NRG/RTOG 0815 Demonstrates That Short-term ADT Improves Metastasis-free Survival in Men Receiving Dose-escalated Radiation Therapy with Intermediate-risk Prostate Cancer
Daniel Krauss, MD
By Daniel E. Spratt, MD, Chairman and Vincent K. Smith Professor, Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, Ohio
The use of androgen deprivation therapy (ADT) has consistently been shown to improve outcomes in men with intermediate-risk prostate cancer when combined with radiation therapy (RT). The landmark trials that established this, such as RTOG 9408, began 25-40 years ago and used lower doses of RT than are used today. However, post-hoc and retrospective data has influenced practice patterns and guidelines to more selectively use ADT with RT in intermediate-risk prostate cancer:
- Zachary Zumsteg, MD, created the prognostic system used by NCCN guidelines to define favorable (FIR) and unfavorable intermediate-risk (UIR) disease. Based on retrospective data it was shown that men with FIR do not derive benefit from ADT when treated with dose-escalated RT. Based on retrospective data this changed national guidelines.
- Anthony D’Amico, MD, PhD, reported a post-hoc analysis of the effect of ADT based on the ACE-27 comorbidity index and showed that patients with high comorbidity scores have worse outcomes from short-term ADT (ST-ADT) versus RT alone.
- Multiple experts have reported based on retrospective data that the use of dose-escalation, especially with dose-escalation with a brachytherapy boost, obviates the need for ADT in intermediate-risk disease. To this effect, national guides have followed their recommendation to allow omission of ADT when a brachytherapy boost is used for men with intermediate-risk disease.
Given all of the above opinions were based on expert opinion, retrospective, and/or post-hoc unplanned analyses, it was unknown the true benefit and/or harm of ADT in men with intermediate-risk prostate cancer treated with dose-escalated RT. Thus, the NRG/RTOG 0815 trial was conducted. This landmark trial randomized 1,538 men to either dose-escalated RT alone +/- short-term ADT for six months. Dose-escalation could either be solely from external beam RT (EBRT) to 79.2 Gy or via brachytherapy boost (11.4% of enrolled patients). Very importantly, the trial stratified by number of intermediate-risk factors (a close proxy to FIR versus UIR), ACE-27 comorbidity status, and use of a brachytherapy boost Thus, RTOG 0815 was designed to answer the three unproven opinions listed above.
This trial excluded patients with all three intermediate risk factors and >50% biopsy cores positive, as there is data to suggest they have a prognosis more similar to men with high-risk prostate cancer. Additionally, 67% of patients had only one intermediate risk factor. The exact definition of FIR versus UIR were not reported (the system was created after the trial began), but 26.7% of patients had Gleason 4+3, 65% had Gleason 3+4, and only 8.2% had Gleason ≤6. Additionally, 33.3% had two or three intermediate risk features. Thus, if there was complete overlap of the Gleason 4+3 and the 2+ intermediate-risk factor groups, then about 1/3 of the trial would be expected to be UIR. However, if minimal overlap (especially given percent positive cores were not reported) the trial could have enrolled >50% UIR.
At a median follow-up of only six years, the addition of ST-ADT significantly improved biochemical control (HR 0.52), distant metastasis (DM; HR 0.25) and prostate cancer-specific mortality (PCSM; HR 0.1). There were no significant differences in late grade ≥3 adverse events (p=0.27) and no increase in other-cause mortality (p=0.5). The primary endpoint was OS, but the follow-up remains too short for this relatively favorable risk population. Of the 219 deaths that have occurred, only 11 are from prostate cancer, meaning 95% of the events contributing to OS are not from prostate cancer and would be unlikely to be significantly impacted by any oncologic treatment intervention at such an early time point. Despite the short follow-up, there was a 5% absolute improvement in OS and a 15% relative improvement in OS favoring RT plus ST-ADT (HR 0.85, 95% CI 0.65-1.11). Notably, these results are consistent with EORTC 22991, which recently reported long-term (12-year) outcomes. This trial showed that the addition of short-term ADT improved event-free survival, irrespective of lower versus higher doses of RT. There was a meaningful 6.5% absolute improvement in DM-free survival at 12 years (p=0.065).
Dr. Krauss also demonstrated that on subgroup analysis there was no evidence of a treatment interaction for biochemical control or DM based on number of intermediate-risk factors, ACE-27 index or use of a brachytherapy boost. In fact, the use of ADT improved outcomes almost identically for patients that had dose-escalated EBRT or a brachytherapy boost. While some unfamiliar with appropriate statistical methodology might state the p-value was not significant in the brachytherapy boost subset and conclude there was not benefit of ADT in these men, this is invalid. Due to the trial being only powered for the overall cohort size, one must show through a significant treatment interaction that a given subgroup has a different relative benefit. With a clear negative treatment interaction this means that there is similar relative benefit irrespective of dose intensification method. This provides the strongest level of evidence to date for the benefit of ADT across these patient populations.
The 10-year DM-free rates were excellent in patients treated with either dose-escalated EBRT + ADT (99.1%) or brachytherapy boost + ADT (98.8%). As the method of dose-escalation was not a randomized comparison, these groups should not be directly compared given the large potential for bias. However, omission of ADT regardless of dose-escalation method resulted in inferior DM-free rates by ~5%.
Did RTOG 0815 answer the initial three opinions? Mostly.
- The addition of ADT to men with one intermediate risk factor has approximately a 2% improvement in 10-year DM compared to 4.5% for men with multiple intermediate risk factors. Although too small to accurately assess, it does appear that men with Gleason 6 and one intermediate-risk factor do not derive improvement in outcomes from ADT. Thus, until a true FIR subset analysis is conducted in RTOG 0815, guidelines need to change to state that FIR derives “less” absolute benefit than UIR, rather than no benefit.
- The follow-up remains too short to validate if ACE-27 status augmented the effect of ADT on OS. Study authors stated to date there is no evidence of differential ADT benefit on any outcome, including OS by ACE-27 status.
- RTOG 0815 definitively proved wrong many experts who have stated that dose-escalation obviates the benefit of ST-ADT in intermediate-risk prostate cancer. ADT benefits men similarly whether treated with dose-escalated EBRT and those treated with a brachytherapy boost.
NCCN and other guidelines should be updated to reflect that RT+ADT should be recommended based on level 1 evidence, irrespective of dose-escalation method. Additionally, we need to reassess guidelines that state that all FIR patients do not derive benefit from short-term ADT, as it is clear some do. Prior work utilizing prognostic biomarkers have shown that approximately one third of NCCN FIR patients have outcomes more analogous to UIR disease. This underscores the need for ultra-prognostic and predictive biomarkers to best understand which men should receive short-term ADT.
Abstract 1 - Dose Escalated Radiotherapy Alone or in Combination With Short-Term Androgen Suppression for Intermediate Risk Prostate Cancer: Outcomes From the NRG Oncology/RTOG 0815 Randomized Trial was presented on October 25, 2021, during the Plenary session.
Published October 26, 2021