is a very chemotherapy-sensitive disease. The response rates are in the 80 percent [range] upfront, so it would be hard to beat something that is so effective in the frontline setting. I do think chemotherapy will still have a place. Even though [patients] have such high initial response rates with chemotherapy, the majority of patients with ovarian cancer relapse; therefore, there is a true need for newer agents and targeted agents like PARP inhibitors and other immunotherapy agents.Currently, there are data looking at combining a PARP inhibitor with an antiangiogenesis inhibitor. There are NRG Oncology trials with Lynparza and cediranib — NRG-GY004 and NRG-GY005 — and we have both of those open at our institution at NYU Langone Medical Center. These trials are exciting because there are data in the phase 2 setting showing activity with a combination that’s even greater than with a single-agent PARP inhibitor. There are other trials that are underway looking at combining immune checkpoint inhibitors with PARP inhibitors. All of these data are very exciting and we all await it eagerly. There is certainly a potential for benefit in uterine cancers, especially uterine serous cancers. However, we need more data to really establish the role in treating other cancers. There have also been data looking at PARP inhibitors and sensitizing radiation in cervical cancer. We need more information.