Sequencing of androgen-deprivation therapy with radiotherapy has a significant impact on long-term outcomes in localized prostate cancer, according to data presented during the virtual edition of the 2020 American Society for Radiation Oncology (ASTRO) Annual Meeting.1
Pooled individual patient analysis of two phase III randomized trials has shown, for the first time, that the addition of adjuvant androgen-deprivation therapy to prostate-alone radiotherapy leads to superior outcomes when compared with a neoadjuvant approach. Findings demonstrated significantly improved progression-free survival, biochemical recurrence, distant metastasis, and metastasis-free survival with an adjuvant androgen-deprivation therapy sequence with radiotherapy, and this was accomplished without an increase in observed rates of toxicity.
“We believe this analysis currently serves as the highest level of evidence to support the importance of sequencing of androgen-deprivation therapy with radiotherapy,” said lead study author, Daniel E. Spratt, MD, of the University of Michigan Rogel Cancer Center, Ann Arbor.
Daniel E. Spratt, MD
As Dr. Spratt explained, the timing of systemic therapy in relation to radiotherapy is important in most malignancies. However, androgen-deprivation therapy has largely been investigated in relation to its duration rather than its sequencing with radiotherapy.
“If systemic therapy is biologically synergistic rather than purely additive with radiotherapy, then the sequencing should matter,” said Dr. Spratt. “The field has concluded, in my opinion potentially incorrectly, that low-risk men do not need androgen-deprivation therapy, intermediate-risk men need short-term androgen-deprivation therapy, and high-risk men need longer-term androgen-deprivation therapy, but there is no discussion of the optimal sequencing.”
For this study, Dr. Spratt and colleagues performed a systematic literature search to identify randomized trials that tested the sequencing of androgen-deprivation therapy with radiotherapy without altering the duration. Although only two trials were identified, he said, both trial groups were willing to sign data-sharing agreements and pool their data for individual patient-level data analysis.
The first trial (by Malone et al) randomly assigned patients to receive neoadjuvant/concurrent or concurrent/adjuvant androgen-deprivation therapy for 6 months with prostate-alone radiotherapy.2 This was combined with the prostate-alone radiotherapy arms of RTOG 9413, which randomly assigned patients to 4 months of neoadjuvant/concurrent or adjuvant androgen-deprivation therapy.3
Researchers excluded the whole-pelvis radiotherapy arms of the latter trial to harmonize the prostate-alone delivery between the trials. The neoadjuvant/concurrent arms of both trials were combined into the “neoadjuvant” group, whereas the concurrent/adjuvant (Malone et al) and adjuvant arm (RTOG 9413) were combined in the “adjuvant” group.
Improved Survival, Lower Rates of Biochemical Recurrence
As Dr. Spratt reported, more than 1,000 men were included in the analysis, with a median follow-up of 14.9 years. Baseline characteristics were extremely well matched between the groups, he noted, and the majority of patients had Gleason 7 disease, palpable T2 or T3 tumors, and a baseline prostate-specific antigen level higher than 10 ng/mL.
Progression-free survival—the primary endpoint—was shown to be statistically superior with adjuvant vs neoadjuvant androgen-deprivation therapy. There was a 25% relative improvement in progression-free survival with the use of adjuvant androgen-deprivation therapy, said Dr. Spratt, which translated into a 7% absolute improvement at 15 years.
Biochemical recurrence was also significantly lower with adjuvant androgen-deprivation therapy; there was a 37% relative improvement and a 10% absolute improvement in recurrence at 15 years. The cumulative incidence of distant metastases was significantly lower with adjuvant androgen-deprivation therapy as well; there was a 40% relative reduction and a 6% absolute reduction at 15 years.
Although prostate cancer–specific -mortality and overall survival rates were both lower with adjuvant androgen-deprivation therapy, neither endpoint reached statistical significance. “The point estimates favor adjuvant vs neoadjuvant androgen-deprivation therapy for all endpoints, with no increase in late toxicity,” said Dr. Spratt. He noted that the cumulative incidence of late grade 3 to 5 toxicity was low regardless of androgen-deprivation therapy sequencing, and it did not significantly differ between genitourinary and gastrointestinal domains.
According to Dr. Spratt, this post hoc analysis is supported by many trials testing the use of neoadjuvant androgen-deprivation therapy or prolonging the duration of adjuvant androgen-deprivation therapy. Although there are many caveats, said Dr. Spratt, these trials were all negative for metastasis, prostate cancer–specific mortality, or overall survival. Conversely, trials that used either adjuvant androgen-deprivation therapy or extended the duration of adjuvant androgen-deprivation therapy were all positive for metastasis, prostate cancer–specific mortality, or overall survival, he concluded.
DISCLOSURE: Dr. Spratt has served as a consultant or advisor to AstraZeneca, Blue Earth Diagnostics, and Janssen Oncology.
1. Spratt DE, Malone S, Roy S, et al: Short-term adjuvant vs neoadjuvant hormone therapy in localized prostate cancer: A pooled individual patient analysis of two randomized phase 3 trials. 2020 ASTRO Annual Meeting. Abstract 32.
2. Malone S, Roy S, Eapen L, et al: Sequencing of androgen-deprivation therapy with external-beam radiotherapy in localized prostate cancer: A phase III randomized controlled trial. J Clin Oncol 38:593-601, 2020.
3. Roach M, Moughan J, Lawton CAF, et al: Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): Long-term results of a randomised, phase III trial. Lancet Oncol 19:1504-1515, 2018.
Discussant of the abstract, Alejandro Berlin, MD, MSc, Assistant Professor at the Princess Margaret Cancer Centre, Toronto, called the study “thought-provoking” and applauded the data-sharing approach to answer a clinically relevant question. According to Dr. Berlin, this work resurfaces the...