Robert L. Coleman, MD, FACOG, FACS
With 3 PARP inhibitors approved by the FDA for use as frontline maintenance in patients with BRCA1/2
-mutated ovarian cancer as well as in the recurrent setting, researchers continue to evaluate the role of this class of drugs in the treatment paradigm and how their use may be expanded, according to Robert L. Coleman, MD, FACOG, FACS.
One such inhibitor, rucaparib (Rubraca), received approval in April 2018 as a maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy based on data from the phase III ARIEL3. Median progression-free survival (PFS) was 10.8 months with rucaparib versus 5.4 months with placebo. The overall response rate with rucaparib was 18%. In those with either germline or somatic BRCA
mutations, a 77% reduction in the risk of progression or death was reported with rucaparib compared with placebo (HR, 0.23; 95% CI, 0.16-0.34; P
Many of the toxicities observed with the agent are similar to those observed with the other 2 FDA-approved PARP inhibitors: olaparib (Lynparza) and niraparib (Zejula). The most common associated toxicities observed with the agent are gastrointestinal (GI) events as well as fatigue, according to Coleman. However, the hematologic toxicities observed with rucaparib may slightly differ from what is seen with the other PARP inhibitors, Coleman added. Rucaparib is now being examined in combination with other agents in ongoing trials.
“Rucaparib was 1 of these 3 PARP inhibitors that has a similar effect in respect to inhibition of the catalytic activity of PARP,” said Coleman, a professor and Ann Rife Cox Chair in Gynecology, in the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, at The University of Texas MD Anderson Cancer Center. “The agent was initially studied in patients who carried a BRCA
mutation, as well as those who had a vulnerability identified via a loss of heterozygosity test.”
Clinical trials are now evaluating the potential combination of PARP inhibitors with immunotherapy or other agents in patients with ovarian cancer. In particular, investigators are combining PARP inhibitors with immune checkpoint inhibitors in the frontline setting. Although the population of PARP inhibitor–naïve patients is becoming smaller over time as more of these inhibitors are used in the frontline setting, the hunt to find a combination regimen that would provide these patients with more benefit than that of single-agent PARP inhibition continues.
In an interview with OncLive
during the 2020 SGO Winter Meeting, Coleman discussed the role of rucaparib as a treatment option for patients with ovarian cancer, how this agent compares with other PARP inhibitors in this space, and where research is headed for these agents.OncLive: How have PARP inhibitors evolved in ovarian cancer over the past few years?Coleman
: We have known for quite a long time now, almost 15 years, that cells that lack an intact homologous recombination pathway, best defined by a BRCA
mutation, are exquisitely sensitive to PARP inhibitors. The hypothesis for the mechanism of action for these inhibitors [is that they] would prevent single-strand repair or they would be trapped on the DNA during the replication process and lead to these double-strand breaks, which would then tax the cell to come up with a mechanism to fix. Several mechanisms can be leveraged for repair on double-strand DNA breaks, the highest fidelity of which is homologous recombination; however, other pathways can lead to [error-]prone repair.
The concept was that if we gave this medication in tumor cells that lack this high fidelity repair mechanism, they would have this synthetic lethality leading to cell death. PARP [inhibitors alone] weren’t necessarily killing the cells, and the lack of an intact homologous recombination pathway in the cell would not necessarily kill it either; having the 2 together led to the heightened cell kill that we saw. With that in mind, we knew we could identify patients whose tumors carried a BRCA
mutation. That is where the story started with the incorporation of PARP inhibitors into the clinical domain.What are the data that support the use of rucaparib in ovarian cancer?