Further Results from SOLO2 Underscore Need for New Strategies to Treat BRCA1/2+ Recurrent Epithelial Ovarian Cancer

Richard Penson, MBBS

A reduction in the effectiveness of chemotherapy administered subsequently to maintenance olaparib (Lynparza) was seen when patients with BRCA 1/2-mutated recurrent epithelial ovarian cancer progressed on olaparib vs patients who do not receive prior PAPR inhibition, according to findings from a post hoc analysis of the phase 3 SOLO2 trial (ENGOT Ov-21; NCT01874353).¹

Based on these findings, there is a need for research to determine the optimal strategy for patients who relapse after treatment with a PARP inhibitor.

“Our recently published further analysis of the SOLO2 study confirms concerns about PARP inhibitors driving up tumor resistance later in the clinical course of BRCA-mutated ovarian cancer, by further compromising DNA damage repair,” Richard T. Penson, MBBS, clinical director of Medical Gynecologic Oncology, associate professor Harvard Medical School, and IRB Chair at Dana Farber Harvard Cancer Center said, in a statement to Targeted Oncology™.

Previously in the SOLO2 trial, maintenance olaparib was shown to significantly improve progression-free survival (PFS) and overall survival (OS) in patients with platinum-sensitive relapsed ovarian cancer, but there was no knowledge around the efficacy of subsequent therapy in patients who progressed on maintenance olaparib. In the post-hoc analysis, investigators assessed time to second progression (TTSP) in 147 patients who were treated with chemotherapy after RECIST progression on olaparib or placebo.

In the study, 69 patients were randomized to receive placebo and 78 were randomized to the olaparib arm. Of the patients given placebo, 27 received non-platinum chemotherapy as subsequent treatment and 42 received platinum-based chemotherapy. Among those treated with olaparib, 24 patients received non-platinum chemotherapy after olaparib and 54 received platinum-based chemotherapy.

In the chemotherapy arm, there was a significantly better TTSP of 12.1 months vs 6.9 months with placebo (HR, 2.17; 95% CI, 1.47-3.19). This result showed similarity to a multivariable analysis in which prognostic factors were adjusted at RECIST progression (HR, 2.13; 95% CI, 1.41-3.22). Among the 96 patients treated with platinum-based chemotherapy, TTPS was significantly longer at 14.3 months compared with 7.0 months in the placebo arm (HR, 2.89; 95% CI, 1.73-4.82). Those treated with non-platinum-based chemotherapy showed comparable TTSP with the placebo group at 8.3 months vs 6.0 months (HR, 1.58; 95% CI, 0.86-2.90).

“The strongest signal was observed with subsequent platinum-based therapy with mPFS twice as long after subsequent therapy in those in the placebo arm,” Penson noted.

Overall, the study showed that disease progression patterns are similar in patients who were treated with olaparib or given placebo.

“PARP inhibitors unequivocally improve survival as first and second line maintenance therapy but at the cost of complicating later lines of chemotherapy, Pension explains. “PARP inhibitor therapy was associated with a worse survival than palliative chemotherapy in those enrolled to SOLO3 with 3 or more prior lines of chemotherapy.”

Investigators of SOLO2 recommend better characterization of the mechanism of resistance in these patients to aid in the development of new therapies.

_REFERENCES:

_{Frenel JS, Kim JW, Aryal N, et al. Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial. Ann Oncol. 2022;33(10):1021-1028. doi:10.1016/j.annonc.2022.06.011}