PTEN loss: From biomarker to treatment strategy in mHSPC

PTEN deficiency identifies a poor-prognosis subset of metastatic hormone-sensitive prostate cancer (mHSPC) and is now a target for treatment with capivasertib plus abiraterone, according to Daniel J. George, MD.¹ George, the Eleanor Easley Distinguished Professor of Medicine, Surgery, and Urology at Duke University School of Medicine, presented “PTEN Loss: From Biomarker to Treatment Strategy” at the 2026 LUGPA Annual Meeting.¹ He reviewed updated CAPItello-281 (NCT04493853) efficacy and safety data along with practical strategies for managing early toxicity.¹

On June 12, 2026, the FDA approved capivasertib (Truqap) with abiraterone acetate (Zytiga) and prednisone for adults with PTEN-deficient metastatic androgen pathway modulation-naive or -sensitive (mAPMN/S) prostate cancer detected by an FDA-authorized test.² The agency also approved the VENTANA PTEN (SP218) RxDx Assay as a companion diagnostic.²

In a real-world analysis of 1508 patients with mHSPC presented by Rathkopf et al, 516 patients (34.2%) had PTEN-altered tumors.³ Median overall survival (OS) was 33.4 months (95% CI, 29.3-38.2) with PTEN alterations vs 43.5 months (95% CI, 39.7-47.9) without them (P < .001).³ At 24 months, OS was 62.8% vs 74.2%, respectively.³

The biology of PTEN deficiency and AKT inhibition in prostate cancer

In PTEN-proficient hormone-sensitive tumor cells, androgen receptor signaling is the key driver of proliferation, George explained.¹ When PTEN is lost, upregulation of the PI3K/AKT pathway provides an additional proliferative drive, complementing androgen receptor signaling and offering an alternative survival mechanism.⁴ PTEN deficiency is associated with poor prognosis.^3,4,5

Capivasertib is an oral, selective inhibitor of all 3 AKT isoforms.¹ Phase 2 and 3 evidence with ipatasertib, another AKT inhibitor, showed benefit when combined with abiraterone in PTEN-deficient metastatic castration-resistant prostate cancer.^4,5 CAPItello-281 was designed to test the same hypothesis in hormone-sensitive disease, George said.¹

CAPItello-281 trial design and primary radiographic progression-free survival results

CAPItello-281 enrolled patients with de novo PTEN-deficient mHSPC, defined as 90% or more of viable malignant cells with no specific cytoplasmic PTEN staining by immunohistochemistry.⁶ Of approximately 6200 patients submitting tumor tissue, 97% had a valid result and 25% were PTEN deficient.⁶ In total, 1012 patients were randomly assigned 1:1 to capivasertib 400 mg twice daily, 4 days on and 3 days off, or placebo, each with abiraterone 1000 mg, prednisone 5 mg, and androgen deprivation therapy.⁶

The primary end point was investigator-assessed radiographic progression-free survival (rPFS).⁶ At a median follow-up of about 18 months, median rPFS was 33.2 months (95% CI, 25.8-44.2) with capivasertib vs 25.7 months (95% CI, 22.0-29.9) with placebo (HR, 0.81; 95% CI, 0.66-0.98; P = .034).⁶ Events occurred in 183 patients (36.1%) vs 215 (42.6%).⁶

At this primary analysis, OS was only 26% mature (HR, 0.90; 95% CI, 0.71-1.15; P = .401), and formal hierarchical testing of key secondary end points stopped after the OS analysis.⁶ George noted the median rPFS improvement of 7.5 months emerged early in follow-up.¹

Updated CAPItello-281 overall survival with longer follow-up

George reviewed updated CAPItello-281 data presented at the European Society for Medical Oncology Congress 2026, adding about 17 months of follow-up.^1,7 At 42% maturity, median OS was 57.4 months (95% CI, 47.0-not calculable) with capivasertib vs 46.5 months (95% CI, 40.7-53.2) with placebo (HR, 0.82; 95% CI, 0.68-0.99; P = .044).⁷ The descriptive, alpha-controlled analysis did not meet statistical significance.⁷

George described the 11-month difference in median OS as a strong signal favoring capivasertib, with curves separating and remaining apart.¹ Benefit increased with degree of PTEN loss, with OS HRs of 0.76 (95% CI, 0.61-0.93) for 95% or greater loss, 0.75 (95% CI, 0.56-1.02) for 99% or greater, and 0.74 (95% CI, 0.53-1.02) for 100% loss.⁷ Subsequent anticancer therapy was received by 38.7% of patients receiving capivasertib vs 40.8% receiving placebo, including cytotoxic chemotherapy in 25.6% vs 30.5%.⁷

Updated median rPFS was 35.5 months (95% CI, 29.7-40.5) vs 26.0 months (95% CI, 22.4-31.3; HR, 0.83; 95% CI, 0.70-0.99; nominal P = .033), consistent with the primary analysis.⁷ Median symptomatic skeletal event-free survival was 43.8 months vs 35.9 months (HR, 0.83; 95% CI, 0.69-0.99; nominal P = .044).⁷

Time to castration resistance and PSA progression in PTEN-deficient mHSPC

Median time to castration resistance, a composite of radiographic progression, PSA progression, and symptomatic skeletal events, was 29.5 months with capivasertib vs 22.0 months with placebo (HR, 0.77; 95% CI, 0.63-0.94; nominal P = .009).⁶ Time to PSA progression alone favored capivasertib (HR, 0.73; 95% CI, 0.52-1.01; nominal P = .060), with 60 events (11.8%) vs 82 (16.2%).⁶

George highlighted the gap between the 2 end points in the placebo arm, where 231 castration resistance events occurred but only 82 PSA progression events.^1,6 In this PTEN-deficient population, detrimental clinical events occurred in some patients before PSA progression.⁶ Clinicians therefore need to monitor these patients with imaging and symptom assessment rather than relying on PSA alone, he said.¹

Patient-reported outcomes and safety with capivasertib plus abiraterone

Time to a clinically meaningful decrease in FACT-P physical well-being was shorter with capivasertib (median, 7.2 vs 14.6 months; HR, 1.43; 95% CI, 1.15-1.78), with events in 175 patients (34.5%) vs 152 (30.1%).¹ George noted the difference emerged mainly in the first 3 months, likely reflecting diarrhea, rash, and other early adverse events (AEs), after which the curves ran parallel.¹ Functional well-being (HR, 1.06; 95% CI, 0.86-1.32) and FACT-P total score (HR, 1.10; 95% CI, 0.89-1.37) did not differ meaningfully between arms.¹

Grade 3 or higher AEs occurred in 337 of 503 patients (67.0%) receiving capivasertib vs 203 of 503 (40.4%) receiving placebo.⁶ AEs led to discontinuation of capivasertib or placebo in 92 patients (18.3%) vs 24 (4.8%), dose interruption in 316 (62.8%) vs 135 (26.8%), and dose reduction in 146 (29.0%) vs 18 (3.6%).⁶ AEs leading to death occurred in 36 patients (7.2%) vs 26 (5.2%), with 6 (1.2%) vs 1 (0.2%) considered by investigators to be related to capivasertib or placebo.⁶

Most patients were able to continue treatment through interruptions, George said, noting patients already receive an intermittent schedule with 3 days off each week.¹ Median treatment duration was 13.6 months with capivasertib vs 14.9 months with placebo, and the AE profile was consistent across PTEN deficiency cutoffs.⁶

Diarrhea, hyperglycemia, and rash: The timing of capivasertib toxicity in mHSPC

At the updated analysis, the most common AEs with capivasertib were diarrhea (52.7%; 6.4% grade 3 or higher), hyperglycemia (40.4%; 11.3%), and rash (36.4%; 12.7%).⁷ Incidence changed little from the primary analysis despite 17 additional months of follow-up, indicating no cumulative toxicity.^1,6,7 Diabetic ketoacidosis occurred in 6 patients (1.2%) receiving capivasertib vs 1 (0.2%) receiving placebo, with no new cases since the primary analysis.⁷

“If you haven’t had those events, you’re not going to,” George said, noting most toxicity occurs early and becomes manageable, with relatively smooth sailing once patients get through the first couple of months.¹ The prescribing information includes warnings and precautions for hyperglycemia, diarrhea, cutaneous adverse reactions, and embryo-fetal toxicity.²

For urologists, George emphasized PTEN deficiency confers poor survival in mHSPC even with combined androgen receptor pathway inhibition.¹ He described capivasertib plus abiraterone as a manageable option alongside chemotherapy, stressing the need for close monitoring in the first months of treatment.¹ Patients with this aggressive disease need every available option, he said.¹

REFERENCES

1. George DJ. PTEN loss: from biomarker to treatment strategy. Presented at: 2026 LUGPA Annual Meeting; November 5-7, 2026.

2. FDA approves capivasertib with abiraterone and prednisone for PTEN-deficient androgen pathway modulation-naïve or -sensitive prostate cancer. US Food and Drug Administration. June 12, 2026. Accessed November 6, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-abiraterone-and-prednisone-pten-deficient-androgen-pathway-modulation

3. Rathkopf D, Zhao D, Kovacevic L, et al. Real-world patient (pt) characteristics, treatment patterns, and overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC): Insights by PTEN status. J Clin Oncol. 2025;43(16_suppl):5096. DOI:10.1200/JCO.2025.43.16_suppl.5096

4. de Bono JS, De Giorgi U, Rodrigues DN, et al. Randomized phase II study evaluating Akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res. 2019;25(3):928-936. doi:10.1158/1078-0432.CCR-18-0981

5. Sweeney C, Bracarda S, Sternberg CN, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021;398(10295):131-142. doi:10.1016/S0140-6736(21)00580-8

6. 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

7. Fizazi K, Clarke NW, De Santis M, et al. Capivasertib (capi) + abiraterone (abi) vs placebo (pbo) + abi in patients (pts) with PTEN-deficient metastatic hormonesensitive prostate cancer (mHSPC): Updated overall survival (OS) from CAPItello-281. Presented at: 2026 European Society for Medical Oncology Congress. October 23-27, 2026. Madrid, Spain. LBA56. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2026_abstracts/LBA56.html.pdf