Expert Discusses Impact of PARP Inhibitors in Ovarian Cancer Treatment Landscape

David O'Malley, MD

The introduction of PARP inhibitors has given patients with ovarian cancer the opportunity for more effective treatment in the frontline and recurrent settings. PARP inhibition has also led to more durable outcomes, according to David O'Malley, MD.

According to findings from the phase III SOLO-1 trial presented at the 2018 ESMO Congress, olaparib (Lynparza), a PARP inhibitor, has significantly improved progression-free survival (PFS) as a frontline maintenance therapy for patients withBRCA-positive advanced ovarian cancer.¹Median PFS by independent central review with olaparib was not reached (n = 260) versus 14.1 months in the placebo arm (n = 131). Patients on this trial received maintenance olaparib following platinum-based chemotherapy.

Also presented at the 2018 ESMO Congress was the posthoc analysis of the phase II QUADRA study, which evaluated the use of niraparib (Zejula) in patients with relapsed ovarian cancer who haveBRCAmutations.²Niraparib demonstrated an overall response rate of approximately 30% when used in the fourth-line setting or later. These findings support the use of niraparib in a later line of therapy for patients with relapsed ovarian cancer.

O’Malley said that the data from these 2 trials have altered the treatment of patients with ovarian cancer in multiple settings, and have shed light on the importance of early germline testing forBRCA1/2mutations. 

In an interview withTargeted Oncology, O’Malley, a professor in the Department of Obstetrics and Gynecology, The Ohio State University Comprehensive Cancer Center, discussed the findings from both these clinical trials investigating PARP inhibition in ovarian cancer. He also shares some insights into the future of these agents.

TARGETED ONCOLOGY:Could you reflect on the impact of the SOLO-1 findings?

O’Malley:This will lead us to revisit our treatment of women with ovarian cancer in multiple ways. One of which is early germline testing for patients with mutations in BRCA1/2, and then in those patients, utilizing the combination of cytotoxic chemotherapy followed by PARP. The improvements that we saw in PFS and the 3-year disease-free survival were marked, and even better than we had anticipated. Ultimately, our goal of curing more patients may now be achievable in patients with BRCA1/2 mutations. 

TARGETED ONCOLOGY:What are the findings from the QUADRA analysis?

O’Malley:This gives us further support that PARP inhibitors may be utilized in patients who have had received prior chemotherapy as a treatment option. However, as we have seen with the recent SOLO-1 data, our best option for patients is upfront or first-line therapy with PARP inhibitors. Additionally, with data from 3 randomized prospective trials, if patients with BRCA-positive disease have not had the opportunity to have PARP inhibitors upfront, they should be utilized in platinum-sensitive maintenance therapy. 

PARP inhibitors have revolutionized the treatment landscape. Testing for germline and somatic BRCA mutations needs to be done in all patients—period. 

TARGETED ONCOLOGY:What should we be looking forward to in this landscape?

O’Malley:There are multiple publicly available clinical trials, and more that are being designed in the upfront and platinum-sensitive populations. Many of these include PARP inhibitors alone or combined with immunotherapy or vascular therapy like bevacizumab (Avastin). Some include combining all 3.

The use of PARP inhibitors will be extensive throughout our treatment of patients with ovarian cancer in the upfront and recurrent settings. Our challenge is identifying those patients beyond BRCA who are going to benefit the most, as well as when we should use combination therapy. There are multiple trials out there.

TARGETED ONCOLOGY:Are there any remaining unmet needs that you hope to see addressed?

O’Malley:Curing more people. Like we have seen in SOLO-1, we have more than 50% of patients who have not recurred at 4 years. We now how the option of identifying agents and biologic markers, which will help us predict response and ultimately lead to patients being cured of ovarian cancer at a much higher rate. In SOLO-1, they stopped the PARP inhibitor at 2 years, and we did not see much of a drop-off in efficacy, so there is some sustainability of responses. However, we all can imagine if they had continued the PARP inhibitor beyond 2 years, we may have seen even better results.

References:

1. Moore K, Colombo N, Scambia G, et al. Olaparib maintenance therapy following first-line platinum-based chemotherapy in patients with FIGO stage III—IV ovarian cancer (OC) with a BRCA1/2 mutation (BRCAm): phase III SOLO1 trial. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA7_PR.
2. Moore KN, Secord AA, Geller MA, et al. QUADRA: a phase 2, open-label single-arm study to evaluate niraparib in patients with relapsed ovarian cancer in 4th or later line of therapy: results from the BRCAmut subset. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 944P.