ASCO GU 2025: Radical Prostatectomy Versus Radiotherapy in High-Risk Prostate Cancer: Emulated Randomized Comparison with Individual Patient Data from Two Phase III Randomized Trials

(UroToday.com) The 2025 GU ASCO annual meeting featured a prostate cancer session and a presentation by Soumyajit Roy discussing radical prostatectomy versus radiotherapy in high-risk prostate cancer, an emulated randomized comparison with individual patient data from two phase III randomized trials. Standard of care treatment options for high-risk prostate cancer include radiation therapy with long-term ADT (NCCN Category 1 recommendation) or radical prostatectomy with selective use of postoperative radiation therapy +/- ADT (NCCN Category 2A recommendation). The optimal treatment approach has been assessed in retrospective population-based and multi-center comparisons, which have yielded mixed results with substantial bias. As such, Dr. Roy and colleagues conducted an emulated randomized comparison of radiation therapy versus radical prostatectomy in high-risk prostate cancer leveraging patients enrolled in RCTs.

This study utilized a search of Medline for RCTs in high-risk prostate cancer with a standard of care arm of radiation therapy- or radical prostatectomy-based regimen. Inclusion required similar experimental treatment and contemporaneous enrollment in the same country to reduce bias. Two trials were identified:

NRG/RTOG 0521¹ (radiation therapy + long-term ADT +/- 6 cycles docetaxel)
CALGB 90203² (radical prostatectomy +/- neoadjuvant 6 cycles docetaxel and ADT)

Due to the inherent difference in the biochemical recurrence criteria after radiation therapy vs radical prostatectomy, the investigators chose inverse probability of treatment weighted (IPTW) cumulative incidence of distant metastasis as the primary endpoint, considering deaths as competing events. Death after distant metastasis was measured to create a harmonized metric of deaths likely attributed to prostate cancer. To assess potential residual selection bias, death without distant metastasis to capture non-cancer associated deaths was analyzed.

Overall, 1,290 patients (radiation therapy n = 557, radical prostatectomy n = 733) were included, with a similar median follow-up of 6.4 years:

Prior to IPTW, radical prostatectomy patients were significantly younger with lower baseline PSA compared to radiation therapy patients. Adjuvant (18%) and salvage therapy (44%) were used in the radical prostatectomy cohort:

Cumulative incidence of distant metastasis was significantly lower in patients who underwent radiation therapy compared to radical prostatectomy (8-year IPTW cumulative incidence of distant metastasis: 16% vs 23%; subdistribution HR 0.56, 95% CI 0.38-0.81, p = 0.002):

Looking at a standard of care assessment of radiation therapy + long-term ADT versus radical prostatectomy + personalized post-operative therapy also showed a higher cumulative incidence of distant metastasis for the surgical cohort (8-year IPTW cumulative incidence of distant metastasis: 16% vs 26%; subdistribution HR 0.59, 95% CI 0.37-0.94, p = 0.03):

On a cross-arm comparison, the 8-year cumulative incidence of distant metastasis when comparing standard of care radiation therapy + long-term ADT group versus the docetaxel + ADT + radical prostatectomy group was 18% vs 21%, respectively (subdistribution HR 0.84, 95% CI 0.51-1.37], p = 0.48):

Radiation therapy patients had a significantly greater risk of death without distant metastasis (HR 2.14, 95% CI 1.12-4.19) with early differences measured. The complete secondary endpoints are listed in the following table:

The current study has the following limitations: (i) residual unmeasured confounding and selection bias (seen by early and large differences in overall cause mortality, as anticipated), (ii) intermediate follow-up of 6.4 years, with limited prostate cancer specific mortality events, and (iii) contemporary practice implications (PSMA PET imaging, abiraterone acetate + prednisone is now standard of care with radiotherapy in very high risk patients).

Dr. Roy concluded his presentation by discussing radical prostatectomy versus radiotherapy in high-risk prostate cancer, an emulated randomized comparison with individual patient data from two phase III randomized trials with the following take-home points:

Of the current NCCN guideline recommended treatment regimens, a radiotherapy-based treatment regimen appears to result in a lower incidence of distant metastasis than a surgery-based regimen for patients enrolled in phase III RCTs
Approximately 80% of men with high risk prostate cancer treated with surgery will receive further treatment or experience recurrence. Adjuvant and early salvage radiotherapy remains critical for this population
Use of triple or quadruplet therapy of neoadjuvant chemotherapy + ADT, radical prostatectomy, and personalized post-operative radiotherapy + ADT may mitigate these differences when compared to a doublet of radiotherapy + long-term ADT. However, toxicity and cost implications require further study
SPCG-15 is an actively enrolling phase III trial aimed to directly address this question. Notably, it is a more favorable risk population than the present study

Presented by: Soumyajit Roy, MD, Rush University Medical Center, Chicago, IL

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.

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