The optimal management strategy for high-risk prostate cancer remains an area of active debate. This analysis pooled patient-level data from two major randomized phase III trials- RTOG 0521 and CALGB 9020, to compare outcomes between radiation-based and surgery-based treatment paradigms.

Patients on RTOG 0521 received radiotherapy with 24 months of ADT and were randomized to the addition of six cycles of adjuvant docetaxel, whereas patients on CALGB 90203 underwent radical prostatectomy and were randomized to six cycles of neoadjuvant docetaxel plus 18–24 weeks of ADT.

 The primary endpoint was the cumulative incidence of distant metastasis (DM), analyzed with death as a competing risk. Across the 1,290 aggregated patients, the CALGB 90203 (surgical) population was younger and had more favorable baseline prognostic features compared with the RTOG 0521 (radiotherapy-based) cohort. Despite this, the incidence of distant metastasis was significantly lower among patients treated with radiotherapy and long-term ADT: 15% vs 22% at 8 years. No significant difference was observed in the rate of death after development of distant metastasis between the two treatment strategies.

Authors concluded significantly lower incidence of distant metastasis with a radiotherapy-based approach than a surgical (radical prostatectomy) based treatment strategy.

Reference (Pub-Med Link):  Roy S, Sun Y, Eastham JA, et al. Radiotherapy- versus surgery-based treatment strategy in high-risk prostate cancer. Eur Urol Oncol 2025. https://doi.org/10.1016/j.euo.2025.06.009

Key Institution: Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Multi-institutional

Keywords: Prostate cancer

Clinical cohort study that sought to develop and validate a multimodal artificial intelligence (MMAI)-derived predictive biomarker to predict the benefit of long-term ADT on distant metastasis (DM) in men with high-risk prostate cancer. The MMAI was trained for long-term vs short-term ADT using pretreatment digital prostate biopsy images and clinical data like age, PSA, Gleason, and T stage from six NRG Oncology phase III trials.  The MMAI was validated on a seventh trial, RTOG 9202 (N= 1192), which randomly assigned men to RT+ST-ADT vs RT+LT-ADT and showed significant reduction in distant mets with 28 months vs 4 months of ADT. A significant predictive interaction was observed with the digital biomarker for DM, where MMAI biomarker-positive men, 66%, had reduced DM with LT-ADT vs ST-ADT, whereas no treatment benefit was observed for MMAI biomarker-negative men. The estimated 15-year DM risk difference between RT+LT-ADT and RT+ST-ADT was 14% in MMAI biomarker-positive men and 0% in MMAI biomarker-negative men. Of note, the biomarker was also prognostic for DM, irrespective of treatment. It is an interesting new tool to help in management decisions for patients with HRPC. This, as well as the decipher genomic assay test, will be interesting to follow in the coming years to see how it evolves practice.   

Reference (Pub-Med Link):   Armstrong AJ, Liu VYT, Selvaraju RR, et al. 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. J Clin Oncol 2025;43:3494-3504. https://doi.org/10.1200/jco.24.00365

Key Institution: Duke University Medical Center, Multi-institutional

Keywords: Prostate Cancer

The PEACE-1 phase 3 trial investigated whether adding radiotherapy (74 Gy) to current treatments improves outcomes for metastatic prostate cancer patients. 1,173 patients were enrolled in European hospitals. The study compared standard care (androgen-deprivation therapy with/without docetaxel) alone or combined with abiraterone, radiotherapy, or both. In patients with low-volume disease, adding radiotherapy to abiraterone plus standard care significantly improved progression-free survival from 4.4 to 7.5 years (HR 0.65); this benefit wasn't seen without abiraterone. There was no significant improvement in overall survival (6.9 vs 7.5 years, HR 0.98). The overall rate of severe adverse events did not differ with the addition of radiotherapy, but severe genitourinary complications were decreased with radiotherapy. The combination could become a component of standard of care in patients with both high-volume and low-volume de novo metastatic castration-sensitive prostate cancer.

Reference (Pub-Med Link): Bossi A, Foulon S, Maldonado X, et al. Efficacy and safety of prostate radiotherapy in de novo metastatic castration-sensitive prostate cancer (peace-1): A multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 2024;404:2065-2076. https://doi.org/10.1016/s0140-6736(24)01865-8

Key Institution: Institut Gustave Roussy, Multi-institutional

Keywords: Prostate Cancer

This study used tissue collected from NRG Oncology/RTOG 01-26, a randomized phase 3 trial of men with intermediate-risk prostate cancer who received either 70.2 Gy or 79.2 Gy of radiation therapy without androgen deprivation therapy. Tissues were assigned a genomic classifier according to the Decipher test. Of 1,532 participants in the trial, 215 had archived tissues with sufficient sample volume and passed a quality control assay. In the multivariable model, Decipher score was prognostic for disease progression, biochemical failure, distant metastasis, and prostate cancer-specific mortality. When patients were stratified according to existing Decipher score thresholds for low-, intermediate-, and high-risk groups, the high-risk group were found to be 12% more likely to develop a distant metastasis at 10 years. In an interaction analysis, dose escalation was associated with a significant reduction in distant metastasis in patients with intermediate- and high-risk Decipher classification. In conclusion, the Decipher score tracked clinically important outcomes in these intermediate-risk prostate cancer patients.

Reference (Pub-Med Link): Spratt et al. (2023). Spratt DE, Liu VYT, Michalski J, et al. Genomic classifier performance in intermediate-risk prostate cancer: Results from nrg oncology/rtog 0126 randomized phase 3 trial. Int J Radiat Oncol Biol Phys 2023;117:370-377.https://doi.org/10.1016/j.ijrobp.2023.04.010

Key Institution: Memorial Sloan Kettering Cancer Center, Multi-institutional

Keywords: Prostate Cancer

The ORIOLE trial phase 2 trial was conducted across 3 US institutions. The trial included 54 patients with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6months of enrollment or 3 or more years total. The patients were randomized to observation vs. SABR for the metastatic sites. The results showed that 7 out of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation experienced disease progression at 6 months (p=0.005). Treatment with SABR improved median progression-free survival (not received vs. 5.8 mon; HR 0.30; 95% CI0.11-0.81, p=0.002). In conclusion, treatment with SABR for oligometastatic prostate cancer improved outcomes.

(Open Access)

Reference (PubMed Link): Phillips R, Shi WY, Deek M, et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: The oriole phase 2 randomized clinical trial. JAMA Oncol 2020;6:650-9.

Key Institution: Multi-Institutional (US)
Keywords: Oligometastatic prostate cancer, SABR

The HYPRO trial I a phase 3 study evaluating the effects of hypofractionated (HF) RT compared to conventionally fractionated (CF) RT in the treatment of intermediate and high risk prostate cancer.  Patients were randomly assigned to 64.6 Gy in 19 (BED 90.4) fractions or 78 Gy in 29 fractions (BED 78).  The primary endpoint was relapse-free survival at 7 years.  A total of 820 patients were enrolled on the trial.  ADT was given to a total of 67% of patients on the study.  At 7 years, there was no significant difference in relapse-free survival on the two arms (71.7% on the HF arm vs 67.6% on the CF arm).  Additionally, there were no differences in OS or treatment failure on the two arms.

These updated results confirmed the author’s previously reported findings that hypofractionation (with dose escalation based on EQD2) did not translate to improved treatment outcomes compared to conventionally fractionated RT.

Reference (PubMed Link): de Vries KC, Wortel RC, Oomen-de Hoop E, et al. Hyprofractionated versus conventionally fractionated radiation therapy for patients with intermediate- or high-risk, localized, prostate cancer: 7-year outcomes from the randomized, multicenter, open-label, phase 3 hypro trial. Int J Radiat Oncol Biol Phys 2020;106:108-115.

Key Institution: Multi-Institutional (Europe)
Keywords: Hypofractionated, Prostate cancer, EBRT, high risk, intermediate risk 

External beam radiation is a common treatment for localized prostate cancer, traditionally given over 7-8 weeks of treatment with fraction sizes of 2Gy or smaller. Several recent trials have demonstrated that moderately hypofractionated treatments given over ~4 weeks in fraction sizes larger than 2Gy, have equivalent 5-year disease control rates. Clinician assessed toxicity suggests a possible increase in late genitourinary (GU) toxicity with hypofractionation, however there is little data on patient reported outcomes. 

The present study looked at patient reported outcomes from a cohort of 17,058 men in England who underwent prostate RT with curative intent between April 2014 and September 2016. All patients were mailed a survey that included the EPIC-26 questionnaire (addressing urinary, bowel and sexual function) and the EuroQol EQ-5D-5L questionnaire (quality of life).  There was a 77% response rate resulting in 13,131 completed surveys. 64% of patients received conventional RT and 36% received hypofractionated. Hypofractionation was associated with statistically better sexual and hormonal function scores, however these were small differences that did not meet prespecified thresholds for clinically significant change. There was no difference between the treatments in urinary function, bowel function, or overall quality of life. 

Strengths of the study include the large size and high response rate. The study reflects a real-world population of patients treated in the British NHS as opposed to a carefully selected clinical trial population. Limitations include the fact that some late toxicity may only manifest with a longer follow up period. Also, as the surveys were conducted after treatment, patient reported information was not available on baseline GI and GU function. Overall, the study suggests there is no significant difference in patient reported outcomes between conventional and hypofractionated RT for prostate cancer and adds to the growing evidence base for the use of hypofractionated treatment.

Reference (PubMed Link): Nossiter J, Sujenthiran A, Cowling TE, et al. Patient-reported functional outcomes after hypofractionated or conventionally fractionated radiation for prostate cancer: A national cohort study in england. J Clin Oncol 2020;38:744-752.

Key Institution: United Kingdom 
Keywords: Prostate cancer, hypofractionation, quality of life, patient reported outcomes

This is a randomized trial comparing adjuvant radiotherapy versus observation for men with prostate adenocarcinoma pT2a with positive margins or pT3a. All patients were N0M0, had a preoperative PSA of ≤20 ug/l and post-operative PSA <0.5 ug/l. Of 250 patients in the study, 126 received adjuvant radiotherapy to 66.6 Gy. 

The primary endpoint of this study was biochemical recurrence free survival, and secondary endpoints included overall survival, cancer-specific survival, local recurrence, and adverse events. 

At median follow up of 9.3 years in the adjuvant group the 10 year freedom from biochemical recurrence was 82% with adjuvant therapy versus 61% in the observation group (HR 0.26 0.14-0.48, p<0.001). The difference in OS of 92% versus 87% in the adjuvant and observation groups, respectively, was not statistically significant. There was also no statistically significant difference in metastatic free survival or prostate cancer specific survival.  

This trial is unique from historical trials given that patients with pT2 with positive margins were included, most adjuvant trials have limited to pT3-4. Evaluating the pT2 patients as a single group, 3/73 patients that received adjuvant RT experienced biochemical progression, compared with 21/63 in the observation group. Of the 43 patients in observation group with biochemical progression, 37 went on to receive salvage RT median 20 weeks from progression, and 28 of those patients achieved PSA remission.  

When this study was designed a PSA of <0.5 ug/l was defined as undetectable, whereas in today’s era <0.2 ug/l is most commonly accepted.  

In conclusion, this study demonstrates improved freedom from biochemical progression with adjuvant radiotherapy versus observation for pT2 with positive margins or pT3 patients. There is a slightly higher risk of grade 3 toxicity, most commonly seen as erectile dysfunction and urinary incontinence, so there should be informed discussion between the physician and patient when deciding if adjuvant therapy should be delivered.  

(Open Access)

Reference (PubMed Link): Hackman G, Taari K, Tammela TL, et al. Randomised trial of adjuvant radiotherapy following radical prostatectomy versus radical prostatectomy alone in prostate cancer patients with positive margins or extracapsular extension. Eur Urol 2019;76:58+F106-595.

Key Institution: Multi-institutional/Finland
Keywords: Prostate cancer, adjuvant radiotherapy, positive margins 

Updated report of ProtecT trial which reported intention-to-treat analysis of UK men with localized prostate cancer randomized to active monitoring (AM), radical prostatectomy (RP), or radiation (RT). 1643 men included. More men in AM group died of PCa (AM=1.85%, RP=0.67%, RT=0.73%), p= 0.003 when comparing AM vs treatment arms. Metastases (AM 5.6%, RP 2.4%, RT 2.7%) and disease progression (AM 20.35%, RP 5.87%, RT 6.62%) were both more common in AM arm. There were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after RP, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after RT. Overall, more than 95% of patients with low or intermediate risk localized prostate cancer do not die of prostate cancer within 10 year, irrespective of treatment or active monitoring, though risk of disease progression is higher with AM.  

(Open Access)

Reference (PubMed Link): Neal DE, Metcalfe C, Donovan JL, et al. Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the protect randomised controlled trial according to treatment received. Eur Urol 2019.

Key Institution: Multi-Institutional (UK)
Keywords: Prostate cancer, active monitoring, prostatectomy, radiation therapy

The purpose of this retrospective study was to evaluate the efficacy and toxicity profile of salvage SBRT in patients with locally recurrent prostate cancer who were previously treated with definitive RT.

This study examined 100 patients treated between 2010 and 2017 across 7 centers. Local recurrence was determined by pelvic MRI and choline PET scans, and all patients were required to undergo biopsies to prove recurrence. Primary endpoint was second biochemical RFS (bRFS) defined by the Phoenix criteria. Median SBRT dose was 36 Gy in 6 fractions

The median follow-up was 29.3 months. The second bRFS at 3 years was 55%.. The authors found that no patient developed higher than grade 1 acute GI toxicity. There were approximately 21% and 1% of patients who developed 3-year grade 2 or greater GU and GI toxicity, respectively.

This retrospective study showed promising results regarding efficacy and toxicity outcomes of salvage SBRT in patients with prostate cancer who were previously irradiated. SBRT in this setting needs to be evaluated in a prospective manner and with longer follow-up to confirm these results.

Reference (PubMed Link): Pasquier D, Martinage G, Janoray G, et al. Salvage stereotactic body radiation therapy for local prostate cancer recurrence after radiation therapy: A retrospective multicenter study of the getug. Int J Radiat Oncol Biol Phys 2019;105:727-734.

Key Institution: Centre Oscar Lambret, Lille, France
Keywords: Prostate cancer, salvage radiation, SBRT, reirradiation, biochemical failure 

There is randomized evidence that moderately hypofractionated radiation therapy (typically 2.5 – 4 Gy per fraction) is a valid alternative for some patients with prostate cancer. Extreme hypofractionation, typically defined as >6 Gy per fraction, delivered with SBRT in 4 or 5 treatments, also has some encouraging supportive data. 

The present study, the ONE-SHOT trial, addresses the role of single fraction SBRT in prostate cancer. The radiation therapy was 19 Gy in a single fraction of SBRT designed to spare the urethra, with the Calypso System used to continuously track motion. 6 patients with localized (low or intermediate risk) prostate cancer received this treatment. There was no acute toxicity greater than grade 2 during the 3-month follow-up. 50% of patients experienced grade 1 or 2 GU toxicities which decreased to baseline at week 12. 33% of patients had grade 1 rectal toxicity at week 6 which was resolved by week 12.  

Although the results are intriguing and warrant further study, this is a very small number of patients and there is no long-term follow-up data available, so it should remain investigational for the time being. Longer follow-up and larger prospective comparative studies would be needed before adopting this into practice.  

Reference (PubMed Link): Zilli T, Franzese C, Bottero M, et al. Single fraction urethra-sparing prostate cancer sbrt: Phase i results of the one shot trial. Radiother Oncol 2019;139:83-86.

Key Institution: Geneva University Hospital, Switzerland 
Keywords: Prostate SBRT, urethral sparing radiation therapy, single-fraction treatment 

More ultra-hypofractionated regimens are being implemented in treatment of prostate cancer. This study is a phase 3 non-inferiority study comparing prostate stereotactic body radiation therapy (SBRT) to conventionally-fractionated radiation therapy with co-primary endpoints of acute gastrointestinal (GI) and genitourinary (GU) toxicity. Very early outcomes (median follow-up of 12 weeks) are reported. At 12 weeks, SBRT appeared non-inferior to conventionally-fractionated radiation therapy in regards to acute GI and GU toxicity. Though this information is important to physicians, we need longer follow-up to determine the risks of late toxicity before broad application in the clinic. 

(Open Access)

Reference (PubMed Link): Brand DH, Tree AC, Ostler P, et al. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (pace-b): Acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial. Lancet Oncol 2019;20:1531-1543.

Key Institution: Multi-Institutional (Royal Marsden Hospital, Institute of Cancer Research, London, UK)
Keywords: Prostate cancer,  SBRT, acute toxicity 

Stereotactic body radiation therapy (SBRT) is an attractive alternative to traditionally fractionated external beam radiation therapy in patients diagnosed with localized prostate adenocarcinoma.  

This meta-analysis reviewed the results from more than 6000 patients enrolled on 38 studies with localized prostate cancer treated between 1980 and 2018 with SBRT. Studies included patients with low, intermediate, and high risk disease, although the former was substantially more represented than the latter. The study investigated the biochemical RFS, patient reported quality of life, and acute and late toxicities. 5 and 7 year bRFS was above 90%, GI/GU toxicities were 1-2% with the Expanded Prostate Cancer Index Composite urinary and bowel domain scores returning to baseline at 2 years.  

The results of this study further confirm the efficacy of SBRT as an excellent treatment modality for localized prostate cancer. While we await the final outcome of a phase II study comparing SBRT with standard fractionation proton IMRT (link below), this study continues to show encouraging results in this emerging therapy. 

Reference (PubMed Link): Jackson WC, Silva J, Hartman HE, et al. Stereotactic body radiation therapy for localized prostate cancer: A systematic review and meta-analysis of over 6,000 patients treated on prospective studies. Int J Radiat Oncol Biol Phys 2019;104:778-789.

Key Institution: University of Michigan Medical Center
Keywords: SBRT, localized prostate cancer, Quality of Life

In the HYPO-RT-PC trial, over 1200 men with intermediate- and high-risk prostate cancer were randomized to receive either standard fractionation (2 Gy x 39 = 78 Gy) or ultra (6.1 Gy x 7 = 42.7 Gy)—this latter dose was chosen to be equi-effective for late normal tissue complications. Barely 10% of enrollees ultimately fit this description. And while cT3a disease was also allowed, only 5% had it. So what we end up with is a largely intermediate-risk population, though nobody received androgen deprivation. The trial was initially designed to prove superior failure-free survival (FFS) at 5 years with ultra. However, an interim analysis demonstrated much better FFS (87%) than anticipated (70-80%), so the trial was switched to a non-inferiority design with a 4% absolute non-inferiority margin. At 5 years, the rate of FFS was 84% in both arms, which was deemed non-inferior, with similar overall survival. Ultra-hypofractionated treatment resulted in slightly worse acute grade 2+ GU toxicity (28 versus 23%) but similar grade 2+ GI and GU toxicity at 5 years (<5%). Finally, rates of erectile function dropped from 70% at enrollment to 35% at 5 years.

Reference (PubMed Link): Widmark A, Gunnlaugsson A, Beckman L, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the hypo-rt-pc randomised, non-inferiority, phase 3 trial. Lancet 2019;394:385-395.

Key Institution: Umea University, Umea Sweden 
Keywords: HYPO-RT, ultra-hypofractionation, prostate cancer, intermediate-risk, high-risk  

The question of how aggressively to treat oligometastatic disease, and whether or not there is a benefit to doing so, is an evolving paradigm in multiple disease sites. This is of particular importance in primary histologies with a long natural history, such as breast and prostate cancer, where patients may live for years with a diagnosis of metastatic disease. These authors report on the results of a Phase II, multi-center study in which patients with asymptomatic patients with prostate cancer and fewer than 4 extracranial metastases were randomized to either surveillance or metastasis-directed therapy (MDT) at all detected lesions (using either surgery or stereotactic body radiotherapy). The primary endoint was androgen-deprivation free survival, and ADT was started at symptomatic progression, progression to more than 3 metastases, or local progression of known metastases. This study enrolled 62 patients, with 31 patients in each arm. The median ADT-free survival time was 13 months for patients in the surveillance arm and 21 months in the MDT arm (HR 0.60, 80% CI 0.40 –0.90). There were no symptomatic or local progression events observed in the MDT group, whereas 3 and 6 events occurred in the surveillance arm, respectively. The authors conclude that MDT is safe and effective compared to surveillance.
This is an important study that provides support of metastasis-directed therapy for oligometastatic disease. Metastasis-directed therapy has become more common in recent years, particularly as SBRT becomes more widely used and available. 

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Journal & Date: Journal of Clinical Oncology 36, no. 5 (February 2018) 446-453.
Key Institution: Ghent University Hospital, Ghent, Belgium
Keywords: Oligometastatic disease, prostate cancer, metastasis-directed therapy

High risk prostate cancer, particularly with high Gleason score (9-10) has high risk of distant metastasis and prostate cancer-related death. Due to inherent challenges in participant accrual, there are no prospective randomized trials comparing prostatectomy (RP), external beam radiotherapy with androgen deprivation (EBRT), and external beam radiotherapy with brachytherapy boost and androgen deprivation (EBRT+BT). The current study performed a multi-institutional consortium retrospective review of 1809 men across 12 institutions who underwent RP (n=639), EBRT(n=734), or EBRT+BT(n=436) in order to identify any prostate-cancer specific survival (PCSS) benefit using this larger dataset. EBRT+BT had a significantly lower PCSS than RP (HR=0.38) or EBRT (HR=0.41).

5-year PCSS was 12%, 13%, and 3% for RP, EBRT, and EBRT+BT respectively.

Distant metastasis rate was significantly lower with EBRT+BT as compared to RP (HR=0.27) or EBRT (HR=0.30). There was an overall survival benefit in the first 7.5 years of follow-up with EBRT+BT versus RP (HR=0.66) or EBRT (HR=0.61). Of note, 43% of patients undergoing RP required post-operative radiotherapy. This study presents novel findings to suggest both a distant metastasis and prostate-cancer specific survival benefit from EBRT+BT. Strengths of the study include large statistical power, generalizability, and robust statistical methods including propensity score matching. Limitations include those inherent to the retrospective study design. Overall, these are valuable and statistically powerful data suggesting that patients with Gleason score 9-10 prostate cancer should be treated with extremely dose-escalated radiotherapy, including external beam radiotherapy and brachytherapy boost along with androgen deprivation too optimize clinical outcomes.

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