ODAC Endorses TRUQAP Combination Therapy Based on Phase III CAPItello-281 Results Showing Improved Progression-Free Survival and Addressing Unmet Need
The U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee (ODAC) has voted in favor of a new treatment approach involving TRUQAP® (capivasertib) in combination with abiraterone and androgen deprivation therapy (ADT) for patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC). The committee reached its conclusion by a vote of 7 to 1, with one member abstaining, indicating strong support for the therapy’s favorable benefit-risk profile based on findings from the Phase III CAPItello-281 clinical trial.
This recommendation marks an important milestone for patients with PTEN-deficient mHSPC, a subgroup of prostate cancer known for its aggressive progression and limited treatment options. The combination of TRUQAP with abiraterone and ADT represents the first and only targeted therapy regimen to demonstrate meaningful clinical benefit in this population, addressing a significant unmet medical need.
The FDA had previously accepted a supplemental New Drug Application (sNDA) for this combination therapy in August 2025. The application was supported by positive results from the CAPItello-281 Phase III trial, which were presented at the European Society for Medical Oncology Congress 2025 and simultaneously published in the journal Annals of Oncology.
According to Dr. Daniel George, Director of Genitourinary Oncology at the Duke Cancer Institute and a principal investigator in the study, patients with PTEN-deficient metastatic hormone-sensitive prostate cancer typically face a poor prognosis. The disease tends to progress rapidly, significantly diminishing quality of life and leading to advanced stages associated with high mortality rates. He emphasized that current treatment options remain limited, making the ODAC’s recommendation a promising development for both patients and clinicians seeking more effective therapies to delay disease progression.
From AstraZeneca’s perspective, the CAPItello-281 trial represents a critical advancement in understanding and treating this aggressive cancer subtype. Susan Galbraith, Executive Vice President of Oncology Haematology R&D at AstraZeneca, highlighted that this trial is the first pivotal study to prospectively define PTEN-deficient mHSPC and characterize its clinical course. She noted that the ODAC’s recognition of both the unmet need and the clinical benefits observed with the TRUQAP combination underscores its potential to improve outcomes for approximately one in four patients affected by this form of prostate cancer.
The primary results of the CAPItello-281 trial demonstrated a statistically significant and clinically meaningful improvement in outcomes for patients receiving the TRUQAP combination. Specifically, the treatment reduced the risk of radiographic disease progression or death by 19% compared to the control group receiving abiraterone and ADT with placebo. This corresponds to a hazard ratio (HR) of 0.81, with a 95% confidence interval (CI) of 0.66 to 0.98 and a p-value of 0.034.
In terms of progression-free survival, patients treated with the TRUQAP combination experienced a median radiographic progression-free survival (rPFS) of 33.2 months, compared to 25.7 months in the comparator arm. This represents a clinically meaningful improvement of 7.5 months, further reinforcing the therapeutic benefit of the combination regimen.
Beyond the primary endpoint, the study also demonstrated consistent improvements across several key secondary endpoints. These included a prolonged time to castration resistance, which was extended to 29.5 months in the TRUQAP group compared to 22.0 months in the control group (HR 0.77; 95% CI: 0.63–0.94). Additionally, the combination therapy showed favorable trends in delaying prostate-specific antigen (PSA) progression, with a hazard ratio of 0.73.
The treatment also showed benefits in symptomatic skeletal event-free survival (SSE-FS), with patients in the TRUQAP arm experiencing fewer and delayed skeletal complications. Median SSE-FS was 42.5 months compared to 37.3 months in the control arm, reflecting another positive outcome associated with the therapy.
While overall survival (OS) data were still immature at the time of the primary analysis, interim results have shown a numerical advantage favoring the TRUQAP combination. The trial remains ongoing and will continue to evaluate overall survival as a key secondary endpoint.
In terms of safety, the TRUQAP combination demonstrated a profile that was broadly consistent with the known effects of its individual components. However, as expected with the addition of a targeted therapy, higher rates of adverse events were observed. Grade 3 or higher adverse events occurred in 67% of patients receiving the TRUQAP combination, compared to 40.4% in the control group.
The most commonly reported severe adverse events in the TRUQAP arm included rash (12.3%), hyperglycemia (10.3%), hypokalemia (8.7%), diarrhea (6.2%), hypertension (5.8%), and anemia (5.2%). These side effects highlight the importance of careful monitoring and management during treatment.
Hyperglycemia, in particular, is a notable risk associated with TRUQAP. Severe cases, including diabetic ketoacidosis and even fatal outcomes, have been reported. In clinical studies, 37% of patients experienced increased fasting glucose levels, with a small percentage developing Grade 3 or 4 hyperglycemia. The median time to onset was approximately 15 days. As a result, regular monitoring of blood glucose and HbA1c levels is essential before and during treatment. Patients with pre-existing diabetes may require intensified management and closer supervision.
Diarrhea is another common adverse event, affecting 72% of patients, with 9% experiencing severe cases. Early intervention with antidiarrheal medications and adequate hydration is recommended to manage symptoms effectively. Similarly, cutaneous adverse reactions—including serious conditions such as erythema multiforme and drug reaction with eosinophilia and systemic symptoms (DRESS)—have been reported in 58% of patients, with 17% experiencing severe forms. Dermatologic evaluation and prompt management are advised in such cases.
The drug also carries a risk of embryo-fetal toxicity, based on findings from animal studies and its mechanism of action. Patients of reproductive potential are advised to use effective contraception during treatment and for a specified period after the last dose.
Despite these safety considerations, the overall benefit-risk profile of TRUQAP in combination with abiraterone and ADT has been deemed favorable by the ODAC. The committee’s role is to provide independent expert advice to the FDA, which will ultimately make the final regulatory decision. While the FDA is not obligated to follow the committee’s recommendation, such strong support often plays a significant role in the approval process.
In addition to the U.S. review, a regulatory application for this combination therapy is currently under evaluation in the European Union, further highlighting global interest in this potential new treatment option.
If approved, TRUQAP in combination with abiraterone and ADT could become the first targeted therapy specifically indicated for PTEN-deficient metastatic hormone-sensitive prostate cancer. This would represent a major advancement in precision oncology, offering a new standard of care for patients who currently have limited therapeutic options and face a challenging prognosis.
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