Olaparib Demonstrates Clinically Meaningful Overall Survival Benefit in Phase 3 SOLO2 Trial for BRCA-Mutated Platinum-Sensitive Relapsed Ovarian Cancer

Recently, The Lancet Oncology published the final analysis results of a double-blind, randomized, placebo-controlled Phase 3 clinical trial (SOLO2/ENGOT-Ov21) evaluating olaparib as maintenance therapy in patients with BRCA1/2-mutated, platinum-sensitive recurrent ovarian cancer. The primary objective of this final analysis was to assess the impact of olaparib on overall survival in this patient population. The results demonstrated that olaparib provides an unprecedented improvement in overall survival (OS) for patients with BRCA1/2-mutated, platinum-sensitive recurrent ovarian cancer, extending median OS by 12.9 months.

Olaparib is a “first-in-class” PARP inhibitor jointly developed by AstraZeneca and MSD. It has previously received approval from the U.S. FDA for the treatment of various cancer types, including advanced ovarian cancer, breast cancer, and pancreatic cancer in patients with germline BRCA mutations. Additionally, it is the first targeted novel drug approved for marketing in China for ovarian cancer.

Olaparib is effective in treating various cancers harboring germline BRCA mutations, primarily by leveraging the critical principle of “synthetic lethality” in cancer therapy. This concept implies that cell death occurs when two specific signaling pathways in cancer cells are simultaneously inhibited. BRCA proteins play a vital role in repairing DNA damage, while PARP also contributes significantly to DNA repair mechanisms. In tumor cells with BRCA gene mutations, the BRCA-mediated DNA damage repair pathway is already compromised. The subsequent use of PARP inhibitors to block PARP’s function in DNA repair leads to cell death due to the accumulation of unrepaired DNA damage.

Published in The Lancet Oncology, the SOLO2 (ENGOT-Ov21) phase 3 clinical trial aimed to evaluate the efficacy of olaparib monotherapy as maintenance treatment in patients with BRCA-mutated, platinum-sensitive recurrent ovarian cancer. Between September 2013 and November 2014, a total of 295 patients who had previously received two or more lines of therapy were enrolled. Patients were randomized to receive either olaparib (n = 196) or placebo (n = 99). The primary endpoint was progression-free survival (PFS), and one of the key secondary endpoints was overall survival (OS).

The median follow-up time was 65.7 months in the olaparib group and 64.5 months in the placebo group. Previously reported results demonstrated that olaparib maintenance therapy significantly improved progression-free survival (PFS) compared with placebo, extending median PFS by 13.6 months (19.1 months vs. 5.5 months) and reducing the risk of disease progression or death by 70% (HR=0.30). In the final analysis, focusing on the key secondary endpoint of overall survival (OS), olaparib conferred a significant OS benefit. The median OS was 51.7 months in the olaparib group versus 38.8 months in the placebo group, representing a 26% reduction in the risk of death (HR=0.74).

Researchers stated that, compared with placebo, olaparib extended median overall survival by 12.9 months in patients with BRCA1/2-mutated, platinum-sensitive recurrent ovarian cancer. Although the results did not reach statistical significance, these findings are arguably clinically meaningful and support the use of olaparib as maintenance therapy in this patient population.

References:

[1]Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial. Retrieved Mar 18, 2021, from https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00073-5/fulltext

[2]Olaparib Treatment in BRCA Mutated Ovarian Cancer Patients After Complete or Partial Response to Platinum Chemotherapy. Retrieved Mar 35, 2021, from https://www.clinicaltrials.gov/ct2/show/results/NCT01874353?term=NCT01874353&draw=2&rank=1

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