An open-label randomized active-controlled phase II clinical study to assess the efficacy and safety of afuresertib plus paclitaxel versus paclitaxel in patients with platinum-resistant ovarian cancer (PROFECTA-II/GOG-3044)

Objectives

To evaluate the efficacy and safety/tolerability of paclitaxel with and without the AKT inhibitor afuresertib in patients with platinum-resistant ovarian cancer (PROC).

Methods

This phase II open-label randomized trial (NCT04374630) enrolled 150 PROC patients to evaluate progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate, and duration of response. Eligible patients received 1–5 prior chemotherapies (≤1 post-PROC therapy). Biomarker analysis assessed PI3K/AKT/PTEN alterations, BRCA1/2-mutations, and phospho-AKT levels. Patients with prior AKT or mTOR inhibitor use were excluded. Randomization was stratified by country and prior use of bevacizumab and platinum-based treatment lines.

Results

In the intent-to-treat population, no statistically significant difference was observed in PFS between afuresertib+paclitaxel (A + P) vs. paclitaxel (Pac) alone (median PFS 4.3mos [95 % CI, 3.58–5.62] vs 4.1mos [95 % CI 2.63–5.36]. PFS HR: 0.7 (95 % CI, 0.50–1.10; P = 0.139). No statistically significant difference in median OS was observed either (11.2mos with A + P, 95 % CI, 8.38–13.77) vs. 13.1mos in Pac arm (95 % CI, 7.75–18) and HR = 1.2 (95 % CI, 0.77–1.81). In AKT mutation biomarker+ (IHC > 1) patients, the median PFS of A + P vs. Pac was 5.4mos vs. 2.9mos (HR = 0.4; 95 % CI, 0.12–1.00). Treatment-emergent adverse events (TEAEs) were consistent with AKT inhibitors, with serious TEAEs in 34.3 % (A + P) vs. 25.5 % (Pac), including diarrhea and gastrointestinal perforations.

Conclusions

The addition of afuresertib to paclitaxel did not significantly improve PFS/OS in patients with PROC. However, exploratory biomarker findings suggest potential efficacy in phospho-AKT positive patients, warranting further investigation. The safety/tolerability profile of A + P was consistent with prior AKT-inhibitor studies.