Association of the circulating lipid panel, PCPro, with clinical outcomes in metastatic hormone-sensitive prostate cancer: post hoc analysis of the ENZAMET phase III randomised trial (ANZUP 1304)

H-M Lin; T Scheinberg; N Portman; R M N Kim; R Mellor; K Huynh; A N Faulkner; N A Mellett; I D Davis; A Martin; D Sullivan; A Joshua; M McJannett; V Subhash; S Yip; A A Azad; I C Marschner; S A North; R S McDermott; K N Chi; M R Stockler; C J Sweeney; P J Meikle; L G Horvath

doi:10.1016/j.annonc.2025.05.529

Association of the circulating lipid panel, PCPro, with clinical outcomes in metastatic hormone-sensitive prostate cancer: post hoc analysis of the ENZAMET phase III randomised trial (ANZUP 1304)

Ann Oncol. 2025 Sep;36(9):1068-1077. doi: 10.1016/j.annonc.2025.05.529. Epub 2025 May 20.

Authors

H-M Lin¹, T Scheinberg², N Portman³, R M N Kim⁴, R Mellor⁵, K Huynh⁶, A N Faulkner⁷, N A Mellett⁷, I D Davis⁸, A Martin⁹, D Sullivan¹⁰, A Joshua¹¹, M McJannett¹², V Subhash¹², S Yip¹³, A A Azad¹⁴, I C Marschner¹⁵, S A North¹⁶, R S McDermott¹⁷, K N Chi¹⁸, M R Stockler¹⁹, C J Sweeney²⁰, P J Meikle⁶, L G Horvath²¹

Affiliations

¹ Garvan Institute of Medical Research, Sydney, Australia; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia.
² Garvan Institute of Medical Research, Sydney, Australia; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; Chris O'Brien Lifehouse, Sydney, Australia; University of Sydney, Sydney, Australia.
³ Garvan Institute of Medical Research, Sydney, Australia; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia.
⁴ Garvan Institute of Medical Research, Sydney, Australia.
⁵ Garvan Institute of Medical Research, Sydney, Australia; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; Chris O'Brien Lifehouse, Sydney, Australia.
⁶ Baker Heart and Diabetes Institute, Melbourne, Australia; Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, Australia.
⁷ Baker Heart and Diabetes Institute, Melbourne, Australia.
⁸ Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia; Cancer Services, Eastern Health, Melbourne, Australia.
⁹ Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; Centre for Clinical Research, University of Queensland, Brisbane, Australia.
¹⁰ New South Wales Health Pathology, Department of Chemical Pathology, Royal Prince Alfred Hospital, Sydney, Australia.
¹¹ Garvan Institute of Medical Research, Sydney, Australia; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, Australia.
¹² Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia.
¹³ Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia.
¹⁴ Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
¹⁵ National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia.
¹⁶ University of Alberta, Edmonton, Canada.
¹⁷ Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; St Vincent's University Hospital Dublin, Dublin, Ireland; Cancer Trials Ireland, Dublin, Ireland.
¹⁸ British Columbia Cancer Agency, Vancouver, Canada.
¹⁹ Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; Chris O'Brien Lifehouse, Sydney, Australia; University of Sydney, Sydney, Australia; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia.
²⁰ Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; South Australian Immunogenomics Cancer Institute, Adelaide, Australia.
²¹ Garvan Institute of Medical Research, Sydney, Australia; School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia; Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), Sydney, Australia; Chris O'Brien Lifehouse, Sydney, Australia; University of Sydney, Sydney, Australia. Electronic address: lisa.horvath@lh.org.au.

PMID: 40403846
DOI: 10.1016/j.annonc.2025.05.529

Abstract

Background: Enzalutamide significantly improves overall survival (OS) of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, ∼10% of patients will die within 2 years. PCPro is a plasma lipid panel associated with decreased OS in metastatic castration-resistant prostate cancer. In this study, we assessed the association between PCPro and clinical outcomes in mHSPC by carrying out a post hoc analysis of ENZAMET, the landmark phase III trial comparing enzalutamide with nonsteroidal anti-androgen (NSAA).

Patients and methods: PCPro status was determined by liquid chromatography-mass spectrometry analysis of plasma samples from 866 participants (77% of the ENZAMET trial cohort), before treatment (n = 866) and at first progression (n = 282). Outcomes examined were OS and clinical progression-free survival (clinPFS).

Results: Participants with a positive PCPro status at baseline (13.4%) had a significantly shorter OS and clinPFS compared with those with a negative PCPro status [OS hazard ratio (HR) 1.81, 95% CI 1.40-2.33, clinPFS HR 1.65, 95% CI 1.32-2.07, P < 0.0001]. PCPro is an independent prognostic factor when modelled with key clinical prognostic factors (P < 0.001). Enzalutamide (compared with NSAA) improved the OS of PCPro-negative participants (HR 0.61, P < 0.0001), but not the survival of PCPro-positive participants (HR 1.10, P = 0.69; interaction P = 0.024). Participants who were PCPro positive at progression have a shorter OS than those who were negative, irrespective of baseline status (median OS 24-28 months versus 42-45 months).

Conclusions: PCPro status is a prognostic biomarker and predictive of the lack of OS benefit from enzalutamide compared with NSAA in mHSPC. These findings provide a rationale for testing therapeutic agents that can modify circulating lipid profiles in mHSPC.

Keywords: ceramide; enzalutamide; lipid biomarker; metastatic hormone-sensitive prostate cancer; therapeutic resistance.

Publication types

Clinical Trial, Phase III
Randomized Controlled Trial

MeSH terms

Aged
Benzamides
Biomarkers, Tumor* / blood
Humans
Lipids* / blood
Male
Middle Aged
Nitriles
Phenylthiohydantoin* / analogs & derivatives
Phenylthiohydantoin* / therapeutic use
Prognosis
Progression-Free Survival
Prostatic Neoplasms, Castration-Resistant* / blood
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / mortality
Prostatic Neoplasms, Castration-Resistant* / pathology

Substances

enzalutamide
Benzamides
Phenylthiohydantoin
Nitriles
Lipids
Biomarkers, Tumor