Dose-Escalated Radiotherapy Alone or in Combination With Short-Term Androgen Deprivation for Intermediate-Risk Prostate Cancer: Results of a Phase III Multi-Institutional Trial

Author(s): Daniel J. Krauss, MD¹; Theodore Karrison, PhD²; Alvaro A. Martinez, MD³; Gerard Morton, MD⁴; Di Yan, PhD¹; Deborah Watkins Bruner, PhD, RN⁵; Benjamin Movsas, MD⁶; Mohamed Elshaikh, MD⁶; Deborah Citrin, MD⁷; Bruce Hershatter, MD⁵; Jeff M. Michalski, MD, MBA⁸; Jason Alexander Efstathiou, MD, PhD⁹; Adam Currey, MD¹⁰; Vivek S. Kavadi, MD¹¹; Fabio L. Cury, MD¹²; Michael Lock, MD¹³; Adam Raben, MD^14,15; Samantha Andrews Seaward, MD¹⁶; Ali El-Gayed, MD¹⁷; Joseph P. Rodgers¹⁸; and Howard M. Sandler, MD¹⁹

Source: DOI: 10.1200/JCO.22.02390 Journal of Clinical Oncology 41, no. 17 (June 10, 2023) 3203-3216.

Dr. Anjan Patel's Thoughts

Large phase III study showing short-term ADT + EBRT did not show an improvement in OS compared to EBRT alone. There was an improvement in PSA failure, metastasis rates and prostate cancer-related deaths. If used, SADT+EBRT should be highly individualized, preferably in patients with longer life expectancies and higher SE risk tolerance.

PURPOSE

It remains unknown whether or not short-term androgen deprivation (STAD) improves survival among men with intermediate-risk prostate cancer (IRPC) treated with dose-escalated radiotherapy (RT).

METHODS

The NRG Oncology/Radiation Therapy Oncology Group 0815 study randomly assigned 1,492 patients with stage T2b-T2c, Gleason score 7, or prostate-specific antigen (PSA) value >10 and ≤20 ng/mL to dose-escalated RT alone (arm 1) or with STAD (arm 2). STAD was 6 months of luteinizing hormone–releasing hormone agonist/antagonist therapy plus antiandrogen. RT modalities were external-beam RT alone to 79.2 Gy or external beam (45 Gy) with brachytherapy boost. The primary end point was overall survival (OS). Secondary end points included prostate cancer–specific mortality (PCSM), non-PCSM, distant metastases (DMs), PSA failure, and rates of salvage therapy.

RESULTS

Median follow-up was 6.3 years. Two hundred nineteen deaths occurred, 119 in arm 1 and 100 in arm 2. Five-year OS estimates were 90% versus 91%, respectively (hazard ratio [HR], 0.85; 95% CI, 0.65 to 1.11]; P = .22). STAD resulted in reduced PSA failure (HR, 0.52; P <.001), DM (HR, 0.25; P <.001), PCSM (HR, 0.10; P = .007), and salvage therapy use (HR, 0.62; P = .025). Other-cause deaths were not significantly different (P = .56). Acute grade ≥3 adverse events (AEs) occurred in 2% of patients in arm 1 and in 12% for arm 2 (P <.001). Cumulative incidence of late grade ≥3 AEs was 14% in arm 1 and 15% in arm 2 (P = .29).

CONCLUSION

STAD did not improve OS rates for men with IRPC treated with dose-escalated RT. Improvements in metastases rates, prostate cancer deaths, and PSA failures should be weighed against the risk of adverse events and the impact of STAD on quality of life.

Author Affiliations

¹Corewell Health Beaumont University Hospital, Royal Oak, MI;²NRG Oncology Statistics and Data Management Center, University of Chicago, Chicago, IL;³21st Century Oncology of Michigan, Pontiac, MI;⁴Toronto-Sunnybrook Regional Cancer Center, Toronto, ON, Canada;⁵Emory University, Atlanta, GA;⁶Henry Ford Cancer Institute, Detroit, MI;⁷National Cancer Institute, Bethesda, MD;⁸Washington University School of Medicine, Saint Louis, MO;⁹Dana-Farber/Harvard Cancer Center, Boston, MA;¹⁰Froedtert and the Medical College of Wisconsin, Milwaukee, WI;¹¹The US Oncology Network, Fairfax, VA;¹²McGill University Health Center, Montreal, QC, Canada;¹³London Regional Cancer Program, London, ON, Canada;¹⁴Delaware/Christiana Care NCI Community Oncology Research Program, Newark, DE;¹⁵Milwaukee Veterans Administration Medical Center, Milwaukee, WI;¹⁶Kaiser Permanente NCI Community Oncology Research Program, Oakland, CA;¹⁷Saskatoon Cancer Centre, Saskatoon, SK, Canada;¹⁸NRG Oncology Statistics and Data Management Center, Philadelphia, PA;¹⁹Cedars-Sinai Medical Center, Los Angeles, CA

Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer

Overall survival was 78.9% in the combination group compared with 69.5% in the leuprolide-alone group (HR 0.60). Enzalutamide monotherapy resulted in an overall survival of 73.1%, which was not statistically significant. We were already aware of the progression-free survival benefit; now we have overall survival data. This case was also presented in the MOC questions, where the correct answer was to add enzalutamide for a patient with a rising PSA on an LHRH agonist without imaging evidence of disease.

Metformin Active Surveillance Trial in Low-Risk Prostate Cancer

Metformin did not significantly reduce the risk of disease progression compared with active surveillance in patients with low-risk prostate cancer.

177Lu-Prostate-Specific Membrane Antigen Neoadjuvant to Stereotactic Ablative Radiotherapy for Oligorecurrent Prostate Cancer (LUNAR): An Open-Label, Randomized, Controlled, Phase II Study

For our radiation oncology colleagues, the addition of PSMA-directed therapy prior to stereotactic body radiation therapy (SBRT) improved progression-free survival (PFS) in patients with oligometastatic prostate cancer. Two cycles of PSMA-directed therapy were administered before SBRT.

Development and Validation of an Artificial Intelligence Digital Pathology Biomarker to Predict Benefit of Long-Term Hormonal Therapy and Radiotherapy in Men With High-Risk Prostate Cancer Across Multiple Phase III Trials

A new MMAI-derived digital pathology biomarker was trained and prospectively validated across multiple NRG/RTOG phase III trials, including RTOG 9202 (N=1,192), to predict which high-risk/locally advanced PCa patients benefit from LT-ADT vs ST-ADT with RT. In the overall cohort, LT-ADT reduced DM (17% vs 26% at 15 years) and DDM (15% vs 23% at 15 years), but this benefit was limited to biomarker-positive patients (DM: 19% vs 33%; DDM: 19% vs 30%), with no advantage seen in biomarker-negative patients (DM: 11% vs 11%; DDM: 9% vs 10%). This tool could allow about a third of our "high-risk" patients to avoid two extra years of ADT without compromising metastasis outcomes, while ensuring we intensify for those most likely to benefit. In short, this is a practical step toward personalizing ADT duration and sparing toxicity for a significant subset of our patients.

European Study of Prostate Cancer Screening — 23-Year Follow-up

A 13% reduction in mortality was observed in the screening group, with an improved harm-benefit ratio. For every 456 men screened, one prostate cancer death was prevented. It is an easy and inexpensive test, though concerns remain regarding unnecessary biopsies and overtreatment.