FDA ODAC Votes in Favor of Risk:Benefit Profile of Capivasertib Plus Abiraterone in PTEN-Deficient mHSPC

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 7 to 1, with 1 abstention, that the benefit of adding capivasertib (Truqap) to abiraterone acetate (Zytiga) did outweigh risk in the treatment of patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC).¹

The committee reviewed data from the phase 3 CAPItello-281 trial (NCT04493853), which are the basis of a supplemental new drug application seeking the approval of capivasertib tablets in combination with abiraterone for the treatment of adult patients with mHSPC that is PTEN-deficient as detected by an FDA-approved test.²

Presentations on behalf of AstraZeneca, the developer of capivasertib, highlighted the efficacy, safety, and patient-reported outcome data from CAPItello-281. Daniel J. George, MD, of Duke Cancer Institute and Duke University School of Medicine, offered insights into the clinical aspects of the data, contending that capivasertib could fill an unmet need for patients with PTEN-deficient mHSPC who are ineligible for chemotherapy.

“Based on the body of data, the benefits of adding capivasertib to abiraterone and prednisone outweigh the risks for the population with PTEN-deficient mHSPC,” George said. “Capivasertib is the first targeted therapy to delay progression and alter the clinical course for these patients. Other systemic treatments, such as docetaxel, will remain an alternative, particularly for our high-risk, high-volume patients. But many of our patients are either not fit for chemotherapy or refuse it. In addition, 36% of CAPItello-281 patients had low-risk cancer for whom chemotherapy is not indicated. Capivasertib addresses an unmet need in 25% of mHSPC patients. For these patients, the risk tolerance for adding targeted therapy with capivasertib will be an individual decision.”

The FDA argued that there was insufficient magnitude of improvement in radiographic progression-free survival (rPFS), insufficient supportive data from secondary end points and other studies, and increased toxicity with the combination therapy.

“While CAPItello-281 met its primary end point of rPFS, we are concerned that the demonstrated magnitude of rPFS treatment effect may not be clinically meaningful,” Daniel Lee, MD, PhD, a clinical reviewer in the Division of Oncology and Office of Oncologic Diseases at the FDA, said during the meeting. “Overall, the combination of capivasertib, abiraterone, and prednisone led to high rates of toxicities such as hyperglycemia and rash accompanied by complications.”

What prior data have been reported from CAPItello-281?

Findings from CAPItello-281 published in Annals of Oncology revealed that patients treated with capivasertib plus abiraterone (n = 507) experienced a median rPFS of 33.2 months (95% CI, 25.8-44.2) compared with 25.7 months (95% CI, 22.0-29.9) among those treated with abiraterone plus placebo (n = 505; HR, 0.81; 95% CI, 0.66-0.98; P = .034).³ Patients with 100% PTEN deficiency in the investigational (n = 169) and placebo (n = 162) arms achieved a median rPFS of 34.1 months (95% CI, 22.1-not calculable) and 22.1 months (95% CI, 14.7-26.5), respectively (HR, 0.68; 95% CI, 14.7-26.5).

How was CAPItello-281 designed?

CAPItello-281 was a global, double-blind, placebo-controlled, prospective study that enrolled adult patients with de novo mHSPC. Patients were also required to have an ECOG performance status of 0 or 1 and adenocarcinoma tumors with PTEN deficiency per histology. Prior treatment with androgen deprivation therapy (ADT) with or without abiraterone, plus prednisone/prednisolone for de novo disease from 0 days up to a maximum of 93 days prior to random assignment was permitted. Those who received any other therapy for prostate cancer before random assignment were excluded from the study.

Eligible patients were randomly assigned 1:1 to receive capivasertib at 400 mg twice daily for 4 days on, 3 days off or matching placebo, both in combination with abiraterone at 1000 mg once daily plus prednisone/prednisolone and ADT until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capivasertib or placebo dose reduction was permitted from 400 mg twice daily to 320 mg twice daily, then to 200 mg twice daily if indicated; dose re-escalation was not allowed. Dose reduction of abiraterone was performed according to local prescribing information, and dose re-escalation was permitted per local practice.

The primary end point was investigator-assessed rPFS per RECIST 1.1 criteria and/or Prostate Cancer Clinical Trials Working Group 3 criteria. Key secondary end points included overall survival (OS), time to first subsequent therapy, symptomatic skeletal event-free survival, and time to pain progression.

What safety data were reported from CAPItello-281?

In the safety populations of the investigational and placebo arms (both n = 503), any-grade adverse effects (AEs) occurred at rates of 98.8% and 92.0%, respectively. Grade 3 or higher AEs were reported at rates of 67.0% and 40.4%, respectively. Deaths attributed to an AE were reported in 7.2% and 5.2% of patients, respectively.

The most common any-grade AEs included diarrhea (capivasertib arm, 51.9%; placebo arm, 8.0%); hyperglycemia (38.0%; 12.9%), rash (35.4%; 7.0%), anemia (23.9%; 12.7%), hypokalemia (22.1%; 12.7%), hypertension (19.9%; 23.9%), fatigue (15.9%; 12.5%), increased alanine aminotransferase levels (14.1%; 13.3%), urinary tract infection (13.7%; 10.1%), increased aspartate aminotransferase levels (12.9%; 11.7%), nausea (12.1%; 4.4%), COVID-19 (11.7%; 8.7%), asthenia (11.3%; 5.0%), pyrexia (10.9%; 2.8%), hot flush (10.5%; 13.5%), pruritus (10.5%; 2.6%), back pain (9.9%; 10.9%), constipation (8.3%; 11.9%), and arthralgia (7.6%; 10.1%).

References

1. Meeting of Oncologic Drugs Advisory Committee (ODAC). FDA. July 17, 2025. Accessed April 30, 2026. https://www.youtube.com/live/CLhBI3UXWyg
2. Meeting of Oncologic Drugs Advisory Committee (ODAC). Draft agenda. Center for Drug Evaluation and Research/FDA. Accessed April 30, 2026. https://www.fda.gov/media/192151/download
3. Fizazi K, Clarke NW, De Santis M, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann Oncol. 2026;37(1):53-68. doi:10.1016/j.annonc.2025.10.004