For men with localized prostate cancer undergoing radiotherapy, adjuvant androgen deprivation therapy (ADT) may yield superior oncologic outcomes compared with neoadjuvant ADT, pooled data from two phase III trials suggested.
In the analysis of over 1,000 patients receiving radiation to the prostate, progression-free survival (PFS) was significantly improved in men receiving adjuvant ADT, with an estimated 15-year PFS rate of 36% versus 29% with neoadjuvant ADT (HR 1.25, 95% CI 1.07-1.47, P=0.01), reported Daniel Spratt, MD, of the University of Michigan in Ann Arbor.
“The hypothesis of this study was that sequencing of ADT with radiotherapy — independent of ADT duration — will have a clinically meaningful impact on oncologic outcomes, just as it does in other disease settings,” said Spratt during the virtual American Society for Radiation Oncology (ASTRO) annual meeting.
With a median follow-up of 14.9 years, biochemical recurrence was lower in the adjuvant group, with 15-year rates of 33% compared with 43% in the neoadjuvant group (HR 1.37, 95% CI 1.12-1.68, P=0.002), and point estimates for all other secondary endpoints favored adjuvant ADT:
- Distant metastasis: HR 1.40, 95% CI 1.00-1.95
- Metastasis-free survival: HR 1.17, 95% CI 1.00-1.37
- Prostate cancer-specific mortality (PCSM): HR 1.29, 95% CI 0.95-1.75
- Overall survival: HR 1.11, 95% CI 0.95-1.30
Late grade ≥3 genitourinary toxicity was no different between the two groups, with a cumulative incidence of 5% in each. For late grade ≥3 gastrointestinal toxicity, 15-year rates were 3% with neoadjuvant ADT and 2% with adjuvant treatment. There was also no difference in patient-reported quality of life, said Spratt.
“We believe this analysis currently serves as the highest level evidence to support the importance of sequencing ADT with radiotherapy,” he said.
Spratt pointed out that numerous trials testing different durations of neoadjuvant ADT have failed to show improvements in metastasis, PCSM, or overall survival. “But when you look at trials that either used adjuvant ADT, or those extending the duration of adjuvant ADT, all of them were positive for either metastasis, PCSM, or overall survival,” he said.
ASTRO discussant Alejandro Berlin, MD, MSc, of Princess Margaret Cancer Centre in Toronto, called the study “thought-provoking” and said it resurfaces the longstanding need “to better understand the biological underpinnings” behind the improved outcomes seen in prostate cancer patients treated with ADT and radiation therapy.
“It’s important to remember that studies exploring different durations of neoadjuvant hormonal therapy have not shown benefit of extending its duration, something that is fundamentally different to what we have seen in the adjuvant setting,” he said. “When patients are referred to us with an already-started ADT treatment, it poses a challenge to determine the optimal total overall duration of that therapy.”
But Berlin also cautioned that the takeaway should not be to avoid neoadjuvant ADT.
“In fact, most studies exploring the use of adjuvant hormonal therapy have had a component of neoadjuvant treatment,” he said. “What I think is relevant here is that in the future we should move beyond exploring solely the radiotherapy’s local treatment effect because there are impacts of what we do before, during, and after treatment, and this seems to be a dynamic field.”
The pooled analysis from Spratt and colleagues used patient-level data from two randomized trials — Ottawa 0101 and RTOG 9413 — to compare use of prostate-only radiotherapy plus ADT delivered either in the concurrent/neoadjuvant setting (n=531) or concurrent/adjuvant setting (n=534). All patients in Ottawa 0101 were included, while in RTOG 9413, those in the whole-pelvis arm were excluded to “harmonize” the datasets.
Patients had a median age of 70 years. Median prostate-specific antigen (PSA) level was 14.1 ng/mL, with more than a third having a PSA above 20 ng/mL. A majority (58%) of men had Gleason score 7 tumors, 25% had a score below 7, and 17% had a score of 8-10. For tumor stage, 42% had T1-T2a tumors, 38% had T2b-T2c tumors, and 20% had T3-T4 tumors.
Spratt reported personal fees from Janssen, AstraZeneca, and Blue Earth.
Berlin disclosed consulting fees from AbbVie, Astellas, Ferring, and Janssen; research funding from Bayer and AbbVie; and he previously served on the board of directors for Vaccinex.