FDA Advisory Committee Backs TRUQAP® (capivasertib) for PTEN-Deficient Metastatic Hormone-Sensitive Prostate Cancer
The U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee has delivered a largely favorable assessment of TRUQAP, an investigational targeted therapy developed by AstraZeneca, when used in combination with abiraterone and androgen deprivation therapy (ADT) for patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC). The advisory committee voted 7 to 1 in favor of a positive benefit-risk profile, with one member abstaining, signaling strong support for the therapeutic approach in a patient population with significant unmet medical need.
Regulatory Momentum and Background
The ODAC recommendation represents an important milestone in the regulatory pathway for TRUQAP in this indication. The FDA had previously accepted a supplemental New Drug Application (sNDA) for the combination therapy in August 2025, based on data from the pivotal CAPItello-281 Phase III clinical trial. These results were first presented at the European Society for Medical Oncology Congress 2025 and simultaneously published in the journal Annals of Oncology, highlighting the scientific and clinical relevance of the findings.
The ODAC serves as an independent panel of oncology experts that provides non-binding recommendations to the FDA regarding the safety and efficacy of cancer therapies. While the FDA is not obligated to follow the committee’s vote, such recommendations often carry significant weight in the agency’s final decision-making process.
Addressing an Aggressive Disease Subtype
Metastatic hormone-sensitive prostate cancer represents an earlier stage of advanced prostate cancer in which tumors still respond to hormonal therapy. However, within this category, patients whose tumors exhibit PTEN deficiency—a genetic alteration involving the loss of a tumor suppressor gene—face particularly aggressive disease progression and poorer clinical outcomes.
According to clinical experts, these patients experience faster disease advancement, earlier transition to castration-resistant prostate cancer, and ultimately higher mortality rates. Current treatment options for PTEN-deficient mHSPC remain limited, underscoring the urgency for new targeted therapies.
Daniel George, MD, Director of Genitourinary Oncology at the Duke Cancer Institute and an investigator in the CAPItello-281 trial, emphasized the clinical significance of the ODAC’s recommendation. He noted that patients with PTEN-deficient disease often have diminished quality of life and limited therapeutic choices, making the availability of a new treatment option particularly meaningful. He highlighted that delaying disease progression in this population could have a substantial impact on patient outcomes.
CAPItello-281 Trial: Key Efficacy Findings
The CAPItello-281 Phase III study represents the first pivotal trial to prospectively identify and evaluate patients with PTEN-deficient metastatic hormone-sensitive prostate cancer. The trial assessed the addition of TRUQAP to standard-of-care therapy consisting of abiraterone and ADT, compared with abiraterone and ADT plus placebo.
Results from the primary analysis demonstrated a statistically significant improvement in radiographic progression-free survival (rPFS), the study’s primary endpoint. The addition of TRUQAP reduced the risk of disease progression or death by 19% compared to the control arm, corresponding to a hazard ratio of 0.81. Median rPFS improved from 25.7 months in the placebo group to 33.2 months in the TRUQAP combination arm—an increase of 7.5 months.
These findings indicate that targeting the AKT pathway with capivasertib may effectively delay tumor progression in patients with PTEN loss, a subgroup historically associated with resistance to standard therapies.
Secondary Endpoints Reinforce Clinical Benefit
Beyond the primary endpoint, the trial demonstrated consistent benefits across multiple key secondary endpoints. Time to castration resistance—a critical milestone in prostate cancer progression—was significantly prolonged in patients receiving TRUQAP, with a median duration of 29.5 months compared to 22.0 months in the control group (hazard ratio 0.77).
Similarly, progression based on prostate-specific antigen (PSA) levels showed improvement, with a hazard ratio of 0.73, indicating a trend toward delayed biochemical progression. Although the confidence interval for this endpoint approached statistical significance, the overall direction of effect aligned with the broader efficacy profile observed in the trial.
Another clinically meaningful outcome was symptomatic skeletal event-free survival (SSE-FS), which reflects the time until complications such as fractures or spinal cord compression occur. Patients treated with TRUQAP experienced fewer and delayed skeletal events, with median SSE-FS extending to 42.5 months compared to 37.3 months in the comparator arm.
Overall Survival Data Still Maturing
At the time of the primary analysis, overall survival (OS) data were not yet mature. However, interim analyses have shown a numerical trend favoring the TRUQAP combination over standard therapy alone. The study is ongoing, and further follow-up will be required to determine whether these early trends translate into a statistically significant survival benefit.
Safety Profile and Adverse Events
The safety profile of TRUQAP in combination with abiraterone and ADT was generally consistent with the known effects of each component therapy. As expected with the addition of a targeted agent, the incidence of higher-grade adverse events was greater in the TRUQAP arm.
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 included rash (12.3%), hyperglycemia (10.3%), hypokalemia (8.7%), diarrhea (6.2%), hypertension (5.8%), and anemia (5.2%).
While these adverse events are clinically significant, they are generally manageable with appropriate monitoring, dose adjustments, and supportive care. The safety findings underscore the importance of careful patient selection and ongoing management when incorporating targeted therapies into combination regimens.
Important Safety Considerations
TRUQAP carries specific safety warnings that clinicians must consider. Hyperglycemia is a notable risk, with some patients experiencing severe elevations in blood glucose levels, including rare cases of diabetic ketoacidosis. Monitoring of fasting glucose and hemoglobin A1C levels is recommended before and during treatment, with dose modifications implemented as needed.
Diarrhea is another common side effect, occurring in a majority of patients, with a smaller proportion experiencing severe symptoms. Early intervention with antidiarrheal medications and hydration is essential to prevent complications.
Cutaneous adverse reactions, including serious conditions such as erythema multiforme and drug reaction with eosinophilia and systemic symptoms (DRESS), have also been reported. Patients should be closely monitored for skin-related symptoms, and dermatologic consultation may be required in severe cases.
Additionally, TRUQAP has the potential to cause embryo-fetal toxicity, necessitating the use of effective contraception for both male and female patients of reproductive potential during treatment and for a defined period afterward.
Strategic Implications and Future Outlook
Susan Galbraith, Executive Vice President of Oncology R&D at AstraZeneca, described CAPItello-281 as a landmark study that not only demonstrated the clinical benefit of TRUQAP but also established PTEN-deficient mHSPC as a distinct and clinically important subgroup. She emphasized that approximately one in four patients with metastatic hormone-sensitive prostate cancer exhibit PTEN deficiency, highlighting the potential impact of introducing a targeted therapy for this population.
The ODAC’s favorable vote reinforces the potential of TRUQAP to become the first targeted treatment specifically approved for PTEN-deficient mHSPC. AstraZeneca has indicated its commitment to working closely with regulatory authorities to bring this therapy to patients as quickly as possible.
In addition to the U.S. regulatory review, a similar application is currently under evaluation in the European Union, reflecting the global scope of the development program.
The ODAC’s endorsement of TRUQAP in combination with abiraterone and ADT marks a significant step forward in the treatment landscape for metastatic hormone-sensitive prostate cancer, particularly for patients with PTEN-deficient disease. The CAPItello-281 trial has demonstrated meaningful improvements in progression-free survival and other key clinical endpoints, supported by a manageable safety profile.
While final regulatory decisions are still pending, the strong advisory committee vote and compelling clinical data position TRUQAP as a promising new option in a field where innovation is urgently needed. If approved, this combination therapy could redefine the standard of care for a subset of prostate cancer patients who currently face limited treatment options and poor prognoses.
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