The phase 2 PROFECTA-II/GOG-3044 trial investigating afuresertib, an ATP-competitive pan-AKT inhibitor, in combination with paclitaxel has failed to demonstrate significant survival improvements compared to paclitaxel monotherapy in patients with platinum-resistant ovarian cancer, according to data presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women's Cancer.
At the data cutoff date of October 31, 2023, the combination therapy showed a median progression-free survival (PFS) of 4.3 months (95% CI, 3.58-5.62) compared to 4.1 months (95% CI, 2.63-5.36) with paclitaxel alone in the intention-to-treat population (HR, 0.7; 95% CI, 0.5-1.1; P = .139). The median overall survival (OS) was 11.2 months (95% CI, 8.38-13.77) with the combination versus 13.1 months (95% CI, 7.75-18.00) with paclitaxel monotherapy (HR, 1.2; 95% CI, 0.77-1.81).
Biomarker Analysis Shows Potential for Targeted Approach
Despite the overall negative findings, biomarker analysis revealed potentially important insights. Patients with pAKT expression greater than 1 showed a more pronounced benefit from the combination therapy, with a median PFS of 5.4 months (95% CI, 3.42-6.41) versus 2.9 months (95% CI, 1.25-not evaluable) with paclitaxel alone (HR, 0.4; 95% CI, 0.12-1.00).
"Biomarker-driven strategies targeting phospho-AKT may refine patient selection and enhance treatment outcomes in platinum-resistant ovarian cancer. However, further validation will be required to confirm this biomarker strategy," said presenting study author Thomas J. Herzog, MD, the Paul and Carolyn Flory Professor and deputy director of the University of Cincinnati Cancer Center.
Trial Design and Patient Population
The randomized trial enrolled 150 patients who were assigned in a 2:1 ratio to receive either 125 mg of oral afuresertib once daily plus 80 mg/m² of paclitaxel on days 1, 8, and 15 every 3 weeks (n = 99) or paclitaxel monotherapy at the same dosage (n = 51).
Eligible patients had platinum-resistant ovarian cancer, including fallopian tube and primary peritoneal carcinoma, with relapse occurring 1 to 6 months after the last dose of first-line platinum-based therapy. Additional eligibility criteria included:
- Progression on 1 to 5 prior chemotherapies, with no more than 1 after platinum-resistant ovarian cancer diagnosis
- ECOG performance status of 0 to 2
- At least one measurable lesion per RECIST v1.1
The patient population was well-balanced between arms, with a median age of 61 and 60 years in the combination and monotherapy arms, respectively. Most patients had received prior bevacizumab (78.8% and 84.3%), had high-grade serous histology (80.8% and 86.3%), and had metastatic disease (81.8% and 90.2%).
Response Rates and Disease Control
In the intention-to-treat population, the confirmed overall response rate was 25% (95% CI, 17.1%-35.0%) with the combination versus 18% (95% CI, 8.4%-30.9%) with paclitaxel alone. The disease control rate was 68% (95% CI, 57.5%-76.7%) with the combination compared to 57% (95% CI, 42.3%-70.6%) with monotherapy.
Safety Profile
The combination therapy demonstrated a manageable but more challenging toxicity profile compared to paclitaxel alone. Treatment-emergent adverse events (TEAEs) of any grade occurred in 99.0% of patients in the combination arm and 97.9% in the monotherapy arm. However, grade 3 to 5 TEAEs were more common with the combination (69.7% vs 51.1%).
The combination therapy also led to higher rates of treatment discontinuation (20.2% vs 6.4%) and treatment interruption (76.8% vs 68.1%). The most common adverse events included:
- Diarrhea: 64.6% with combination vs 19.1% with monotherapy
- Anemia: 54.5% vs 44.7%
- Neutropenia: 50.5% vs 51.1%
- Fatigue: 45.5% vs 38.3%
Unmet Need in Platinum-Resistant Ovarian Cancer
Dr. Herzog emphasized the continuing unmet need in this patient population: "Effective treatments for platinum-resistant ovarian cancer remain limited, thus novel agents are needed."
The study authors noted that strengths of the trial included high compliance and a patient group that aligns with the real-world platinum-resistant ovarian cancer population. Weaknesses included lack of dose optimization and potential pharmacokinetic differences between US and Chinese populations.
While the overall results did not demonstrate a significant benefit for the combination therapy, the biomarker findings suggest that a more targeted approach focusing on patients with higher pAKT expression might be worth further investigation in this difficult-to-treat cancer population.
