Prolonging PFS With PARP Inhibitors in Platinum-Sensitive Ovarian Cancer

Alexander Olawaiye, MD

By blocking PARP, a key enzyme involved in DNA damage repair, investigators have been able to induce synthetic lethality, which in turn has led to dramatic clinical responses for patients with platinum-sensitive ovarian cancer.

Currently, olaparib (Lynparza) and rucaparib (Rubraca) are approved for the treatment of women with BRCA-mutated ovarian cancer following >3 and >2 prior lines of therapy, respectively. All 3 inhibitors—niraparib (Zejula), olaparib, and rucaparib—are indicated in the recurrent setting as maintenance therapy following platinum-based chemotherapy, said Alexander Olawaiye, MD, in a presentation during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer.

At the meeting, Olawaiye, director, Gynecologic Oncology Research Program, and assistant professor of gynecologic oncology at the University of Pittsburgh and Magee-Womens Hospital, University of Pittsburgh Medical Center Hillman Cancer Center, discussed the trials that led to the expanded approvals of PARP inhibitors as maintenance therapy in women with platinum-sensitive ovarian cancer.

In 2017, niraparib was approved as maintenance therapy based on the results of the phase III NOVA trial. In the trial, women who had received ≥2 lines of platinum-based chemotherapy and achieved a complete response (CR) or partial response (PR) to chemotherapy were randomized 2:1 to receive either niraparib (n = 372) or placebo (n = 181). Patients were eligible for enrollment, irrespective of biomarker status but were grouped according to their germline BRCA status.

Results showed a significant survival advantage with niraparib versus placebo in the germline BRCA-mutant cohort, one which translated to a 73% reduction in the risk of progression or death (HR, 0.27; 95% CI, 0.17-0.41; P <.0001).¹ At 18 months, 50% of patients on the niraparib arm were alive compared with 16% on the placebo arm.

“This was something no one had ever seen before,” said Olawaiye.

The results of the non-germline BRCA-mutant cohort also favored niraparib over placebo, but to a lesser extent (HR, 0.45; 95% CI: 0.34-0.61; P <.0001).

The phase III SOLO-2/ENGOT-Ov21 trial was similarly designed to evaluate the activity of olaparib as maintenance therapy. The study was launched after investigators reported the PFS benefit with olaparib as maintenance therapy versus placebo in the phase II Study 19 trial (HR, 0.35; 95% CI: 0.25-0.49; P < .001).² Notably, patients were required to have a known BRCA1/2 mutation in order to be eligible for enrollment in SOLO-2 as opposed to Study 19, which did not possess that requirement.

Here too, investigators noted a significant survival advantage with olaparib versus placebo. According to investigator assessment, the median progression-free survival (PFS) was 19.1 months in the olaparib arm (n = 196) versus 5.5 months in the placebo arm (n = 99; [HR, 0.30; 95% CI, 0.22-0.41; P <.0001]).³ Both studies served as the basis for the agent’s approval in 2017 as maintenance therapy following a CR or PR to platinum-based therapy.

The phase III ARIEL3 trial was a similar design, explained Olawaiye. However, in this study, patients with a BRCA1/2 mutation or non-BRCA homologous recombination deficiency (HRD) were randomized 2:1 to receive either rucaparib (n = 375) or placebo (n = 189).

“Genomic-wide loss of heterozygosity (LOH) is an indirect surrogate for HRD, which means that if a patient has a high LOH, they’re likely to have HRD,” said Olawaiye.

Investigators noted a striking PFS benefit with rucaparib compared with placebo across the BRCA-mutant (HR, 0.23; 95% CI, 0.16-0.34; P <.0001), HRD (HR, 0.32; 95% CI, 0.24-0.42; P <.0001), and intent-to-treat (HR, 0.36; 95% CI, 0.30-0.45; P <.0001) populations.⁴

These findings recapitulated those observed in part 1 of the phase II ARIEL2 trial, which classified patients into 1 of 3 subgroups: BRCA-mutant (n = 40), LOH-high (n = 82), or LOH-low (n =70). The median PFS after treatment with rucaparib was 12.8 months, 5.7 months, and 5.2 months in the BRCA-mutant, LOH-high, and LOH-low subgroups, respectively. ⁵

“If there is any difference between these drugs, it’s not in efficacy,” said Olawaiye. “We should be paying attention to the inclusion criteria in the trial because that could help us decipher who to treat and with which agent.”

Most recently, results of the multicenter phase II QUADRA trial were presented, in which patients with advanced disease who could have been exposed to prior PARP inhibition (n = 37) but must have received ≥3 prior lines of chemotherapy received niraparib (n = 456).

“With the exception of TOPACIO, this is one of the first PARP inhibitor trials to allow platinum-refractory/resistant patients to enroll,” explained Olawaiye.

Among the entire study population, the median duration of response with niraparib was 9.4 months (95% CI, 6.6-18.3), while the median overall survival (OS) was 17.2 months (95% CI, 14.9-19.8).⁶ Every patient appeared to benefit, said Olawaiye. However, higher platinum sensitivity did correlate with an improved response. On June 24, 2019, the FDA granted a priority review designation to a supplemental biologics license application for niraparib for patients with a BRCA mutation or have HRD and progressed >6 months after their last platinum-based chemotherapy.

Finally, Study 42 is an open-label trial evaluating the safety and efficacy of olaparib in patients with a confirmed BRCA1/2 mutation in several solid tumors that are refractory to all available therapies.

Among 25 of 193 evaluable patients in the ovarian cancer cohort, the objective response rate was 35.9%, the PFS was 7.03 months, and the OS was 16.62 months with the agent.⁷ “[These results show that this] is a very useful treatment for an otherwise extremely concerning group of patients,” said Olawaiye.

In terms of adverse events, all 3 inhibitors have been shown to cause a decrease in hemoglobin, platelets, and neutrophil count. However, grade 3/4 hematologic toxicities have been most apparent with niraparib. Even so, approximately 85% of patients are able to complete their treatment without having to discontinue therapy, said Olawaiye. Treatment interruptions or dose reductions may be necessary, he concluded.

References

1. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164. doi: 10.1056/NEJMoa1611310.
2. Ledermann and Pujade-Lauraine. Olaparib as maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer. Ther Adv Med Oncol. 2019;11:1758835919849753. doi: 10.1177/1758835919849753.
3. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomized, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2.
4. Ledermann J, Oza AM, Lorusso D, et al. ARIEL3: a phase 3, randomised, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma (OC). Ann Oncol. 2017;28(suppl 5; abstr LBA40_PR). doi: 10.1093/annonc/mdx440.034.
5. Swisher EM, Harrell MI, Lin K, et al. BRCA1 and RAD51C promoter hypermethylation confer sensitivity to the PARP inhibitor rucaparib in patients with relapsed, platinum-sensitive ovarian carcinoma in ARIEL2. Gyn Oncol. 2017;145(suppl 1):5. doi: 10.1016/j.ygyno.2017.03.034.
6. Moore KN, Secord AA, Geller MA, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20(5):636-648. doi: 10.1016/S1470-2045(19)30029-4.
7. Open Label Study to Access Efficacy and Safety of Olaparib in Confirmed Genetic BRCA1 or BRCA2 Mutation Pats. www.clinicaltrials.gov/ct2/show/NCT01078662. Updated June 4, 2019. Accessed August 20, 2019.