Biomarker Consortium

GU Cancer

Prostate Cancer

 (folate hydrolase 1) encodes prostate-specific membrane antigen (PSMA), also called glutamate carboxypeptidase II.

PSMA is a type II transmembrane glycoprotein with glutamate carboxypeptidase activity on substrates including folate. It is expressed in normal prostate, nervous system, and kidney and is overexpressed on prostate cancer cells.

 high PSMA expression on prostate cancer with restricted normal-tissue expression allows PSMA PET to identify target-positive disease and PSMA-directed radioligands such as lutetium Lu 177 vipivotide tetraxetan to deliver beta radiation to PSMA-positive cells and the surrounding microenvironment.

High PSMA expression is an independent marker of poor prognosis. Tumors with DNA damage repair defects, such as BRCA2 alterations, show higher PSMA expression.

PSMA-positive disease is common in advanced prostate cancer:

 in VISION, 95.1% (954 of 1003) of men with mCRPC had at least 1 PSMA-positive lesion and 86.6% met full PSMA PET eligibility criteria; in PSMAfore, 92% (505 of 547) met criteria.

 on IHC, membranous PSMA was undetectable in 42% of castration-sensitive and 27% of castration-resistant tissues, and PSMA-negative foci were common within PSMA-expressing tumors; expression was lowest in liver metastases.

 FOLH1 expression is suppressed in neuroendocrine prostate cancer, which limits PSMA imaging and therapy in that setting.

Before PSMA-directed radioligand therapy in metastatic disease, mAPMN/S or castration-resistant. SNMMI recommends PSMA PET within 3 months of starting treatment and repeating it after progression or intervening therapy.

 trial eligibility required at least 1 lesion with uptake greater than normal liver. VISION and PSMAfore excluded patients with any PSMA-negative lesion meeting size criteria (organ 1 cm or larger, lymph node 2.5 cm or larger short axis, bone with soft-tissue component 1 cm or larger); PSMAddition required at least 1 metastatic lesion on conventional imaging.

Agents labeled for selecting patients for PSMA-directed therapy:

 Locametz and Illuccix (gallium Ga 68 gozetotide). The Pluvicto label also allows another approved PSMA PET product. Gozellix, Pylarify, Pylarify TruVu (piflufolastat F 18), and Posluma (flotufolastat F 18) are approved for staging and suspected recurrence but are not labeled for therapy selection.

Contrast CT or MRI helps identify PSMA-negative disease that would not be targeted.

 lutetium Lu 177 vipivotide tetraxetan is appropriate in mCRPC after chemotherapy and ARPI; either 68Ga-PSMA-11 or 18F-DCFPyL PET may be used for selection. This statement predates the 2025 and 2026 label expansions.

 PSMA imaging should be performed before considering PSMA radioligand therapy.

 PSMA PET is used to determine eligibility for PSMA-directed radioligand therapy.

Lutetium Lu 177 Vipivotide Tetraxetan (Pluvicto)

With ARPI therapy for PSMA-positive mAPMN/S prostate cancer (July 31, 2026).

PSMA-positive metastatic androgen pathway modulation-resistant prostate cancer after ARPI therapy, in patients appropriate to delay taxane chemotherapy (2025) or after prior taxane chemotherapy (2022).

Radioligand that binds PSMA and delivers beta-particle radiation from lutetium-177, inducing DNA damage in PSMA-expressing cells and neighboring cells.

Learn more about Lutetium Lu 177 Vipivotide Tetraxetan ›

NCBI Gene. FOLH1 folate hydrolase 1 [Homo sapiens]. Gene ID 2346. Accessed October 2026.

Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. 

. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322

Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore). 

. 2024;404(10459):1227-1239. doi:10.1016/S0140-6736(24)01653-2

Kratochwil C, Fendler WP, Eiber M, et al. Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT). 

. 2023;50(9):2830-2845. doi:10.1007/s00259-023-06255-8

Paschalis A, Sheehan B, Riisnaes R, et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. 

. 2019;76(4):469-478. doi:10.1016/j.eururo.2019.06.030

Bakht MK, Derecichei I, Li Y, et al. Neuroendocrine differentiation of prostate cancer leads to PSMA suppression. 

. 2019;26(2):131-146. doi:10.1530/ERC-18-0226

Pluvicto (lutetium Lu 177 vipivotide tetraxetan) injection. Prescribing information. Novartis Pharmaceuticals Corporation; revised 07/2026. Accessed October 2026.

Hope TA, Antonarakis ES, Bodei L, et al. SNMMI consensus statement on patient selection and appropriate use of 177Lu-PSMA-617 radionuclide therapy. 

. 2023;64(9):1417-1423. doi:10.2967/jnumed.123.265952

Locametz, Illuccix, Gozellix, Pylarify, Pylarify TruVu, and Posluma. Prescribing information. DailyMed. Accessed October 2026.

Fanti S, Briganti A, Emmett L, et al. EAU-EANM consensus statements on the role of prostate-specific membrane antigen positron emission tomography/computed tomography in patients with prostate cancer and with respect to [177Lu]Lu-PSMA radioligand therapy. 

. 2022;5(5):530-536. doi:10.1016/j.euo.2022.05.003

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.

PSMA

 (phosphatase and tensin homolog) is a tumor suppressor that encodes a phosphoinositide phosphatase.

PTEN dephosphorylates phosphatidylinositol-3,4,5-trisphosphate, lowering its level and dampening AKT signaling; it negatively regulates the PI3K/AKT pathway.

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.

 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.

In metastatic hormone-sensitive prostate cancer, PTEN deficiency activates PI3K/AKT, providing a proliferative drive that ARPIs cannot suppress.

 (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.

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.

 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.

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).

 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.

The IHC success rate in CAPItello-281 was 97%. The trial required an FFPE block or slides; tissue from bone metastases was not acceptable.

 the label selects patients by protein loss on IHC, not by NGS. Genomic PTEN loss and IHC loss are related but not interchangeable.

 patients with metastatic prostate cancer should undergo germline and somatic panel testing; findings with prognostic-only value should not guide treatment outside a trial.

 offer somatic tumor testing in metastatic disease; the discussion notes that somatic testing can detect PTEN loss, which may inform prognosis and targeted therapy.

 NCCN recommends somatic tumor testing in metastatic disease.

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).

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.

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.

Ipatasertib plus abiraterone (IPATential150) improved rPFS in PTEN-loss mCRPC but is not FDA approved.

NCBI Gene. PTEN phosphatase and tensin homolog [Homo sapiens]. Gene ID 5728. Accessed October 2026.

Staton A, Abel M, Figg WD. Targeting the PI3K/AKT pathway in prostate cancer: the role of PTEN deficiency and biomarker-guided therapy. 

. 2026;27(1):2694128. doi:10.1080/15384047.2026.2694128

MedlinePlus Genetics. PTEN gene. National Library of Medicine. Accessed October 2026.

Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. 

. 2011;19(5):575-586. doi:10.1016/j.ccr.2011.04.008

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. 

. 2026;37(1):53-68. doi:10.1016/j.annonc.2025.10.004

Jamaspishvili T, Berman DM, Ross AE, et al. Clinical implications of PTEN loss in prostate cancer. 

. 2018;15(4):222-234. doi:10.1038/nrurol.2018.9

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. 

. 2021;398(10295):131-142. doi:10.1016/S0140-6736(21)00580-8

Truqap (capivasertib) tablets. Prescribing information. AstraZeneca Pharmaceuticals LP; revised 09/2026. Accessed October 2026.

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.

US Food and Drug Administration. Oncologic Drugs Advisory Committee meeting, April 30, 2026: capivasertib sponsor briefing materials. Accessed October 2026.

ClinicalTrials.gov. CAPItello-281 (NCT04493853). Accessed October 2026.

Yu EY, Rumble RB, Agarwal N, et al. Germline and somatic genomic testing for metastatic prostate cancer: ASCO guideline. 

. 2025;43(6):748-758. doi:10.1200/JCO-24-02608

Scarpato KR, Cookson MS, Dreicer R, et al. Advanced prostate cancer: AUA/SUO guideline amendment (2026) part I. 

. 2026;216(4):479-486. doi:10.1097/JU.0000000000005220

PTEN

 (BRCA2 DNA repair associated) are tumor suppressor genes central to homologous recombination repair (HRR) of DNA double-strand breaks.

 (ATM serine/threonine kinase) senses DNA double-strand breaks and phosphorylates TP53, CHK2, H2AX, and BRCA1 to coordinate repair.

 Chromosome 17 (17q21.31) for BRCA1; chromosome 13 (13q13.1) for BRCA2; chromosome 11 (11q22.3) for ATM.

Other HRR genes used for patient selection:

 the olaparib label covers 14 genes (ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L); the talazoparib label covers 12 (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C).

BRCA1 coordinates cell-cycle checkpoints and DNA end resection; BRCA2 loads RAD51 onto resected DNA to drive strand invasion and error-free repair.

Loss of both alleles produces HRR deficiency and reliance on error-prone repair. In metastatic castration-resistant prostate cancer (mCRPC), BRCA2 loss is biallelic in about 90% of affected tumors.

 PARP inhibitors block single-strand break repair and trap PARP on DNA, causing replication-fork collapse and double-strand breaks that HRR-deficient cells cannot repair. The same defect underlies platinum sensitivity.

PARP plus androgen receptor pathway inhibitor (ARPI) rationale:

 androgen receptor signaling maintains HRR gene expression; AR inhibition suppresses it and produces a functional HRR-deficient ("BRCAness") state that is synthetically lethal with PARP inhibition in preclinical models.

 (82 of 692) of men with metastatic prostate cancer carry a presumed pathogenic germline DNA-repair gene mutation, most often BRCA2 (5.3%), ATM (1.6%), and BRCA1 (0.9%). Frequency does not differ by age at diagnosis or family history.

 DNA repair gene alterations are found in at least 

 of mCRPC biopsies; BRCA2, BRCA1, or ATM aberrations in 19.3%; BRCA2 loss in 12.7%.

 28% (778 of 2792) of successfully sequenced samples carried a qualifying alteration in 1 of 15 HRR genes.

 germline BRCA carriers more often present with Gleason 8 or higher, nodal involvement, and metastases, with shorter cause-specific survival (8.6 vs 15.7 years). In PROREPAIR-B, germline BRCA2 was an independent adverse prognostic factor in mCRPC (cause-specific survival 17.4 vs 33.2 months; HR, 2.11).

 all patients with metastatic prostate cancer, regardless of age or family history. Germline variants are present from birth, so a prior germline result does not need to be repeated at progression.

 patients with metastatic disease, castration-sensitive or castration-resistant, being considered for biomarker-directed therapy. BRCA2 status now informs treatment in metastatic castration-sensitive prostate cancer (mCSPC) as well as mCRPC.

 may be offered after a meaningful change in status or plan, especially if prior results were negative or uninformative.

Tumor tissue next-generation sequencing (NGS):

 archival primary or metastatic tissue. In PROfound, NGS results were obtained from 58% of samples (69% of patients); newly obtained samples succeeded more often than archival samples (63.9% vs 56.9%).

Plasma circulating tumor DNA (ctDNA) NGS:

 an option when tissue is unavailable or fails; 76.8% of PROfound cohort A plasma samples yielded a result. A negative plasma result does not rule out a tumor alteration.

 CHIP variants in DNA repair genes (mostly ATM) were found in plasma from 10% of men with advanced prostate cancer and can cause false-positive ctDNA calls; a paired whole-blood control helps.

 multigene panel NGS with deletion/duplication analysis on blood or saliva. A pathogenic BRCA finding on tumor-only sequencing needs germline confirmation; variants of uncertain significance are not actionable.

 olaparib, FoundationOne CDx (tissue; 14 HRR genes), BRACAnalysis CDx (blood; germline BRCA1/2), and FoundationOne Liquid CDx (plasma); rucaparib, FoundationOne Liquid CDx (plasma; BRCA1/2); niraparib/abiraterone acetate, FoundationOne CDx and FoundationOne Liquid CDx (BRCA-mutated mCRPC); talazoparib plus enzalutamide, FoundationOne CDx and FoundationOne Liquid CDx (approved June 1, 2026).

 all patients with metastatic prostate cancer should undergo germline testing with NGS, and those being considered for biomarker-directed therapy should undergo somatic NGS. Archival tissue is preferred initially; ctDNA is preferred when no metastatic site can be biopsied or for sequential testing.

 offer germline testing to all patients with advanced prostate cancer; for metastatic disease, offer somatic tumor testing as well.

 recommends germline and somatic tumor testing for HRR gene alterations in metastatic prostate cancer, with multigene tumor testing at metastatic diagnosis and consideration of retesting at progression to mCRPC. NCCN added niraparib/abiraterone acetate plus ADT for BRCA2-mutated mCSPC in 2026.

Deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC after progression on enzalutamide or abiraterone.

In combination with abiraterone and prednisone or prednisolone for deleterious or suspected deleterious BRCA-mutated mCRPC.

Inhibitor of PARP1, PARP2, and PARP3; traps PARP-DNA complexes, causing lethal double-strand breaks in HRR-deficient cells.

Deleterious BRCA mutation (germline and/or somatic)-associated mCRPC previously treated with androgen receptor-directed therapy (regular approval December 17, 2025; prior taxane no longer required).

Inhibitor of PARP1, PARP2, and PARP3 with PARP-trapping activity.

Niraparib and Abiraterone Acetate (Akeega)

With prednisone, for deleterious or suspected deleterious BRCA2-mutated mCSPC (approved December 12, 2025) and BRCA-mutated mCRPC.

Fixed-dose tablet combining niraparib, a PARP1/2 inhibitor, with abiraterone acetate, a CYP17 inhibitor that suppresses androgen biosynthesis.

Learn more about Niraparib and Abiraterone Acetate ›

In combination with enzalutamide for HRR gene-mutated mCRPC. In June 2025, the FDA added final overall survival data to the label and declined to extend the indication to patients without HRR gene mutations.

Inhibitor of PARP1 and PARP2 with potent PARP trapping.

Benefit is concentrated in BRCA-mutated, particularly BRCA2-mutated, disease. In TRITON3, rucaparib showed no rPFS benefit for ATM (HR, 0.95) or BRCA1 (HR, 1.01) alterations; ATM is in the olaparib label but not the rucaparib label.

ASCO identifies patients with BRCA1/2 alterations as candidates for PARP inhibitor monotherapy, PARP inhibitor plus ARPI combinations, and platinum-based chemotherapy.

MedlinePlus Genetics. BRCA1, BRCA2, and ATM genes. National Library of Medicine. Cytobands per NCBI Gene and Human Protein Atlas. Accessed October 2026.

Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. 

Choi M, Kipps T, Kurzrock R. ATM mutations in cancer: therapeutic implications. 

. 2016;15(8):1781-1791. doi:10.1158/1535-7163.MCT-15-0945

Ashworth A, Lord CJ. Synthetic lethal therapies for cancer: what's next after PARP inhibitors? 

. 2018;15(9):564-576. doi:10.1038/s41571-018-0055-6

Asim M, Tarish F, Zecchini HI, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. 

. 2017;8(1):374. doi:10.1038/s41467-017-00393-y

Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. 

. 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001

Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. 

. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144

de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. 

. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440

Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. 

. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882

Castro E, Romero-Laorden N, Del Pozo A, et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. 

. 2019;37(6):490-503. doi:10.1200/JCO.18.00358

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate V.3.2026. © 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.

Lynparza (olaparib) tablets. Prescribing information. AstraZeneca Pharmaceuticals LP; revised 07/2025. Accessed October 2026.

Rubraca (rucaparib) tablets. Prescribing information. pharmaand GmbH; revised 12/2025. Accessed October 2026.

Akeega (niraparib and abiraterone acetate) tablets. Prescribing information. Janssen Biotech, Inc; revised 12/2025. Accessed October 2026.

Talzenna (talazoparib) capsules. Prescribing information. Pfizer Inc; revised 06/2025. Accessed October 2026.

Hussain M, Corcoran C, Sibilla C, et al. Tumor genomic testing for >4,000 men with metastatic castration-resistant prostate cancer in the phase III trial PROfound (olaparib). 

. 2022;28(8):1518-1530. doi:10.1158/1078-0432.CCR-21-3940

Matsubara N, de Bono J, Olmos D, et al. Olaparib efficacy in patients with metastatic castration-resistant prostate cancer and BRCA1, BRCA2, or ATM alterations identified by testing circulating tumor DNA. 

. 2023;29(1):92-99. doi:10.1158/1078-0432.CCR-21-3577

Jensen K, Konnick EQ, Schweizer MT, et al. Association of clonal hematopoiesis in DNA repair genes with prostate cancer plasma cell-free DNA testing interference. 

. 2021;7(1):107-110. doi:10.1001/jamaoncol.2020.5161

HRR Alterations

Expert Sound Bites

Biomarkers

How Biomarkers Now Drive First-Line Therapy in mHSPC

The panelists explain why biomarker testing now selects first-line therapy in metastatic hormone-sensitive prostate cancer (mHSPC) rather than only guiding treatment after progression. They review the recent wave of biomarker-defined options at the onset of metastatic disease, including niraparib plus abiraterone for BRCA2-altered disease, talazoparib plus enzalutamide for homologous recombination repair (HRR)-altered disease, capivasertib plus abiraterone for PTEN-deficient disease, and lutetium Lu 177 vipivotide tetraxetan for PSMA-positive disease, warning that delayed or missing results may cost patients a biomarker-matched third agent. The discussion defines an actionable finding as one linked to an approved therapy or randomized evidence of benefit, led by BRCA1/2 alterations, with other HRR genes actionable as a class for certain regimens and mismatch repair deficiency supporting pembrolizumab. SPOP, TP53, and RB1 alterations carry prognostic weight but no matched drug. The panelists favor ordering PTEN immunohistochemistry (IHC) alongside next-generation sequencing on the same tissue block before considering capivasertib.

The panelists explain why biomarker testing now selects first-line therapy in metastatic hormone-sensitive prostate cancer (mHSPC) rather than only guiding treatment after progression.

Germline Testing and Genomic Classifiers in Prostate Cancer

The panelists recommend germline and somatic testing for every patient with metastatic prostate cancer and germline testing for more aggressive localized disease, where results primarily inform cascade testing of relatives rather than treatment. They acknowledge ongoing disagreement over testing lower-risk patients and stress a detailed family history of breast, ovarian, and pancreatic cancers and melanoma. The conversation then turns to RNA-based genomic classifiers, which estimate risk of metastasis and cancer-specific mortality but cannot detect BRCA2 or other targetable alterations; a low-risk score does not imply HRR proficiency. The strongest evidence for classifiers lies after prostatectomy, where higher scores support early salvage radiation plus androgen deprivation therapy, and they can help with active surveillance decisions in favorable intermediate-risk disease, but they do not change management of metastatic disease. The panelists discuss emerging data linking high-risk classifier scores to docetaxel benefit and advise prioritizing clinical features and NCCN risk groups when classifier results conflict.

The panelists recommend germline and somatic testing for every patient with metastatic prostate cancer and germline testing for more aggressive localized disease, where results primarily inform cascade testing of relatives rather than treatment. 

Expert Sound Bites

How Biomarkers Now Drive First-Line Therapy in mHSPC

Beyond the Report