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 - ScienceDirect
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 - ScienceDirect:
Introduction
The adjuvant prolongation of androgen deprivation therapy (ADT) in combination with definitive radiotherapy significantly improves clinical outcomes in men with high-risk prostate cancer.(1) The addition of second-generation androgen receptor signaling inhibitors (ARSIs) such as abiraterone acetate with prednisone can further improve outcomes.(2, 3) These benefits are thought to be largely mediated by the radiosensitizing effects of ADT on the primary tumor, which increases the chance of local disease eradication.(4) However, cytostatic impacts on occult extraprostatic disease may also contribute.
The initial prostate-specific antigen (PSA) response to ADT in the neoadjuvant setting may provide insights into the importance of serum testosterone on androgen receptor (AR) signaling in a particular patient's cancer. Smaller or less-sustained reductions in PSA may portend the presence of pre-existing or rapidly emerging castration resistance or suggest a de-coupling between neoplastic proliferation and traditional AR-based signaling. Indeed, several studies have suggested that the PSA response to neoadjuvant ADT in men receiving radiotherapy may predict long-term clinical outcomes.(5, 6) However, these studies generally included patients from various risk groups, did not control for the receipt of adequate durations of ADT, were purely retrospective in nature, or originated from a single institution.
To fill this gap, we analyzed the prognostic impact of poor PSA response in a large population of men with high-risk prostate cancer receiving long-term ADT with definitive radiotherapy in the context of two multicenter randomized clinical trials (RCTs).
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Method and Materials
This was a post hoc, pooled analysis of two multicenter RCTs: the TROG 03.04 RADAR Trial (NCT00193856) and the PCS IV Trial (NCT00223171). In the TROG 03.04 RADAR trial, 1,071 men with unfavorable intermediate-risk or high-risk prostate cancer were randomized 1:1:1:1 in a 2 × 2 factorial design to 6 versus 18 months of ADT with or without 18 months of zoledronic acid.(7) Participants commenced ADT upon randomization and began definitive radiotherapy 5 months later. In the PCS IV trial, 630 men
Results
930 patients met inclusion criteria for this analysis (Figure 1). Median follow-up was 130 months (interquartile range [IQR], 89–154 months). Patient and treatment characteristics are described in Table 1.
After a median of 3 months (IQR, 3–4.2 months) of neoadjuvant ADT, the median PSA decreased from 17.1 ng/mL (IQR, 9.0–29.0) to 0.60 ng/mL (IQR, 0.29–1.59). 535 patients (57.5%) had PSA>0.5 ng/mL and 395 patients (62.5%) had PSA ≤0.5 ng/mL. There were statistically significant differences
Discussion
While there is mounting clinical evidence that adjuvant ADT prolongation may afford more clinical benefits than neoadjuvant extension, the present study suggests that the PSA response to neoadjuvant ADT is highly prognostic for endpoints ranging from BCR to OS among men with high-risk prostate cancer. These conclusions are supported by the fact that all men in this study received standard-of-care definitive radiotherapy with 18-36 months of ADT.
In this context, neoadjuvant PSA may present a
Authors Responsible for Statistical Analysis
Tahmineh Romero. Email Address: TahminehRomero@mednet.ucla.edu. John Nikitas. Email Address: jnikitas@mednet.ucla.edu.
Funding Statement
This study was supported by the Christiaan W. Schiepers Theranostics Fellowship (Dr. Nikitas), by the RANZCR-TROG Research Grant (Dr. Ong), grants P50CA09213 (Dr. Kishan) and P50CA186786 (Dr. Spratt) from the Prostate Cancer National Institutes of Health (NIH) Specialized Programs of Research Excellence, grant RSD1836 from the Radiological Society of North America (RSNA) (Dr. Kishan), the STOP Cancer organization (Dr. Kishan), grants PC210066 (Dr. Kishan) and PC151068 (Dr. Spratt) from the
Data Sharing Statement
Research data are stored in an institutional repository and will be shared upon request to the corresponding author.
References
- 1.
Kishan AU, Sun Y, Hartman H, et al. Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis. Lancet Oncol. 2022;23:304–316.
- 2.
James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. New England Journal of Medicine. 2017;377:338–351.
- 3.
Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk
Conflict of Interest Statement
Dr. Kishan reported receiving personal fees from ViewRay, Inc, Varian Medical Systems, Inc, and Janssen Pharmaceuticals outside the submitted work, as well as research funding from ViewRay. Dr. Spratt reported receiving personal fees from Janssen Pharmaceuticals and Blue Earth outside the submitted work. Dr. Nabid reported speaker fees from Janssen Canada and Sanofi outside the submitted work. No other disclosures were reported.
Acknowledgements
We would like to thank all the patients who enrolled on this trial. We would like to also thank Dr. James Denham, who served as the principal investigator of the RADAR trial and Dr. Abdenour Nabid, who served as the principal investigator of the PCS IV trial.
© 2023 Elsevier Inc. All rights reserved.
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