Why this matters
The role of short-term androgen deprivation therapy alongside modern dose-escalated radiotherapy for intermediate-risk prostate cancer has remained a clinically important balancing act.
Earlier results from NRG/RTOG 0815 showed that adding 6 months of ADT improved biochemical control and reduced distant metastases, but failed to improve overall survival.
With approximately a decade of follow-up, the trial now provides a more mature answer. The overall survival endpoint remains negative, but the reduction in clinically meaningful prostate cancer events has become increasingly clear.
Study design
NRG/RTOG 0815 was a randomized phase III trial enrolling patients with intermediate-risk prostate cancer.
Patients were randomized to:
- dose-escalated radiotherapy alone
- dose-escalated radiotherapy plus 6 months of short-term ADT
Short-term ADT consisted of an LHRH agonist or antagonist plus an oral anti-androgen.
Radiotherapy could be delivered as:
- EBRT alone to 79.2 Gy
- EBRT to 45 Gy followed by LDR or HDR brachytherapy boost
The primary endpoint was overall survival.
Patients were stratified according to:
- number of intermediate-risk factors
- baseline ACE-27 comorbidity score
- radiotherapy boost modality
The trial accrued 1,538 patients between 2009 and 2016, with 1,493 eligible for analysis:
- 751 received radiotherapy alone
- 742 received radiotherapy plus short-term ADT
Most patients, 88%, received dose-escalated EBRT alone.
Median follow-up was 9.4 years overall and 10.3 years among surviving patients.
Key results
The primary endpoint remained negative.
At 14 years, overall survival was:
- 53% with RT alone
- 58% with RT plus short-term ADT
- HR 0.87
- 95% CI 0.72-1.04
- p=0.13
Therefore, the trial still does not demonstrate a statistically significant overall survival benefit from adding 6 months of ADT.
However, several disease-specific outcomes significantly favored ADT.
Biochemical failure was reduced:
- HR 0.60
- p<0.001
Local failure was also reduced:
- HR 0.44
- p<0.001
The difference in distant metastases was particularly striking:
- 40 patients with RT alone
- 14 patients with RT plus ADT
- HR 0.35
- p<0.001
Metastasis-free survival at 14 years was:
- 50% with RT alone
- 57% with RT plus ADT
- HR 0.83
- p=0.042
Prostate cancer-specific mortality was also significantly lower:
- 19 prostate cancer deaths with RT alone
- 5 with RT plus ADT
- HR 0.26
- p=0.004
There was no significant difference in mortality from causes other than prostate cancer.
No difference in late high-grade adverse events was reported between the treatment groups.
Interpretation
The central message from the long-term NRG/RTOG 0815 update is that failure to improve overall survival does not mean that short-term ADT had no clinically meaningful effect.
The trial now shows consistent reductions across several prostate cancer endpoints.
Biochemical failure decreased.
Local failure decreased.
Distant metastases were reduced from 40 events to 14.
Prostate cancer deaths fell from 19 to 5.
And metastasis-free survival was significantly improved at 14 years.
This creates an important distinction between overall survival and disease-specific benefit.
Patients with intermediate-risk prostate cancer often have long life expectancy and substantial competing mortality. In that context, an intervention can meaningfully reduce metastases and prostate cancer death without producing a statistically significant difference in all-cause mortality.
The absence of an OS benefit therefore should not be interpreted as evidence that short-term ADT is unnecessary.
At the same time, these results do not imply that every patient with intermediate-risk disease requires ADT. Two-thirds of the study population had only one intermediate-risk factor, and the decision to accept 6 months of hormonal therapy still requires weighing the reduction in disease progression against its short-term quality-of-life and metabolic consequences.
What the mature data strengthen is the oncologic side of that discussion: short-term ADT adds durable disease-control benefit even when radiotherapy is already dose escalated.
Limitations
Overall survival remained the primary endpoint and was not statistically significantly improved.
Although prostate cancer-specific mortality was substantially reduced, the absolute number of prostate cancer deaths was relatively small.
The study population included different radiotherapy approaches, although the large majority received dose-escalated EBRT alone.
The trial also enrolled a broad intermediate-risk population, with 67% of patients having only one intermediate-risk factor. The magnitude of benefit may therefore vary between more favorable and less favorable intermediate-risk subgroups.
The current analysis provides mature disease-control outcomes, but individual treatment decisions still require consideration of ADT-related quality-of-life effects that are not captured by survival endpoints alone.