Afuresertib Plus Paclitaxel Does Not Elicit Substantial Clinical Benefit in Platinum-Resistant Ovarian Cancer

Afuresertib Plus Paclitaxel in Platinum-Resistant

Ovarian Cancer | Image Credit: © Katsyarina

– stock.adobe.com

The addition of afuresertib to paclitaxel did not generate a significant survival advantage compared with paclitaxel monotherapy in patients with platinum-resistant ovarian cancer, although the combination was associated with a manageable toxicity profile, according to dara from the phase 2 PROFECTA-II/GOG-3044 trial (NCT04374630) presented at the 2025 SGO Annual Meeting on Women’s Cancer.

At a data cutoff of October 31, 2023, the combination of afuresertib—an ATP-competitive pan-AKT inhibitor—plus paclitaxel elicited a median progression-free survival (PFS) of 4.3 months (95% CI, 3.58-5.62) vs 4.1 months (95% CI, 2.63-5.36) with paclitaxel alone in the intention-to-treat (ITT) 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) vs 13.1 months (95% CI, 7.75-18.00), respectively (HR, 1.2; 95% CI, 0.77-1.81).

In the ITT population, the confirmed overall response rate (ORR) was 25% (95% CI, 17.1%-35.0%) with the combination vs 18% (95% CI, 8.4%-30.9%) with paclitaxel alone. The confirmed disease control rates (DCRs) were 68% (95% CI, 57.5%-76.7%) vs 57% (95% CI, 42.3%-70.6%), respectively.

In patients with pAKT expression greater than 1, the median PFS was 5.4 months (95% CI, 3.42-6.41) in the combination arm vs 2.9 months (95% CI, 1.25-not evaluable [NE]) with paclitaxel alone (HR, 0.4; 95% CI, 0.12-1.00); in patients without pAKT expression, the median PFS was 4.4 months (95% CI, 2.83-6.97) compared with 2.9 months (95% CI, 1.41-6.74), respectively (HR, 0.7; 95% CI, 0.39-1.27).

“Effective treatments for [platinum-resistant ovarian cancer] remain limited, thus novel agents are needed,” presenting study author Thomas J. Herzog, MD, the Paul and Carolyn Flory Professor and deputy director of the University of Cincinnati Cancer Center and vice chair of the Quality and Safety Department of Obstetrics and Gynecology President at the Gynecologic Oncology Group Foundation, stated in the presentation. “Biomarker-driven strategies targeting pAKT may refine patient selection and enhance treatment outcomes in [platinum-resistant ovarian cancer]. However, further validation will be required to confirm this biomarker strategy.”

A total of 150 patients were randomly assigned in a 2:1 ratio to receive either 125 mg of oral afuresertib once daily and 80 mg/m2 of paclitaxel on days 1, 8, and 15 every 3 weeks (n = 99) or paclitaxel monotherapy (n = 51).

Eligible patients had platinum-resistant ovarian cancer—including fallopian tube and primary peritoneal carcinoma—and had relapsed 1 to 6 months after their last dose of first-line platinum-based therapy. Additional criteria included progression on 1 to 5 prior chemotherapies, no more than 1 of which were permitted to have occurred after platinum-resistant ovarian cancer diagnosis; an ECOG performance status from 0 to 2; and at least 1 measurable lesion per RECIST 1.1 criteria.

The trial’s primary end point was PFS as assessed by the investigators. Secondary end points were OS, ORR, duration of response, DCR, and CA-125 response.

The median age of patients was 61 years and 60 years in the combination arm and monotherapy arm, respectively; most patients in these respective arms were treated with prior bevacizumab (Avastin; 78.8% vs 84.3%), had received 1 to 2 prior lines of therapy (77.8% vs 80.4%), had an ECOG performance status of 0 (58.2% vs 43.1%), had high-grade serous disease histology (80.8% vs 86.3%), and had metastases (81.8% vs 90.2%). pAKT expression levels per immunohistochemistry were greater than 1 in 40.0% and 30.6% of patients and greater than 3 in 27.7% and 22.2% of patients, respectively.

Regarding safety, any grade treatment-emergent adverse effects (TEAEs) occurred in 99.0% of patients in the combination arm and 97.9% of those in the monotherapy arm; CTCAE grade 3 to 5 TEAEs occurred in 69.7% and 51.1%, of patients respectively. TEAEs led to any drug discontinuation in 20.2% and 6.4% of patients, respectively; and any drug interruption in 76.8% and 68.1% of patients, respectively. The most common any-grade TEAEs included diarrhea (combination arm, 64.6%; monotherapy arm, 19.1%), anemia (54.5%; 44.7%), neutropenia (50.5%; 51.1%), and fatigue (45.5%; 38.3%).

The study authors cited high compliance and a patient group that aligns with the real-world platinum-resistant ovarian cancer population as strengths of the trial; no dose optimization and potential pharmacokinetic differences in the United States vs China populations were noted as weaknesses of the trial.

Reference

Herzog TJ, Liao JB, Finkelstein K, et al. 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 (GOG 3044). Presented at: 2025 SGO Annual Meeting; March 14-17, 2025; Seattle, WA. Abstract 843870.