Introduction

In the SOLO 2 trial Olaparib demonstrated significantly enhanced progression-free survival (PFS) and extended overall survival (OS) in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutations.

A considerable proportion of patients develop resistance to PARP inhibitors (PARPi). The optimal management strategy for relapse following PARPi therapy in clinical practice remains undefined. Currently, chemotherapy is the standard treatment for progression after PARPi exposure.

Aim

To determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received Olaparib or placebo.

Patient Profile

Women with BRCA1/2-mutated platinum sensitive relapsing ovarian cancer (PSROC) with RECIST disease progression who received either Olaparib maintenance or placebo.

Methods

• Post hoc analysis of SOLO2/ENGOT-ov21trial
• SOLO2 trial patients (n=147) received chemotherapy as their first subsequent treatment after RECIST progression were randomized

• Placebo Group: 69 patients
• Non-Platinum-Based Chemotherapy: 27 patients
• Platinum-Based Chemotherapy: 42 patients
• Olaparib Group: 78 patients
• Non-Platinum-Based Chemotherapy: 24 patients
• Platinum-Based Chemotherapy: 54 patients
• The remaining patients (n=14) received various therapies including PARPi monotherapy, bevacizumab monotherapy, or endocrine therapy.

Study Endpoints

• The main efficacy criterion in patients receiving chemotherapy was the time to second progression (TTSP) define as the time between RECIST first progression and second progression or death.
• Time between first subsequent treatment (TFST) and second progression, and time between the start dates of the first and second subsequent treatments in chemotherapy-receiving patients.

Results

• TTSP was significantly longer in patients who were treated with chemotherapy (n=147) following progression on placebo than on Olaparib [HR= 2.17] (figure 1)
• TTSP was significantly longer in the placebo arm among patients treated with platinum-based chemotherapy (n=96) (HR 2.89) (figure 1)
• Among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and Olaparib arms: 8.3 vs 6.0 months (HR 1.58).
• In multivariable analysis, similar results were obtained on adjusting for prognostic factors such as performance status at initial disease progression, disease burden at that time, randomized treatment group, number of prior platinum therapy lines, progression-free interval, response to previous platinum chemotherapy at enrollment, and responses to randomized treatment at RECIST progression (HR=2.13; P < 0.001)

Figure 1: Time to second progression according to subsequent therapy type

• The time from first to second progression (TFST) showed median durations of 4.8 months for the Olaparib group and 9.5 months for the placebo group, with a hazard ratio (HR) of 2.97.
• Time between the first and second subsequent treatments showed average intervals of 16.1 months for the placebo cohort & 10.6 months for the Olaparib cohort.
• In 14 patients continued receiving Olaparib beyond RECIST-defined disease progression, the median TTSP was 10.1 months, with 10 patients not experiencing a second progression during follow-up
• Disease progression patterns were comparable between the Olaparib & placebo groups, with similar proportions of patients experiencing one or two progressing RECIST target lesions and no significant difference in the sites of progression, where the peritoneum and lymph nodes were the most commonly affected areas in both groups.

Conclusion

In this post-hoc hypothesis-generating analysis of the SOLO2 trial, following progression on maintenance Olaparib in the recurrent setting, the effectiveness of subsequent platinum-based chemotherapy appears diminished in BRCA1/2-mutated patients with platinum-sensitive relapse of ovarian cancer compared to those who had not previously received poly (ADP-ribose) polymerase inhibitors (PARPi).

Reference

Ann Oncol.2022 Oct;33(10):1021-1028.