Bhavana Pothuri, MD, discusses the available PARP inhibitors and ongoing trials further investigating these agents in ovarian cancer.
Bhavana Pothuri, MD
The addition of 3 PARP inhibitors to the landscape of ovarian cancer—rucaparib (Rubraca), olaparib (Lynparza), and niraparib (Zejula)—have led to practice-changing, targeted treatment options for patients whose diseases progress on chemotherapy. The recent FDA approvals of olaparib and niraparib 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. Rucaparib is currently being explored in combination with atezolizumab (Tecentriq) in a phase Ib 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 rucaparib’s approval, ARIEL4, is comparing rucaparib with chemotherapy in patients with BRCA-positive ovarian, fallopian tube, or primary peritoneal cancer, who have received at least 2 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, MD, an associate professor in the Department of Obstetrics and Gynecology at NYU Langone's Perlmutter Cancer Center.
In an interview during the OncLive® State of the Science SummitTM on Treatment Options in Ovarian Cancer, Pothuri discussed the available PARP inhibitors and ongoing trials further investigating these agents in ovarian cancer.Pothuri: 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% of gynecologic malignancies, but it accounts for over 50% 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 olaparib in December 2014. Olaparib was approved in patients with recurrent ovarian cancer who have had 3 or more prior lines of therapy, and were BRCA-mutation carriers.
This was very exciting. About 2 years later, rucaparib, another PARP inhibitor, was also approved for 2 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 niraparib for maintenance therapy, and this was approved in patients with 2 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, olaparib also received this indication. Again, this is a very exciting time; we now have several PARP inhibitors—2 approved as therapy for recurrent disease and 2 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% [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 olaparib 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 II 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. I hope that everyone understands that PARP inhibitors are approved therapies for patients with ovarian cancer. There is activity in patients who have had multiple lines of prior therapy. The activity of a drug like a PARP inhibitor, which is a pill, is similar to that of chemotherapy. There are studies that compare liposomal doxorubicin to a PARP inhibitor, and the progression-free survival and response rates were equivalent.
Also, [we need to consider] that even maintenance treatment is important. There are patients who we are worried about in the upfront setting, especially patients who have stage IV disease or patients who had neoadjuvant chemotherapy, so considering [maintenance therapy], especially for these high-risk patients, makes a lot of sense.
The other takeaway point that’s important is no therapy is without cost. You think, “It’s just a pill; they have no toxicities.” However, they do have toxicities. Understand that fatigue, myelosuppression, anemia, and thrombocytopenia are important and how these affect quality of life is important. Balancing that and kind of tweaking a personalized plan with the patient is important.