Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials

John Nikitas; Wee Loon Ong; Nathalie Carrier; Tahmineh Romero; Jeremy Millar; Michael L Steinberg; Matthew B Rettig; Paul C Boutros; Robert Reiter; Nicholas G Nickols; Luca Valle; Sean E McGuire; Daniel E Spratt; Luis Souhami; Soumyajit Roy; Jarad M Martin; David Joseph; Abdenour Nabid; Amar U Kishan

doi:10.1016/j.ijrobp.2023.12.022

Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials

Int J Radiat Oncol Biol Phys. 2023 Dec 25:S0360-3016(23)08259-7. doi: 10.1016/j.ijrobp.2023.12.022. Online ahead of print.

Authors

John Nikitas¹, Wee Loon Ong², Nathalie Carrier³, Tahmineh Romero⁴, Jeremy Millar⁵, Michael L Steinberg¹, Matthew B Rettig⁶, Paul C Boutros⁷, Robert Reiter⁷, Nicholas G Nickols⁸, Luca Valle⁸, Sean E McGuire⁹, Daniel E Spratt¹⁰, Luis Souhami¹¹, Soumyajit Roy¹², Jarad M Martin¹³, David Joseph¹⁴, Abdenour Nabid³, Amar U Kishan¹⁵

Affiliations

¹ Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California.
² Alfred Health Radiation Oncology, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Heath Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
³ Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.
⁴ Department of Medicine Statistics Core, University of California, Los Angeles, Los Angeles, California.
⁵ Alfred Health Radiation Oncology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁶ Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, California; Hematology-Oncology Section, Medicine Service, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California.
⁷ Department of Urology, University of California, Los Angeles, Los Angeles, California.
⁸ Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California; Radiation Oncology Service, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California.
⁹ Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
¹⁰ Department of Radiation Oncology, University Hospital Seidman Cancer Center, Case Western Reserve University, Cleveland, Ohio.
¹¹ Department of Radiation Oncology, McGill University Health Centre, Montreal, Quebec, Canada.
¹² Department of Radiation Oncology, Rush University, Chicago, Illinois.
¹³ Department of Radiation Oncology, Calvary Mater Newcastle & School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
¹⁴ University of Western Australia, Perth, Western Australia, Australia; Genesis Cancer Care, Perth, Western Australia, Australia; 5D Clinics, Perth, Western Australia, Australia.
¹⁵ Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California. Electronic address: aukishan@mednet.ucla.edu.

PMID: 38151191
DOI: 10.1016/j.ijrobp.2023.12.022

Abstract

Purpose: A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer.

Methods and materials: This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival.

Results: Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P = .02), worse biochemical recurrence (subdistribution HR, 2.39; P = .003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P = .005), and worse overall survival (HR, 4.51; P = .05).

Conclusions: Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.