Rucaparib shows efficacy as first-line maintenance therapy in ovarian cancer
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CHICAGO — Rucaparib monotherapy significantly prolonged PFS compared with placebo in the first-line maintenance setting among women with advanced ovarian cancer, regardless of BRCA mutation and homologous recombination deficiency status.
The results of the randomized phase 3 ATHENA-MONO trial, presented during ASCO Annual Meeting, additionally demonstrated safety of the oral, small molecule, poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib (Rubraca, Clovis Oncology) with no new adverse events observed.
Rationale and methods
“We conducted this study to answer some of the challenges from previous research and try to better define the biomarker opportunities beyond BRCA and homologous recombination deficiency [HRD] status,” Bradley J. Monk, MD, FACS, FACOG, co-director of the Gynecologic Oncology Group, researcher at HonorHealth Research Institute, and professor at University of Arizona College of Medicine and Creighton University School of Medicine, told Healio.
“In 2003, we published a paper that showed keeping a patient in remission could prolong PFS if the agent was active, but the study was stopped prematurely by the data safety monitoring committee because it worked so well,” he said. “There were two problems, however. One was that although it delayed progression, it caused fatigue, neuropathy and alopecia and all of the problems that traditional chemotherapy does. We then published a paper in 2011 that showed basically the same thing with another agent that had almost an identical prolongation in PFS but there was no biomarker. However, there was no alopecia, fatigue or bone marrow suppression. Various other studies were published thereafter, but there remained several unanswered questions about maintenance therapy, which is why we conducted the current study.”
Monk and colleagues randomly assigned 538 women with high-grade ovarian, fallopian tube or primary peritoneal cancer to either 600 mg twice-daily rucaparib (n = 427) or placebo (n = 111). They grouped patients according to HRD, residual disease status after chemotherapy and timing of surgery.
Investigator-assessed PFS per RECIST, assessed in a step-down fashion first among the HRD population followed by the intent-to-treat population, served as the primary endpoint, with blinded independent central review-assessed PFS as the secondary endpoint. Exploratory endpoints included PFS in patients with BRCA-mutated and BRCA wild-type/LOH high disease.
Key findings
At the time of data cutoff March 23, median time on treatment was 14.7 months with rucaparib and 9.9 months with placebo.
Results showed women with HRD-positive tumors assigned rucaparib experienced significantly longer PFS by investigator review (median, 28.7 months vs. 11.3 months; log-rank P = .0004), for an HR of 0.47 (95% CI, 0.31-0.72).
Moreover, researchers observed a significant PFS benefit with rucaparib by investigator review among all women (median PFS, 20.2 months vs. 9.2 months; P < .0001), for an HR of 0.52 (95% CI, 0.4-0.68).
Findings from exploratory subgroups also showed a PFS benefit by investigator review. Among women with HRD-negative tumors, results showed an HR of 0.65 (95% CI, 0.45-0.95) and median PFS of 12.1 months vs. 9.1 months. Women with BRCA-mutant tumors had an HR of 0.4 (95% CI, 0.21-0.75) with median PFS not reached for rucaparib vs. 14.7 months with placebo. Women with BRCA wild-type/LOH high disease has an HR of 0.58 (95% CI, 0.33-1.01) with median PFS of 20.3 months with rucaparib vs. 9.2 months with placebo.
Common grade 3 or higher treatment-associated adverse events among women assigned rucaparib included anemia (28.7%), neutropenia (14.6%) and alanine aminotransferase/aspartate transaminase increase (10.6%). Overall, 49.4% of women assigned rucaparib experienced a dose reduction, 60.7% had a dose interruption and 11.8% discontinued therapy due to treatment-associated adverse events.
Looking ahead
“There is a significant amount of misunderstanding about the survival issue and there is a concern that we may need to wait for more survival data to gain FDA approval,” Monk told Healio. “However, there is more than enough sufficient OS data, at least according to the other three PARP inhibitors that have been approved, and this needs to be addressed. It’s important for patients to use this medication and maintenance treatment. There’s more than enough survival data in my mind to get approved, and the next step is to work on a supplemental drug approval.”
Perspective
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Mehdi M. Kebria, MD
Results of the phase 3 ATHENA-MONO trial showed significant improvement in PFS using first-line maintenance rucaparib vs. placebo in women with advanced ovarian cancer who responded to platinum-based chemotherapy regardless of biomarker status.
PARP inhibitors have previously been studied for use as single or combination maintenance therapy in women with advanced ovarian cancer. Niraparib (Zejula, GlaxoSmithKline), another PARP inhibitor, has been studied in the PRIMA trial, which showed improvement in PFS when used as first-line maintenance therapy in women with advanced ovarian cancer who have had complete or partial response to platinum-based chemotherapy. This benefit was regardless of biomarker status and led to FDA approval of this drug. Obviously, this benefit was more prominent in women who had HRD.
ATHENA-MONO confirms this concept with use of rucaparib. When a drug is used for maintenance therapy it should have a favorable toxicity profile and quality of life should be maintained. This trial demonstrates an acceptable toxicity profile and discontinuation rate relatively similar to other PARP inhibitor trials. In my opinion, final outcome of this trial will likely lead to FDA approval of rucaparib for women with advanced ovarian cancer who have responded to first-line chemotherapy.
Reference:
González-Martín A, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1910962.
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Monk BJ, et al. Abstract LBA5500. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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