As reported in The Lancet Oncology by Andrés Poveda, MD, and colleagues, the phase III SOLO2/ENGOT-Ov21 trial has shown a large numeric but statistically nonsignificant improvement in the secondary endpoint of overall survival with olaparib tablet maintenance therapy vs placebo in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation.

The primary analysis of the trial supported the August 2017 regular approval of olaparib tablets in this setting on the basis of a significant improvement in progression-free survival.

Andrés Poveda, MD

Study Details

In the double-blind trial, 295 patients from sites in 16 countries were randomly assigned 2:1 between September 2013 and November 2014 to receive 300-mg olaparib tablets twice daily (n = 196) or placebo (n = 99). Treatment continued until disease progression or other discontinuation criteria were met; treatment could continue beyond progression if the investigator deemed the patient was experiencing benefit and did not meet other discontinuation criteria. Patients had relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer; had received at least two previous lines of platinum-based chemotherapy and were in objective response to their most recent platinum regimen; and had platinum-sensitive disease with BRCA1/2 mutation. The primary analysis showed a significant improvement with olaparib treatment in progression-free survival (median = 19.1 vs 5.5 months, hazard ratio [HR] = 0.30, 95% confidence interval [CI] = 0.22–0.41, P < .0001). This final analysis of the trial reported on overall survival, a key secondary endpoint.

Overall Survival

At the final overall survival analysis (performed at 61% data maturity), median follow-up for overall survival was 65.7 months (interquartile range [IQ] = 63.6–69.3 months) in the olaparib group and 64.5 months (IQR = 63.4–68.7 months) in the placebo group among censored patients. After discontinuation of study treatment, subsequent anticancer therapy was received by 66% of the olaparib group vs 82% of the placebo group, including platinum-containing chemotherapy in 45% vs 43%, another chemotherapy-containing regimen (excluding platinum and bevacizumab) in 38% vs 56%, and PARP inhibitor therapy in 10% vs 38%.

Median overall survival was 51.7 months (95% CI = 41.5–59.1 months) in the olaparib group vs 38.8 months (95% CI = 31.4–48.6 months) in the placebo group (HR = 0.74, 95% CI = 0.54–1.00, P = .054), with estimated 5-year survival of 42% vs 33%. In a prespecified exploratory analysis adjusting for subsequent PARP inhibitor therapy in 38% of the placebo group in the full analysis set, median overall survival was 51.7 months (95% CI = 41.5–59.1 months) in the olaparib group vs 35.4 months (95% CI = 24.2–43.5 months) in the placebo group (HR = 0.56, 95% CI = 0.35–0.97).

Median time to first subsequent therapy or death was 27.4 months vs 7.2 months (HR = 0.37, 95% CI = 0.28–0.48); the estimated proportion of patients who were alive and had not received a first subsequent treatment at 5 years was 28% vs 13%.  

Adverse Events

The mean total treatment duration was 29.1 months (IQR = 8.2–56.8 months) for olaparib and 13.1 months (IQR = 3.7–11.0) for placebo. The most common grade ≥ 3 adverse event in the olaparib group was anemia (21% vs 2%). With longer follow-up (data cutoff in February 2020), serious adverse events occurred in 26% vs 8% of patients, with the most common in the olaparib group being anemia (4%), intestinal obstruction (2%), myelodysplastic syndromes (2%), and constipation (2%). Treatment-related adverse events led to discontinuation of treatment in 13% vs 1% of patients, with the most common causes in the olaparib group being anemia (4%), acute myeloid leukemia (2%), myelodysplastic syndromes (1%), neutropenia (1%), and thrombocytopenia (1%). Treatment-related adverse events led to death in six patients (3%) in the olaparib group and none in the placebo group, with causes in the olaparib group consisting of myelodysplastic syndromes in three patients and acute myeloid leukemia in three patients.

The investigators concluded, “Olaparib provided a median overall survival benefit of 12.9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients.”

Dr. Poveda, of Initia Oncology, Hospital Quirónsalud, Valencia, Spain, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was supported by AstraZeneca and Merck. For full disclosures of the study authors, visit thelancet.com.