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Reference: SOLO2/ENGOT-Ov21 trial (Lancet Oncol 2017 Jul 25 early online) (level 3 [lacking direct] evidence)
- Olaparib is approved for women with BRCA-positive advanced ovarian cancer who have been treated with ≥ 3 lines of chemotherapy.
- In the SOLO2/ENGOT-Ov21 trial, 295 adult women (mean age 56 years) with platinum-sensitive, relapsed BRCA-positive ovarian cancer who had received ≥ 2 lines of chemotherapy were randomized to olaparib 300 mg orally twice daily vs. placebo and followed for a median of 22 months.
- Progression-free survival was prolonged with olaparib (19.1 months vs. 5.5 months with placebo, hazard ratio 0.3, 95% CI 0.22-0.41), but longer term follow-up is required to evaluate overall survival, and there was no difference in health-related quality of life.
Olaparib, an oral poly (ADP-ribose) polymerase (PARP) inhibitor, is currently approved as monotherapy for women with BRCA-positive advanced ovarian cancer who have had treatment with ≥ 3 lines of chemotherapy (Food and Drug Administration). The basis for the expedited approval of olaparib included the objective response rate and duration of response in an uncontrolled trial involving 137 women. Recently, olaparib was further evaluated in the SOLO2/ENGOT-Ov21 trial which included adult women with platinum-sensitive, relapsed ovarian cancer with BRCA 1 or BRCA 2 mutation who had been treated with ≥ 2 lines of chemotherapy. In this phase 3 trial, 295 women (mean age 56 years) were randomized 2:1 to olaparib 300 mg orally twice daily vs. placebo and followed for a median of 22 months. Most (in 91%) women had serous ovarian cancer. Platinum sensitivity was defined as disease progression occurring ≥ 6 months after the last dose of platinum chemotherapy. The primary outcome was progression-free survival (PFS) defined as time from randomization to radiological disease progression based on modified RECIST 1.1 criteria or death. Disease progression was assessed with computed tomography or magnetic resonance imaging every 12 weeks until week 72 and every 24 weeks thereafter.
The median time to PFS was 19.1 months with olaparib vs. 5.5 months with placebo (hazard ratio [HR] 0.3, 95% CI 0.22-0.41), but there was no statistically significant difference in overall survival with death in 23% with olaparib vs. 27% with placebo (HR for death 0.8, 95% CI 0.5-1.3). Adverse events resulting in discontinuation of treatment occurred in 11% of patients receiving olaparib vs. 2% with placebo (statistical comparisons were not reported for any adverse outcomes). Anemia occurred in 19.5% with olaparib vs. 2% with placebo and blood transfusions were required in 18% with olaparib vs. 1% with placebo. Incident secondary malignancies occurred in 3% with olaparib vs. 5% with placebo and 1 woman taking olaparib died from myeloid leukemia. No significant difference in health-related quality of life was found.
In the SOLO2/ENGOT-Ov21 trial, PFS was prolonged in women treated with olaparib, but there was no significant difference in health-related quality of life. The effect of olaparib on overall survival is unclear as the 95% confidence interval for risk of death includes both the possibility of benefit and harm. The use of PFS to evaluate clinical benefit in cancer trials has the potential for bias. In contrast to overall survival, an outcome that can be reliably determined, the precision of the estimation of PFS is dependent upon the follow-up interval, and its determination may contain subjective elements. The latter is illustrated in the present trial by the difference in PFS observed between the investigators and the independent central review. PFS for the olaparib group was 19.1 months by the investigator assessment and was 30.2 months by the central review assessment, while both assessor groups determined it to be 5.5 months for the placebo group. Finally, PFS does not always reliably correlate with overall survival and its utility as a surrogate outcome in non-first line treatment for ovarian cancer is unclear (Agency for Healthcare Research and Quality [US]; 2013 Apr). In summary, olaparib may be considered for women with BRCA-positive platinum-sensitive ovarian cancer who have relapsed after multiple lines of chemotherapy. However, it is important to bear in mind the potential for adverse events, that no difference in health-related quality of life was demonstrated, and that the assessment of olaparib on overall survival may change in extended follow-up of this trial.
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