Both dose-escalated radiation therapy and short-course androgen-deprivation therapy have been shown to improve outcomes in intermediate-risk prostate cancer, but it is not clear whether giving both modalities upfront to newly diagnosed patients is of benefit. The phase III RTOG 0815 study presented at the 2021 American Society for Radiation Oncology (ASTRO) Annual Meeting does not fully answer that question, but it does shed more light on the risks and benefits of giving both types of therapy.^1,2

At a median follow-up of 6.3 years, there was no difference in 5-year overall survival (90% for radiation therapy alone and 91% for radiotherapy plus short-course androgen-deprivation therapy). However, at 8 years, a numerical advantage was observed for the combined use of these 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, suggested Daniel J. Krauss, MD, of Beaumont Health, who presented the study findings at the ASTRO meeting.¹

Daniel J. Krauss, MD

The downside of radiation plus short-course androgen-deprivation therapy 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). However, the vast majority of events were low-grade, and this was almost completely driven by the expected side-effect profile of androgen-deprivation therapy. Specifically, the most common adverse events in the combined-modality arm were sexual/reproductive function issues; metabolic laboratory abnormalities; and what would be considered expected endocrine toxicity. Gastrointestinal and renal/genitourinary event incidences were no different between patients receiving and not receiving androgen deprivation, respectively. There was no significant difference in the late adverse event rates between the treatment arms.

“This trial did not find statistically improved overall survival for the combination, and the results will cause some debate. There are tangible benefits to the addition of short-course androgen-deprivation therapy 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 short-course androgen-deprivation therapy for the better part of the year, and we can reduce the odds of PSA [prostate-specific antigen] recurrence from 20% to 10% at 8 years,’” Dr. Krauss said. “[With the addition of short-course androgen-deprivation therapy], we can reduce the odds of developing metastatic disease at 8 years, but this comes at the cost of dealing with the side effects of hormonal therapy for what typically amounts to a duration of time of about a year. This will help with decision-making.”

Study Details

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

The combination-therapy arm had significantly lower rates of PSA failure and distant metastases compared with radiotherapy alone (P < .001 for both comparisons). At 5 years, PSA failure was reported in 14% of those receiving radiotherapy alone and 8% of those in the combination-therapy group; at 8 years, the rates were 21% and 10%, respectively. Distant metastases occurred in 3.1% and 0.6% at 5 years, and at 8 years, the rates of distant metastases were 4.3% and 1%.

Treatment arms were well balanced for demographic and disease characteristics. The median age was 68 years, and about 85% of patients were older than 60; 75% were White; two-thirds had only one intermediate risk factor; 92% had Gleason 7 disease; and 63% had T1 disease.

The requirement for salvage therapy was significantly lower in the combined-modality arm (P = .025). At 5 years, salvage therapy was initiated in 6.1% of patients given radiotherapy alone and 4.2% of those given the combination. 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 short-course androgen-deprivation therapy: at 5 years, that rate was 0.9% vs 0%; and at 8 years, it was 1.6%, vs 0%, respectively. (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. Analysis for distant metastasis found that all subgroups benefited from the combination therapy, with the exception of those with Gleason 2 to 6 disease at diagnosis, who did not seem to benefit clinically from the addition of androgen deprivation.

Patient-Reported Outcomes

A companion study presented at the 2021 ASTRO meeting focused on patient-reported outcomes using three different validated instruments.² Overall, results showed that the addition of short-course androgen-deprivation therapy to dose-escalated radiation therapy led to declines in hormonal and sexual domains vs radiation therapy alone, but these differences between treatment arms were short-lived; by 1 year after treatment initiation, there were no clinically meaningful differences in these patient-reported outcome domains between the two arms. Moreover, there were no clinically meaningful differences between treatment arms on the fatigue scale, in bowel/urinary scores, or in activity scores at any timepoint.

“This randomized trial demonstrated significant clinical benefits by adding 6 months of hormone therapy to modern radiation. While there was no improvement [yet] in overall survival, this benefit included not only better PSA control, but also less metastatic spread of the prostate cancer and fewer deaths. Beyond the clinical outcomes, these patient-reported outcome results … provide added value to help patients make informed decisions among treatment options,” said Benjamin Movsas, MD, Chair of Radiation Oncology and Interim Medical Director at the Henry Ford Cancer Institute, Michigan.

Benjamin Movsas, MD

The patient-reported outcome measures used to evaluate a planned subset of 402 trial participants (half from each treatment arm) included the Expanded Prostate Cancer Index Composite (EPIC), with urinary, bowel, hormonal, and sexual domains; Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue short form; Pittsburgh Sleep Quality Index; and Godin Leisure-Time Exercise Questionnaire for activity levels. Scores were calculated for each patient at the end of radiation therapy and at 6, 12, and 60 months from the start of radiation therapy. Completion rates for patient-reported outcomes at the end of radiation therapy and at 6, 12, and 60 months afterward were 96%, 89%, 86%, and 87%, respectively.

EPIC urinary and bowel scores decreased significantly at the end of radiation therapy in both arms, as expected, but no clinically meaningful differences between the two arms from baseline and between arms were observed in these domains over time. While greater deficits in hormonal and sexual domains were observed early on in the arm receiving short-course androgen-deprivation therapy plus radiation therapy compared with radiation alone (P < .0001), there were no clinically meaningful differences in these patient-reported outcome domains by 1 year after treatment (or 6 months after completion of the short-term hormones). These short-lived hormonal and sexual effects included symptoms such as hot flashes, decreased energy levels and libido, weight gain, and erectile dysfunction.

“Importantly, at 1 year, there were no clinically meaningful differences [in these domains],” Dr. Movsas said.

PROMIS-Fatigue scores increased from baseline in both treatment arms at the end of radiation therapy and were significantly (but not clinically meaningfully) higher in the combined-modality arm at the end of treatment. Fatigue scores were similar between the two arms at 6, 12, and 60 months. No clinically meaningful differences were observed between treatment arms at any time point in sleep quality or activity levels.

“Patients are indicating that the impact of hormones on their quality of life, including sexual and hormonal domains, was short-lived. This is very encouraging, as it comes directly from patients treated with or without the hormones. This quality-of-life information may be helpful to patients in making treatment decisions,” he noted. 

DISCLOSURE: Dr. Krauss has served on an advisory board for Sanofi. Dr. Movsas has received research support to his department from Varian Medical Systems, ViewRay, and Philips; and has been reimbursed for travel expenses from Varian Medical Systems.

REFERENCES

1. Krauss DJ, et al: Dose-escalated radiotherapy alone or in combination with short-term androgen suppression for intermediate-risk prostate cancer. 2021 ASTRO Annual Meeting. Abstract 1. Presented October 25, 2021.

2. Movsas B, et al: Dose-escalated radiation alone or in combination with short-term androgen suppression for intermediate risk prostate cancer. 2021 ASTRO Annual Meeting. Abstract 4. Presented October 24, 2021.