Olaparib Elicits Improved OS Rates in Platinum-Sensitive, Germline/Somatic BRCA+ Relapsed Ovarian Cancer

Although efficacy was observed across all cohorts, treatment of olaparib (Lynparza) was associated with the biggest overall survival (OS) benefit in patients with platinum-sensitive relapsed ovarian cancer harboring germline or somatic BRCA mutations, according to a final OS analysis of the phase 2 LIGHT study (NCT02983799).1

Findings published in Cancer showed that at a median follow-up in of 26.3 months (range 0.6-36.9 months) for the efficacy analysis set (n = 270) and a final data cutoff of August 27, 2020, the 18-month OS rates for the germline BRCA mutation cohort (cohort 1; n = 75), somatic BRCA mutation cohort (cohort 2; n = 25), the homologous recombination deficiency (HRD)–positive, non-BRCA mutation cohort (cohort 3; n = 68), and HRD-negative cohort (cohort 4; n = 89) were 86.4% (95% CI, 76.2%-92.4%), 88.0% (95% CI, 67.3%-96.0%), 78.6% (95% CI, 66.6%-86.8%), and 59.6% (95% CI, 48.6%-68.9%), respectively. The OS rates at 1 year in the respective cohorts were 94.6% (95% CI, 86.3%-97.9%), 92.0% (95% CI, 71.6%-97.9%), 89.4% (95% CI, 79.1%-94.8%), and 71.9% (95% CI, 61.3%-80.1%).

“The final OS analysis of the LIGHT study of olaparib treatment in platinum-sensitive relapsed ovarian cancer showed that the highest OS rates were observed in the germline/somatic BRCA-mutated cohorts,” lead study author Ying L. Liu, MD, MPH, a gynecologic medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and coauthors wrote in the paper. “Among patients without a BRCA mutation, OS rates were highest in the HRD-positive cohort.”

LIGHT Trial Background and Design

The open-label, nonrandomized, noncomparative, multicenter LIGHT study prospectively assessed olaparib in the treatment of patients with platinum-sensitive relapsed ovarian cancer who received 1 or more prior lines of platinum-based chemotherapy with a known BRCA mutation status and HRD status.

Findings from the primary analysis of the study showed the overall response rates (ORRs) were 69.3% (95% CI, 57.6%-79.5%), 64.0% (95% CI, 42.5%-82.0%), 29.4% (95% CI, 19.0%-41.7%), and 10.1% (95% CI, 4.7%-18.3%) in cohorts 1, 2, 3, and 4, respectively.2

The study included 272 patients, of which 270 met the inclusion criteria for the efficacy analysis; 271 patients were included in the safety analysis.1,2 Eligibility criteria included patients at least 18 years of age with histologically confirmed, relapsed high-grade serious or endometrioid ovarian, primary peritoneal, and/or fallopian tube cancer per RECIST criteria 1.1; at least 1 assessable lesion at baseline; disease progression at least 6 months after the end of the last platinum-based chemotherapy regimen; and no previous treatment with PARP inhibitors.

Patients were assigned to cohorts 1, 2, 3, and 4 based on their BRCA mutation and HRD statuses. An unassigned cohort included patients who were not assigned to a specific cohort because of missing or failed BRCA mutation or HRD test results.

The primary end point was investigator-assessed ORR per RECIST 1.1.2 Secondary end points were OS and safety.1

Patient Characteristics and Safety Data

In cohorts 1 (n = 75), 2 (n = 26), 3 (n = 68), and 4 (n = 90), median ages at baseline were 61 years (range, 42-80), 71 years (range, 50-90), 64 years (range, 38-88), and 69 years (range, 35-91).2 Tumor grade in the respective cohorts were mostly high grade (68.0%; 80.8%; 77.9%; 74.4%) and most had an ECOG performance status of 0 (77.3%; 50.0%; 70.6%; 62.2%).

At data cutoff for the final OS analysis, the discontinuation rates for olaparib in cohorts 1, 2, 3, and 4 were 78.7%, 92.0%, 89.7%, and 98.9%, respectively.1 In the unassigned cohort (n = 13), all patients received treatment; 92.3% discontinued treatment, and 7.7% continued treatment at data cutoff.

“A similar pattern of relative benefit between cohorts was observed when patients were stratified by number of prior chemotherapy regimens [1 and 2 or more],” study authors stated. “No new safety signals were observed at the final LIGHT OS analysis compared with the primary analysis and prior olaparib studies.”

Data from the final analysis showed the median total duration of treatment for the overall population was 7.4 months (range, 0.5-30.6). Of note, 29.5% of patients required dose interruptions and 26.9% needed dose reductions; adverse effects (AEs) led to dose interruptions and dose reductions in 26.2% and 21.8% of patients, respectively. Treatment-emergent AEs (TEAEs) leading to treatment discontinuation occurred in 5.2% of patients. The most common TEAEs leading to discontinuation included fatigue/asthenia and nausea, which were each reported in 2 patients (0.7%).

The most common serious treatment-related AEs of any grade included anemia (1.1%) pneumonia (0.7%), and abdominal pain (0.7%). AEs of special interest included 1 patient (0.4%) with grade 2 pneumonitis 57 days after beginning olaparib, and 1 other patient with grade 2 pulmonary fibrosis 110 days after beginning olaparib. Grade 4 acute myeloid leukemia 711 days after beginning olaparib treatment occurred in 1 patient (0.4%); however, this was considered unrelated to olaparib.

AEs led to death in 2 patients (0.7%) but were deemed unrelated to olaparib, including a death from atrial fibrillation in the somatic BRCA mutation cohort 46 days after beginning olaparib treatment, along with a death from intestinal perforation that occurred during the survival follow-up period of the analysis from the unassigned cohort.

References

1. Liu YL, Mathews CA, Simpkins F, et al. Olaparib as treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency: Phase 2 LIGHT study final overall survival analysis. Cancer. 2025;131(2):e35707. doi:10.1002/cncr.35707
2. Cadoo K, Simpkins F, Mathews C, et al. Olaparib treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: Phase II LIGHT study primary analysis. Gynecol Oncol. 2022;166(3):425-431. doi:10.1016/j.ygyno.2022.06.017