FDA ODAC Votes for Capivasertib in Hormone-Sensitive Prostate Cancer

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 7 to 1 in favor of capivasertib (Truqap) in prostate cancer.¹

The proposed indication is for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC) that is phosphatase and tensin homolog (PTEN)-deficient, as detected by an FDA-approved test, in combination with abiraterone (Zytiga) and prednisone/prednisolone.

One member of the ODAC abstained from voting.

“This definitely was not an easy vote,” said ODAC member Toni Choueiri, MD, Dana-Farber Cancer Institute, who voted yes. “The evidence demonstrates this is a statistically significant trial. It’s absolutely biologically plausible… How can patients receive this targeted treatment if we don’t approve it?”

The primary evidence for this application is the phase 3 CAPItello-281 trial (NCT04493853). While the trial met its primary end point of radiographic progression-free survival (rPFS) with statistical significance (HR, 0.81; P =.034), the clinical meaningfulness of this result was under debate. The observed median rPFS improvement was 7.5 months (33.2 vs 25.7 months). The FDA notes this is a smaller treatment effect than observed in previous mHSPC approvals supported by contemporary trials like ARASENS (NCT02799602) and AMPLITUDE (NCT04497844). Overall survival (OS) data remain immature at 51% information fraction, showing no statistically significant benefit (HR, 0.90; P =.401).

The addition of capivasertib to the abiraterone backbone significantly increased toxicity. Serious adverse events (SAEs) occurred in 42.5% of the capivasertib arm compared with 26.0% in the placebo arm. Specific concerns include hyperglycemia, rash, and diarrhea.

The trial enrolled an early metastatic population where patients are often asymptomatic. The FDA questioned the benefit-risk profile of adding substantial toxicity to a well-tolerated, effective backbone therapy (abiraterone) in this setting.

Clinical and Disease Context

mHSPC is an incurable stage of prostate cancer that has spread beyond the prostate but remains responsive to antihormonal therapy. Current standard of care involves androgen deprivation therapy (ADT) intensified with androgen receptor pathway inhibitors (ARPIs) or docetaxel. Despite these treatments, the disease inevitably progresses to a castration-resistant state (mCRPC), which is associated with increased morbidity and lethality.

PTEN is a tumor suppressor; its deficiency leads to uncontrolled tumor proliferation via the AKT pathway. PTEN deficiency is identified in approximately 25% of mHSPC cases and is associated with aggressive disease biology, poor prognosis, higher Gleason scores, and shorter time to castration resistance. In the US, it is estimated that 9750 cases of PTEN-deficient mHSPC will be diagnosed annually by 2027.

Rationale for Capivasertib

Capivasertib is a potent, selective oral inhibitor of all 3 AKT isoforms (AKT1/2/3). The rationale for its use in mHSPC is based on the hypothesis that combined inhibition of the AR axis and the AKT pathway will provide superior disease control in PTEN-deficient tumors, which utilize AKT signaling as an alternative survival mechanism.

The FDA granted approval to the combination of capivasertib with fulvestrant (Faslodex) for the treatment of adult patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer that harbors 1 or more PIK3CA, AKT1, or PTEN alterations.²

CAPItello-281 Study Design and Methodology

CAPItello-281 is a global, randomized, double-blind, placebo-controlled phase 3 trial. The trial randomized 1012 patients 1:1 to receive either capivasertib or placebo with abiraterone and prednisone. Patients were prospectively identified as PTEN-deficient using the VENTANA PTEN (SP218) IHC assay. Stratification factors included geographic region, volume of disease (CHAARTED criteria), and presence of visceral metastases.

The primary end point was rPFS; key secondary end points included OS, time to first subsequent therapy, symptomatic skeletal event-free survival, and time to pain progression. A multiple testing procedure (MTP) was employed, requiring statistical significance in rPFS before testing OS.

FDA’s Perspective

Clinical Meaningfulness of rPFS

The FDA noted that while statistically significant, the magnitude of rPFS improvement is modest. Landmark analyses showed that the difference in progression-free and alive patients at 12 months was only 3.3%. Furthermore, 18% of patients in the experimental arm discontinued capivasertib due to AEs compared with 5% in the placebo arm, potentially impacting the interpretation of long-term benefit.

Results for secondary end points were generally numerically favorable but lacked formal statistical significance due to the MTP hierarchy or immaturity. Interim OS maturity was 26.4% with a median not reached in either arm.

The FDA raised concerns that an HR of 0.81 for rPFS may not be sufficient to support approval in this setting without an OS benefit. Previous approvals in mHSPC demonstrated rPFS HRs ranging from 0.39 to 0.54, clear OS benefits, or both.

“This study design was proposed in 2020. The FDA stated that, while rPFS is an acceptable primary end point, the clinical benefit of any improvement in rPFS would be assessed in terms of the magnitude of improvement and the consistency across other end points, particularly end points that measure how a patient feels, functions, or survives. The FDA stated that an improvement in [OS] or other clinically meaningful end points may be needed to demonstrate clinical benefit in the absence of a large magnitude of improvement and rPFS,” said Elaine Chang, MD, clinical team leader, Division of Oncology 1, Office of Oncologic Diseases, Office of New Drugs, FDA.

Exploratory analyses suggested that the performance of the control arm worsened as the PTEN score increased (moving toward 100% loss), while the experimental arm remained consistent. This suggests capivasertib may have a more pronounced effect in patients with absolute PTEN loss, though the FDA views these results as hypothesis-generating only.

Control Arm Adequacy

The control arm used a doublet therapy of abiraterone and ADT. Current clinical guidelines and expert consensus (NCCN 2026) now encourage triplet therapy of ARPI, docetaxel, and ADT for patients with synchronous high-volume mHSPC. Because the control arm did not include docetaxel, the true value of adding capivasertib to the most active modern standards remains uncertain.

Isolation of Contribution

Because capivasertib is added to an effective backbone of abiraterone, it is clinically challenging to determine if an individual patient is deriving benefit from the add-on drug or simply experiencing the long-term efficacy of the backbone while being exposed to capivasertib's toxicities.

Safety and Tolerability

The addition of capivasertib resulted in increased toxicity across all categories. The day 120 safety update (data cut-off, July 4, 2025) provided approximately 9 additional months of follow-up. Key AEs of interest were diarrhea (53% in experimental arm vs 9% in placebo arm), rash/skin reactions (53% vs 17%), hyperglycemia (51% vs 16%), diabetic ketoacidosis (DKA; 1.2% vs 0%). All cases of DKA were SAEs and led to treatment discontinuation.

The FDA noted that among deaths due to AEs in the capivasertib arm, more than one-third occurred within the first 3 months (14 patients in the experimental arm vs 6 in placebo arm). Fatal events included sepsis, ischemic cardiovascular events, and hemorrhage.

Applicant’s Perspective

During their presentation, representatives for AstraZeneca highlighted the unmet needs in mHSPC and the role capivasertib fills. PTEN deficiency, associated with faster progression to castration-resistant disease and ultimately poorer prognosis, is present in about 25% of mHSPC cases, amounting to about 9750 patients per year. This emphasizes the need for an effective treatment for this population to slow progression.

Along with meeting the primary end point, CAPItello-281 demonstrated a positive benefit-risk profile, according to the applicant. There were clinically impactful benefits in secondary and exploratory end points, including reduced/delayed symptomatic skeletal events, delayed time to chemotherapy, and delayed time to castration resistance. Regarding toxicity, adverse events (AEs) were predictable and manageable with limited effect on functional wellbeing, as most patients reported either no or low bother from AEs.

Daniel George, MD, professor of medicine, surgery, and urology and director of Genitourinary Oncology at Duke Cancer Institute, Duke University School of Medicine, delivered the clinical perspective.

“What does delayed time to progression really mean for patients? I would tell my patient that your particular type of prostate cancer makes it more likely that you'll experience a fracture or painful growth in your bones that could be disabling. It could require surgery or radiation and may have a lasting effect on your quality of life. Adding capivasertib could decrease these complications. Likewise, [this] type of cancer is likely to progress on hormonal therapy more rapidly even without a rise in [prostate-specific antigen (PSA)], but adding capivasertib can prolong the time until hormonal therapy stops working and delay the need for chemotherapy. This matters because chemotherapy in the metastatic castration-resistant setting is life-altering, with high rates of fatigue, nausea, neuropathies, serious infections, and treatment failure,” George said.

ODAC’s Discussion

Much of the clarifying questions and discussion focused on the applicability of PTEN expression and defining PTEN deficiency.

During the vote, Choueiri emphasized that, due to the toxicities, the FDA should enforce that capivasertib is only indicated for patients with PTEN expression ≥90%.

Committee members also raised questions about the lack of chemotherapy triplet therapy included as a control arm.

“I think when we're talking about these patients who present with aggressive prostate cancer, at the beginning, I do think heavily about docetaxel. You do have to talk to patients about it. I think it's a good drug in a good amount of patients,” said ODAC member Kyle Robinson, MD, Perelman School of Medicine, University of Pennsylvania. “There are some [patients] where we’re still just going to go docetaxel, and there are going to be some patients who are still going to be against chemotherapy.”

The hyperglycemia AEs associated with capivasertib requiring use of insulin was also a concern—both for patients who do not want to be dependent on insulin and to avoid undue health care resource usage.

ODAC Meetings Under Makary’s FDA

This convening of the ODAC marks the first of 2026. Since FDA commissioner Marty Makary, MD, MPH, was sworn into office in April 2025, there have been fewer advisory committee meetings per year. In 2024, the ODAC convened 6 times, compared with only twice in 2025.³ While the FDA is not required to vote in concordance with ODAC, it often does.

REFERENCES

1. April 30, 2026 Meeting of the Oncologic Drugs Advisory Committee (ODAC). Accessed April 30, 2026. https://www.youtube.com/live/taCx7enN7hk

2. FDA approves capivasertib with fulvestrant for breast cancer. News release. FDA. November 16, 2023. Accessed April 30, 2026. https://tinyurl.com/2m5rh4jz

3. Oncologic Drugs Advisory Committee. US FDA. Accessed April 30, 2026. https://tinyurl.com/yk8k3yws