NEW YORK — A post-hoc analysis of overall survival (OS) in the SOLO3 trial showed why olaparib (Lynparza) recently had its fourth-line indication in ovarian cancer pulled by the pharmaceutical company AstraZeneca.
The phase III trial, which tested olaparib versus platinum-free chemotherapy for women with BRCA-mutated relapsing platinum-sensitive disease, found divergent OS signals depending on whether women had received two or three prior lines of therapy, reported here Charles Leath III, MD, MSPH, of the University of Alabama at Birmingham.
In women who received two prior lines of chemotherapy, the median OS was 37.9 months with olaparib, compared with 28.8 months for those who received chemotherapy (HR 0.83, 95% CI: 0.51 to 1.38).
On the other hand, for patients who previously received three or more prior lines of therapy, a “potential harm” was observed, with a median OS of 29.9 months vs. 39.4 months, respectively (HR 1.33 , 95% CI 0.84-2.18) , Leath noted.
“Patients with two prior lines of chemotherapy had numerically favorable overall survival and progression-free survival. [PFS] with olaparib over chemotherapy,” Leath said in a presentation at the annual meeting of the International Gynecological Cancer Society.
PFS was 16.4 months with olaparib compared with 9.0 months with chemotherapy in women with two prior lines (HR 0.46, 95% CI 0.29-0.75), but was not different for who received three or more lines (9.4 vs. 9.2 months, respectively; HR 0.87, 95% CI 0.55-1.45).
Olaparib, a PARP inhibitor, received accelerated approval from the FDA in 2014 for the treatment of advanced disease. BRCA-mutated ovarian cancer based on results demonstrating improved objective response rate (ORR) and duration of response in a single-arm phase II study of patients receiving three or more lines of chemotherapy. However, following this approval, the agency requested a confirmatory trial.
ONLY 3 A statistically significant improvement in ORR and PFS with olaparib compared with non-platinum single-agent chemotherapy (paclitaxel, topotecan, gemcitabine, or pegylated liposomal doxorubicin) was confirmed in patients who had received two or more lines of chemotherapy.
The lack of OS benefit in other confirmatory trials such as SOLO3 has haunted the PARP inhibitor class in recent times. Recently, the American Society of Clinical Oncology (ASCO) warned against the routine use of PARP inhibitor monotherapy in the second-line or later setting for patients with recurrent platinum-sensitive ovarian cancer, after the emergence of “practice-changing” data from three phase III clinical trials, including the OS analysis of SOLO3.
In the most recent post-hoc analysis, Leath and colleagues evaluated OS and PFS in women who received two lines of chemotherapy compared with three or more lines. Of these patients, 178 received olaparib and 88 received chemotherapy. The proportion of patients receiving two versus three or more prior lines of chemotherapy was similar in both treatment arms. Most patients in both arms had a BRCA1 mutation.
Leath and colleagues did not see any new safety signals in post-hoc analysis. Adverse events were consistent with the known safety profile of olaparib and previous analyzes of SOLO3.
Overall, 22% of patients receiving olaparib developed BRCA reversal mutations in disease progression, a mechanism of resistance to PARP inhibitors and platinum-based chemotherapy, Leath explained. She said more research will explore whether BRCA reversals in patients receiving olaparib will change clinical outcomes.
Leath noted that this post-hoc subgroup analysis was not based on formal tests of significance.
This study was funded by AstraZeneca.
Leath disclosed material financial relationships with Merck, Seattle Genetics, Immunogen and Natera.