One scientific session at the 2021 ASTRO annual meeting was dedicated to reports of studies of the use of biomarkers and salvage radiotherapy (RT) in prostate cancer patients who had either undergone radical prostatectomy or had intact disease. After the study presentations, they were reviewed by ASTRO designated discussant, Brian C. Baumann, MD. Dr Baumann is Assistant Professor of Radiation Oncology and Chief of Genitourinary Radiology at Washington University School of Medicine in St Louis, MO.
The first study presented was an investigation of androgen receptor (AR) signaling and the potential association of AR splice variants (AR-Vs) with post prostatectomy salvage therapy response that demonstrated the association of AR-V7 with poorer outcomes.1 David J. Konieczkowski MD, PhD, Assistant Professor in the Department of Radiation Oncology at James Cancer Hospital/The Ohio State University, Columbus, presented the results of a retrospective analysis in 46 patients treated with prostatectomy followed by salvage RT+ ADT at a single institution between 1995 and 2012. Ultra-deep targeted RNA sequencing was used to determine the presence of AR splice variants. They also investigated whether AR-V7 expression is predictive for response to salvage RT and androgen deprivation therapy (ADT). As Dr Konieczkowski reported, AR-V7 expression was not associated with worse outcomes after radical prostatectomy, but after salvage RT plus ADT, there was a “dramatic difference” in biochemical progression-free survival (PFS) based on AR-V7 expression, at a median of 10.9 months in AR-V7 positive vs 73.4 months in AR-V7 negative patients (P=0.002).
“To see a P value of 0.002 in a 46-patient study is pretty wild,” Dr Baumann commented. These preliminary results for AR-V7 as a potential predictive biomarker for response to salvage RT plus ADT are “intriguing,” he said, although the study was limited by the small number of patients and in addition, the entire cohort received salvage RT plus ADT, so it remains unclear whether AR-V7 impacts ADT, salvage RT, or both, he noted. However, the data are “compelling and worthy of further study” to elucidate the role of AR-V7 as a potential biomarker, he concluded.
A study of the Decipher genomic classifier (GC; Veracyte) in patients in the SAKK 09/10 trial was presented by Alan Dal Pra, MD, Associate Professor and Director of Radiation Oncology Clinical Research in the Department of Radiation Oncology at the University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center.2 “This study is, to my knowledge, the first phase 3 trial in prostate cancer with a pre-specified GC analysis that has reported out,” Dr Baumann declared. SAKK 09/10 was a multicenter, open-label, randomized phase 3 trial that compared two fractionation schemes (70 Gy vs 64 Gy) targeted to the prostate bed with no ADT.3 GC data were available for analysis from 226 of 350 patients enrolled in the trial.
Dr Baumann noted that the findings of this analysis were similar to those of the recently reported NRG/RTOG 9601 study, which showed that GC was independently associated with risk of metastasis, prostate-cancer specific mortality, and overall survival.4 Although follow-up in the SAKK trial (median 6.3 years) was insufficient to evaluate overall survival, the trial endpoints used surrogate markers such as biochemical progression. The results indicated that the high and low/intermediate GC groups were well stratified and that patients with high-GC were more than twice as likely to experience biochemical progression as the low/intermediate GC group. An “interesting” exploratory analysis showed that even in patients with relatively low pre-salvage PSA (≤5 ng/mL), there was “a pretty big” difference in 5 years free from biochemical progression based on GC score (74% vs 59%). A more dramatic difference was seen in patients with pre-salvage PSA >0.5 ng/mL (64% vs 13%). Dr. Baumann noted that 17 patients is very few, “anything can happen in 17 patients,” and it can be coincidental findings. These results are important, however, they would require confirmation.
These results speak to the potential importance of using GC and pre-salvage PSA to counsel patients on treatment classification strategies, Dr Baumann stressed. ”The especially poor results seen in patients with PSA >0.5 and high GC score argue in favor of using ADT with or without pelvis RT, the winning arms of the SSPORT5 and GETUG-AFU 166 trials,” he asserted.
Dr Baumann revealed that he was an early adopter of GC testing in all his salvage RT patients. For patients with low pre-salvage PSA and high-risk GC score, he routinely recommends short-term ADT and whole pelvis RT, based on clinical trial evidence. “GC testing also helps me counsel patients with low pre-salvage PSA on the potential benefits of RT plus short-term ADT vs RT alone,” he said. For patients with higher pre-salvage PSA, GC testing is useful for shared decision making on short-term vs long-term ADT, he said. “I routinely treat the elective nodes when using ADT, based on the SPPORT trial data,” he said.
Another study presented in patients undergoing radical prostatectomy investigated the value of neoadjuvant stereotactic body radiotherapy (SBRT) in men with locally advanced disease.7 As reported during the session by Liat Hammer, MD, PhD, from the Department of Radiation Oncology, University of Michigan, Ann Arbor, this phase I trial that was stopped early due to unacceptably high toxicity after 16 patients had been enrolled. These high- risk or clinically node-positive patients received 25 Gy in 5 fractions to the pelvic nodes and either 30 Gy or 35 Gy in 5 fractions to the prostate/seminal vesicles, “close to definitive doses,” noted Dr Baumann. Severe complications included 2 patients requiring cystectomy and urinary diversion.
Dr Baumann commended Dr Hammer and her colleagues for evaluating a novel use of radiation with preoperative SBRT for patients with high-risk disease. There are advantages of SBRT in this setting, such as smaller target volume and improved rates of negative margin resections, he acknowledged, but the dose was too toxic. However, Dr Baumann does not believe that preoperative radiation should be discarded as an option. “Future trials should probably focus on toxicity mitigation, lowering the dose, perhaps to 25 Gy in 5 fractions, which has been shown to be safe in rectal cancer preoperatively,” he suggested. Treatment planning techniques such as urethra sparing, online adaptive RT, or protons may be appropriate, he added.
Among the latest studies reported in patients with high-risk intact prostate cancer was a validation of the performance of the Decipher Prostate GC in pretreatment biopsy samples presented by Paul L. Nguyen, MD, Genitourinary Clinical Center Director for Radiation Oncology at Dana-Farber Cancer Institute, Boston, and Professor of Radiation Oncology, Harvard Medical School, Cambridge, MA.8 The study design was similar to that of the NRG/RTOG 9601 study,4 Dr Baumann noted. Data for Dr Nguen’s study came from three phase 3 high-risk definitive RT trials: NRG/RTOG 9202, 9413, and 9902 (total 385 biopsy samples). On multivariate analysis, the GC score was found to be prognostic for distant metastases (P<0.001), prostate cancer specific mortality (P<0.001), and overall survival (=0.001). “This study validates gene expression biomarkers using prospective randomized control trial data,” Dr Baumann concluded. “This tool can improve risk stratification and aid in personalized treatment decisions for patients.” It paves the way for the NRG-GU009/PREDICT-RT (NCT04513717) study, which is examining intensity of treatment of high-risk prostate cancer based on GC scores, he added.
Dr Baumann noted that GC testing is now included in the National Comprehensive Cancer Network (NCCN) prostate cancer guidelines.9 He said that he routinely obtains GC testing for all prostate cancer patients and enrolls the high-risk patients in the NRG-GU009/ PREDICT-RT trial. For patients who are ineligible for, or who decline the study, the Decipher Prostate GC score is used for shared decision-making for patients who are reluctant to continue ADT and to help them decide on 1.5 vs 2 years of treatment.
In the last presentation in this session, Ting Martin Ma MD, PhD, resident physician in the Department of Radiation Oncology at University of California, Los Angeles, reported the testing of a nomogram developed using data from 200 patients with high-risk, clinically node-negative, non-metastatic disease who underwent PSMA PET/CT.10 The prognostic performance of the PSMA nomogram in predicting clinical outcomes was determined in 5275 men identified from a multi- institutional database and compared with the STAR-CAP score, Cancer of the Prostate Risk Assessment (CAPRA) score, Cambridge Prognostic Groups (CPG) risk group, and Memorial Sloan Kettering Cancer Center (MSKCC) nomogram of 5-year recurrence probability. The PSMA nomogram was found to outperform CAPRA, CPG, and MSKCC for all endpoints, including 5- and 10-year metastasis and prostate cancer specific mortality, and performed similarly to STAR-CAP.
“It is remarkable that a database developed using likelihood of PSMA PET-detected nodal or distant metastases in 200 patients throught to have localized disease on conventional imaging could outperform other nomograms developed using data from thousands of patients,” Dr Baumann enthused. “It provides valuable data showing that patients’ predicted risk of upstaging on PSMA PET is closely linked with long-term outcomes,” he declared. Future efforts are needed to further refine the original nomogram and validate it, possibly with additional patients, he urged.
David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.
- Konieczkowski DJ, Otani K, Drumm MR, et al. Impact of AR-V7 and other androgen receptor splice variant expression on outcomes of post-prostatectomy salvage therapy. Int J Radiat Oncol Biol Phys. 2021;111(3 suppl):S49. Abstract 93. DOI: https://doi. org/10.1016/j.ijrobp.2021.07.131
- Dal Pra A, Ghadjar P, Hayoz S, et al. Performance of a genomic classifier (GC) within a phase 3 randomized trial of dose escalated salvage radiotherapy (SRT) after radical prostatectomy (RP). Int J Radiat Oncol Biol Phys. 2021;111(3 suppl):S49-50. Abstract 94. DOI: https://doi.org/10.1016/j.ijrobp.2021.07.132
- Ghadjara P, Hayoz S, Bernhard J, et al. Dose-intensified versus conventional-dose salvage radiotherapy for biochemically recurrent prostate cancer after prostatectomy: the SAKK 09/10 randomized phase 3 trial. Eur Urol. 2021;80(3):306-315. DOI: 10.1016/j. eururo.2021.05.033
- Feng FY, 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 Oncol. 2021;7(4):544-552. DOI: 10.1001/jamaoncol.2020.7671
- Pollack A, Karrison TG, Balogh AG, et al. Short term androgen deprivation therapy without or with pelvic lymph node treatment added to prostate bed only salvage radiotherapy: the NRG Oncology/RTOG 0534 SPPORT trial. Int J Radiat Oncol Biol Phys.2018;102(5):1605. Abstract LBA5. DOI: 10.1016/j.ijrobp.2018.08.052
- de Laroche G, Richaud P, Guerif S, et al. Salvage radiotherapy with or without short- term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016;17(6):747-756. DOI: https://doi.org/10.1016/S1470-2045(16)00111-X
- Hammer L, Jiang R, Hearn JWD, et al. A phase I trial of neoadjuvant stereotactic body radiotherapy (SBRT) prior to radical prostatectomy (RP) in locally advanced prostate cancer. Int J Radiat Oncol Biol Phys. 2021;111(3 suppl):S50-S51. Abstract 96. DOI: 10.1016/j. ijrobp.2021.07.134
- Nguyen PL, Huang HC, Davicio E, et al. Validation of a 22-gene genomic classifier in the NRG Oncology/RTOG 9202, 9413 and 9902 phase III randomized trials: A biopsy-based individual patient meta-analysis in high-risk prostate cancer: Int J Radiat Oncol Biol Phys. 2021;111(3 suppl):S50. Abstract 95. D 10.1016/j.ijrobp.2021.07.133
- National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. Prostate cancer. Version 1.2022. September 10, 2021. https://www.nccn.org/ professionals/physician_gls/pdf/prostate.pdf
- Ma TM, Xiang M, Tilki D, et al. Prognostic significance of the risk of non-localized disease on PSMA/PET: comparative performance of a novel, PSMA/PET-derived risk stratification tool for high-risk prostate cancer in a large, multi-institutional cohort. Int J Radiat Oncol Biol Phys. 2021;111(3 suppl):S51-S52. Abstract 97. DOI: 10.1016/j.ijrobp.2021.07.135