Dr. Ross notes that we now have data from three clinical trials that demonstrate that early salvage radiotherapy is preferred to adjuvant radiotherapy: RADICALS-RT, GETUG-AFU-17,2 and RAVES.3 To complement these three trials was a prospectively planned systematic review and meta-analysis of aggregate data published in The Lancet4 – a meta-analysis of these three trials. There were 2,153 patients recruited between November 2007 and December 2016, with a median follow-up ranging from 60 months to 78 months, with a maximum follow-up of 132 months. There were 1,075 patients randomly assigned to receive adjuvant radiotherapy and 1,078 to early salvage radiotherapy, of whom 421 (39.1%) had commenced treatment at the time of analysis. Based on 270 events, the meta-analysis showed no evidence that event-free survival was improved with adjuvant radiotherapy compared with early salvage radiotherapy (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.75-1.21), with only a 1 percentage point (95% CI -2 to 3) change in 5-year event-free survival (89% vs. 88%):
These three trials and the meta-analysis suggest that adjuvant radiotherapy does not improve event-free survival in men with localized or locally advanced prostate cancer. However, Dr. Ross notes that many of these trials did not include high-risk men (ie. those with seminal vesicle invasion), and thus the appropriate conclusion is that early salvage radiation should be favored among patients with pT2R1 or pT3a, GG1-3 disease.
Dr. Ross notes that there may be a role for adjuvant radiotherapy, particularly among high-risk men that were under-represented in these aforementioned trials. Additional insight is also found in previous literature. Dalela and colleagues assessed a cohort of 512 patients treated with radical prostatectomy of which all men had ≥ pT3a disease, positive surgical margins, and/or pathologic lymph node invasion. Overall, 21.9% of patients received adjuvant radiotherapy over a median follow-up of 8.3 years. The 10-year complete response rate was 4.9% vs. 17.4% in patients treated with adjuvant radiotherapy versus initial observation (p < 0.001). They found that pathologic T3b/T4 stage, Gleason score 8-10, lymph node invasion, and Decipher® score > 0.6 were independent predictors of complete response (all p < 0.01). Additionally, adjuvant radiotherapy was associated with a decreased complete response rate in patients with two or more risk factors (10-year complete response rate 10.1% in adjuvant radiation therapy versus 42.1% in initial observation; p = 0.012), but not in those with fewer than two risk factors (P = 0.18):
Dr. Ross notes that the use of the genomic classifier in the adjuvant setting needs further evaluation and those trials are ongoing, including the MUSIC "Genomics in Michigan Impacting Observation or Radiation (G-MINOR)" trial, and the EGOC-ACRIN "Phase III Double-Blinded Study of Early Intervention after Radical Prostatectomy with Androgen Deprivation Therapy (ADT) with Darolutamide versus Placebo" trial in men at high risk of prostate cancer metastasis by genomic stratification (ERADICATE).
Dr. Ross states that there is also controversy as to whether hormonal therapy should be used at the time of salvage radiotherapy. Dess and colleagues performed a secondary analysis of RTOG 9601 trial5 whereby men were randomized to salvage radiation therapy plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for two years. In this analysis, the objective was to examine the role of pre-salvage radiation therapy prostate-specific antigen (PSA) levels to personalize hormone therapy use with salvage radiation therapy; there were 760 men with PSA elevation after radical prostatectomy that were included. They found that antiandrogen assignment was associated with an overall survival benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (HR 0.45, 95% CI 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR 0.87, 95% CI, 0.66-1.16). Furthermore, in men receiving early salvage radiation therapy with a PSA ≤0.6 ng/mL (n = 389), there was no improvement in overall survival (HR 1.16, 95% CI, 0.79-1.70). Thus, in men receiving early salvage radiation therapy (PSA ≤0.6 ng/mL), long-term antiandrogen treatment was not associated with improved overall survival.
One way to be more definitive as to who should receive ADT with salvage radiotherapy is with use of the Decipher® genomic classifier. Feng and colleagues6 used radical prostatectomy specimens from the Phase III placebo-controlled RTOG 9601 randomized clinical trial to generate genomic classifier scores from 486 of 760 randomized patients with a median follow-up of 13 years. On multivariable analysis, the genomic classifier (continuous variable, per 0.1 unit) was independently associated with distant metastasis (HR 1.17, 95% CI 1.05-1.32), prostate cancer-specific mortality (HR 1.39, 95% CI 1.20-1.63), and overall survival (HR 1.17, 95% CI 1.06-1.29). Additionally, the estimated absolute effect of bicalutamide on 12-year overall survival was less when comparing patients with lower vs. higher genomic classifier scores (2.4% vs. 8.9%), which was further demonstrated in men receiving early salvage radiation therapy at a PSA level lower than 0.7 ng/mL (-7.8% vs. 4.6%).
Dr. Ross concluded his presentation with the following take-home messages:
- The 22-gene genomic classifier is independently prognostic of oncological outcomes post-prostatectomy
- Men with >1 risk factor can consider adjuvant radiation therapy: pT3b/T4, pN1, GG4-5, GC score > 0.6
- Men with GC < 0.45 receiving early salvage radiotherapy should strongly consider omission of ADT
Presented by: Ashley Ross, MD, PhD, Associate Professor of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
Written by: Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021
1. Jairath, Neil K., Alan Dal Pra, Randy Vince Jr, Robert T. Dess, William C. Jackson, Jeffrey J. Tosoian, Sean M. McBride et al. "A Systematic Review of the Evidence for the Decipher Genomic Classifier in Prostate Cancer." European urology (2020).
2. Parker, Christopher C., Noel W. Clarke, Adrian D. Cook, Howard G. Kynaston, Peter Meidahl Petersen, Charles Catton, William Cross et al. "Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial." The Lancet 396, no. 10260 (2020): 1413-1421.
3. Kneebone, Andrew, Carol Fraser-Browne, Gillian M. Duchesne, Richard Fisher, Mark Frydenberg, Alan Herschtal, Scott G. Williams et al. "Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial." The Lancet Oncology 21, no. 10 (2020): 1331-1340.
4. Vale, Claire L., David Fisher, Andrew Kneebone, Christopher Parker, Maria Pearse, Pierre Richaud, Paul Sargos et al. "Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data." The Lancet (2020).
5. Dess, Robert T., Yilun Sun, William C. Jackson, Neil K. Jairath, Amar U. Kishan, David G. Wallington, Brandon A. Mahal et al. "Association of presalvage radiotherapy PSA levels after prostatectomy with outcomes of long-term antiandrogen therapy in men with prostate cancer." JAMA oncology 6, no. 5 (2020): 735-743.
6. Feng, Felix, Huang HC, Spratt DE, et al. "Validation of a 22-Gene Genomic Classifier in Patients with Recurrent Prostate Cancer: An Ancillary Study of the NRG/RTOG 9601 Randomized Clinical Trial." Jama oncology (2021) Feb 11 [Epub ahead of print].