Both dose-escalated radiation therapy and short-course androgen-deprivation therapy (SADT) have been shown to improve outcomes in patients with intermediate-risk prostate cancer. Researchers then posed a new question—is giving both modalities upfront to newly diagnosed patients of benefit? Findings from the phase III RTOG 0815 study, presented by Daniel J. Krauss, MD, of Beaumont Health, and colleagues at the 2021 American Society for Radiation Oncology (ASTRO) Annual Meeting (Abstract 1), do not fully answer the inquiry, but they do shed more light on the risks and benefits of giving both types of therapy.

Daniel J. Krauss, MD

At a median follow-up of 6.3 years, there was no difference in 5-year overall survival between patients treated with each of the therapies: 90% for radiation therapy alone and 91% for both radiation and SADT. However, at 8 years, a numerical advantage was observed for the combined use of the modalities: 79% for radiation alone vs 84% for the combined treatment. It is possible that with longer follow-up, the curves may separate more in favor of the combination, Dr. Krauss noted.

RTOG 0815 Details

Patients (n = 1,538) with intermediate-risk prostate cancer were randomly assigned to receive dose-escalated radiation therapy alone (arm 1) vs the same radiation therapy plus a short course—6 months—of androgen blockade. Stratification factors included number of risk factors, comorbidity status, and radiation therapy modality. Of the randomly assigned patients, 1,492 were evaluable.

Treatment arms were well balanced for demographic and disease characteristics. The median age was 68 years and about 85% of patients were older than age 60; 75% were White; two-thirds had only one intermediate-risk factor; 89% received external-beam radiation therapy alone; 92% were categorized as Gleason stage 7; and 63% were T1 stage.

Patients in the combination therapy arm (arm 2) had significantly lower rates of prostate-specific antigen (PSA) failure and distant metastases compared to patients treated with radiation alone (P < .001 for both comparisons). At 5 years, PSA failure was reported in 14% of patients in arm 1 and 8% of arm 2; at 8 years, the rates were 21% and 10%, respectively. Distant metastases occurred in 3.1% and 0.6% at 5 years; at 8 years, the rates of distant metastases were 4.3% and 1%.

The requirement for salvage therapy was also significantly lower in arm 2 (P = .025). At 5 years, salvage therapy was initiated in 6.1% of patients in arm 1 and 4.2% of those in arm 2. At 8 years, the corresponding rates were 9.8% and 5.3%, respectively.

Prostate cancer–specific mortality was significantly lower for men who received both radiation and SADT: at 5 years, 0.9% vs 0%, and at 8 years, 1.6% vs 0% (P = .007). There was no difference between treatment arms in non–prostate cancer–specific mortality.

Subgroup analysis for PSA failure showed a benefit for combination therapy in all subgroups. Subgroup analysis for distant metastasis found that all groups derived benefits from the combination therapy, apart from those with a classification of Gleason stage 2 to 6 disease at diagnosis, who fared better on radiation therapy alone.

Study Implications

“This trial did not find statistically improved overall survival for the combination. The results will cause some debate. There are tangible benefits to the addition of SADT to radiation. The information from this trial will allow clinicians to counsel their patients with more data-driven recommendations than they had before. We can tell our patients, ‘We can give you SADT for the better part of the year, and we can reduce the odds of PSA recurrence from 20% to 10% at 8 [years],’” Dr. Krauss said.  “[With the addition of SADT]…, we can reduce the odds of developing metastatic disease at 8 years, but this comes at the cost of side effects of hormonal therapy. This will help with decision-making.”

The downside of radiation plus SADT was the risk of adverse events. Acute adverse events were almost nine times more likely to occur with the use of both modalities than with radiation alone, and the difference favoring radiation therapy alone was statistically significant (P < .001). The most commonly reported adverse events in the combined-modality arm were endocrine events, sexual/reproductive function issues, metabolic laboratory abnormalities, gastrointestinal events, and renal/genitourinary events, but these were mostly grades 1 and 2.

The study authors concluded, “While the addition of total androgen suppression to dose-escalated radiotherapy did not improve overall survival for men with intermediate-risk prostate cancer, significant improvements in rates of metastases, deaths due to prostate cancer, and PSA failures support the continued use of combination dose-escalated radiotherapy and total androgen suppression. Benefits will need to be weighed against the increased risk of adverse events and the patient-reported outcomes analysis.”

Disclosure: For full disclosures of the study authors, visit redjournal.org.