PTEN

  • PTEN (phosphatase and tensin homolog) is a tumor suppressor that encodes a phosphoinositide phosphatase.1
  • Gene Location: Chromosome 10 (10q23.31).1

Biology

  • PTEN dephosphorylates phosphatidylinositol-3,4,5-trisphosphate, lowering its level and dampening AKT signaling; it negatively regulates the PI3K/AKT pathway.1,2
  • Somatic PTEN alterations may be the most frequent genetic changes in prostate cancer, and the PI3K/AKT pathway is upregulated in about 50% of prostate cancers, most often through PTEN loss.2,3
  • Reciprocal feedback: in PTEN-deficient prostate cancer, PI3K inhibition activates androgen receptor (AR) signaling and AR inhibition activates AKT, so inhibiting one pathway activates the other. Combined inhibition produced near-complete regressions in preclinical models.4
  • In metastatic hormone-sensitive prostate cancer, PTEN deficiency activates PI3K/AKT, providing a proliferative drive that ARPIs cannot suppress.5

Etiology and Epidemiology

  • 25.3% (1519 of 6003) of patients with newly diagnosed metastatic hormone-sensitive prostate cancer and a valid result were PTEN-deficient by IHC in CAPItello-281 screening.5
  • PTEN deletion or mutation occurs in about 20% of primary tumors at radical prostatectomy and in as many as 50% of castration-resistant tumors; 47% (521 of 1101) of patients with mCRPC in IPATential150 had PTEN loss by IHC.6,7
  • Prognosis: PTEN loss is strongly associated with adverse pathologic features and outcomes. In CAPItello-281, the placebo-plus-abiraterone arm performed progressively worse as the threshold for PTEN loss rose.5,6

Testing

When to Test:

  • Patients with newly diagnosed metastatic androgen pathway modulation-naive or -sensitive (mAPMN/S, formerly mHSPC) prostate cancer who are candidates for capivasertib plus abiraterone. Testing is performed on diagnostic tumor tissue (biopsy or prostatectomy).8,9

Testing Methodologies:

  • Immunohistochemistry (IHC): the VENTANA PTEN (SP218) RxDx Assay (Roche) is the FDA-approved companion diagnostic (June 12, 2026). PTEN deficiency is defined as at least 90% of viable malignant cells with no specific cytoplasmic staining.8,9
  • The IHC success rate in CAPItello-281 was 97%. The trial required an FFPE block or slides; tissue from bone metastases was not acceptable.10,11
  • IHC vs genomic testing: the label selects patients by protein loss on IHC, not by NGS. Genomic PTEN loss and IHC loss are related but not interchangeable.3,8

Guideline Recommendations

  • ASCO (2025): patients with metastatic prostate cancer should undergo germline and somatic panel testing; findings with prognostic-only value should not guide treatment outside a trial.12
  • AUA/SUO (amended 2026): offer somatic tumor testing in metastatic disease; the discussion notes that somatic testing can detect PTEN loss, which may inform prognosis and targeted therapy.13
  • NCCN (Prostate Cancer, V.5.2026): NCCN recommends somatic tumor testing in metastatic disease.14

Targeted Therapy

Approved Agents

Capivasertib (Truqap)

FDA-Approved Indication:

  • In combination with abiraterone and prednisone for adults with metastatic androgen pathway modulation-naive or -sensitive (mAPMN/S) prostate cancer that is PTEN-deficient as detected by an FDA-authorized test (June 12, 2026).8

Mechanism of Action:

  • Oral inhibitor of all 3 AKT isoforms (AKT1/2/3), blocking PI3K/AKT signaling that is activated by PTEN loss; combined with abiraterone to inhibit both the AR and PI3K/AKT pathways.4,8

Drug Information: Learn more about Capivasertib ›

Patient Resources: https://www.truqap.com/

Related Considerations

  • Capivasertib is also approved with fulvestrant for PIK3CA/AKT1/PTEN-altered HR+/HER2-negative breast cancer; the prostate indication is defined by IHC protein loss rather than genomic alteration.8
  • Ipatasertib plus abiraterone (IPATential150) improved rPFS in PTEN-loss mCRPC but is not FDA approved.7

References

  1. NCBI Gene. PTEN phosphatase and tensin homolog [Homo sapiens]. Gene ID 5728. Accessed October 2026.
  2. Staton A, Abel M, Figg WD. Targeting the PI3K/AKT pathway in prostate cancer: the role of PTEN deficiency and biomarker-guided therapy. Cancer Biol Ther. 2026;27(1):2694128. doi:10.1080/15384047.2026.2694128
  3. MedlinePlus Genetics. PTEN gene. National Library of Medicine. Accessed October 2026.
  4. Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19(5):575-586. doi:10.1016/j.ccr.2011.04.008
  5. 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
  6. Jamaspishvili T, Berman DM, Ross AE, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 2018;15(4):222-234. doi:10.1038/nrurol.2018.9
  7. 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
  8. Truqap (capivasertib) tablets. Prescribing information. AstraZeneca Pharmaceuticals LP; revised 09/2026. Accessed October 2026.
  9. FDA approves capivasertib with abiraterone and prednisone for PTEN-deficient androgen pathway modulation-naive or -sensitive prostate cancer. US Food and Drug Administration. June 12, 2026.
  10. US Food and Drug Administration. Oncologic Drugs Advisory Committee meeting, April 30, 2026: capivasertib sponsor briefing materials. Accessed October 2026.
  11. ClinicalTrials.gov. CAPItello-281 (NCT04493853). Accessed October 2026.
  12. Yu EY, Rumble RB, Agarwal N, et al. Germline and somatic genomic testing for metastatic prostate cancer: ASCO guideline. J Clin Oncol. 2025;43(6):748-758. doi:10.1200/JCO-24-02608
  13. Scarpato KR, Cookson MS, Dreicer R, et al. Advanced prostate cancer: AUA/SUO guideline amendment (2026) part I. J Urol. 2026;216(4):479-486. doi:10.1097/JU.0000000000005220
  14. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.5.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed October 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.