Early favorable prostate-specific antigen response prediction in metastatic hormone sensitive prostate cancer

Soumyajit Roy; Yilun Sun; Maha Hussain; Kim N Chi; Karim Fizazi; Ian D Davis; Susan Halabi; Neeraj Agarwal; Simon Chowdhury; Bertrand Tombal; Scott C Morgan; Shawn Malone; Pedro C Barata; Michael Ong; Christopher J D Wallis; Alejandro Berlin; Umang Swami; Amar U Kishan; Angela Y Jia; Nicholas G Zaorsky; Jorge A Garcia; Prateek Mendiratta; Jason R Brown; Vinod V Subhash; Martin R Stockler; Hayley Thomas; Rana R McKay; Eric J Small; Neal D Shore; Fred Saad; Christopher J Sweeney; Daniel E Spratt

doi:10.1038/s41467-025-67298-z

Early favorable prostate-specific antigen response prediction in metastatic hormone sensitive prostate cancer

Nat Commun. 2025 Dec 17;17(1):667. doi: 10.1038/s41467-025-67298-z.

Authors

Soumyajit Roy¹, Yilun Sun², Maha Hussain³, Kim N Chi⁴, Karim Fizazi⁵, Ian D Davis^{6

7

8}, Susan Halabi⁹, Neeraj Agarwal¹⁰, Simon Chowdhury¹¹, Bertrand Tombal¹², Scott C Morgan¹³, Shawn Malone¹³, Pedro C Barata¹⁴, Michael Ong¹⁵, Christopher J D Wallis¹⁶, Alejandro Berlin¹⁷, Umang Swami¹⁰, Amar U Kishan¹⁸, Angela Y Jia¹⁹, Nicholas G Zaorsky¹⁹, Jorge A Garcia¹⁴, Prateek Mendiratta¹⁴, Jason R Brown¹⁴, Vinod V Subhash⁸, Martin R Stockler^{8

20}, Hayley Thomas^{8

20}, Rana R McKay²¹, Eric J Small²², Neal D Shore²³, Fred Saad²⁴, Christopher J Sweeney²⁵, Daniel E Spratt²⁶

Affiliations

¹ Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine Cleveland, Cleveland, OH, USA. soumyajitroy8@gmail.com.
² Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
³ Division of Hematology Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴ BC Cancer and Vancouver Prostate Centre, Vancouver, BC, Canada.
⁵ Department of Cancer Medicine, Institut Gustave Roussy, Centre Oscar Lambret, University of Paris-Saclay, Villejuif, France.
⁶ Cancer Services, Eastern Health, Melbourne, VIC, Australia.
⁷ Eastern Health Clinical School, Monash Hospital, Melbourne, VIC, Australia.
⁸ Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, NSW, Australia.
⁹ Departemnt of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
¹⁰ Division of Medical Oncology, University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA.
¹¹ Guy's, King's and St. Thomas' Hospitals and Sarah Cannon Research Institute, London, UK.
¹² Department of Surgery, Université Catholique de Louvain (UCL), Cliniques Universitaires Saint-Luc, Brussels, Belgium.
¹³ Department of Radiation Oncology, Radiology, and Medical Physics, The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada.
¹⁴ Department of Internal Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
¹⁵ Department of Medical Oncology, The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada.
¹⁶ Division of Urology, Department of Surgery, Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON, Canada.
¹⁷ Radiation Medicine Program, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
¹⁸ Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA.
¹⁹ Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine Cleveland, Cleveland, OH, USA.
²⁰ National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
²¹ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
²² Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
²³ Carolina Urologic Research Center, Myrtle Beach, SC, USA.
²⁴ Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
²⁵ South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, Australia.
²⁶ Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine Cleveland, Cleveland, OH, USA. Daniel.Spratt@uhhospitals.org.

Abstract

There is an unmet need for a tool that could predict early favorable prostate-specific antigen (PSA) response in metastatic hormone sensitive prostate cancer (mHSPC) patients receiving androgen receptor pathway inhibitor (ARPI). Here, we train and validate a multivariable logistic regression model to predict early favorable PSA response (≤0.2 ng/mL by 6 months) in these patients. Patients randomly allocated to the ARPI arms of the LATITUDE (abiraterone), TITAN (apalutamide), and ARASENS (darolutamide) trials, are split 60:40 into training (n = 1030) and internal validation (n = 688) cohorts. The locked model is validated in an independent external validation cohort - the enzalutamide arm of the ENZAMET trial (n = 540). The area under curve and Brier score for the locked model in the external validation cohort are 0.82 (95% confidence interval [CI] = 0.78-0.85) and 0.16, respectively. Stratification by predicted probability tertiles show PSA response rates of 92% (95% CI = 88-96), 74% (95% CI = 68-81), and 39% (95% CI = 32-47), respectively. Pending prospective validation, our model predicts early favorable PSA response supporting its potential role in guiding treatment decisions.

Publication types

Randomized Controlled Trial

MeSH terms

Aged
Androgen Receptor Antagonists / therapeutic use
Benzamides
Humans
Male
Middle Aged
Neoplasm Metastasis
Nitriles
Phenylthiohydantoin / analogs & derivatives
Phenylthiohydantoin / therapeutic use
Prostate-Specific Antigen* / blood
Prostate-Specific Antigen* / metabolism
Prostatic Neoplasms* / blood
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms* / pathology
Receptors, Androgen / metabolism
Thiohydantoins / therapeutic use
Treatment Outcome

Substances

Prostate-Specific Antigen
Benzamides
Nitriles
enzalutamide
Phenylthiohydantoin
Androgen Receptor Antagonists
apalutamide
Thiohydantoins
Receptors, Androgen