Dose-escalated RT plus androgen suppression yields mixed outcomes in prostate cancer

Combining dose-escalated radiotherapy with short-term androgen deprivation (STAD) significantly improved PSA failure, metastases, and cancer-related death rates in men with intermediate-risk prostate cancer; however, a similar benefit was not observed with overall survival (OS), according to findings from the phase 3 trial RTOG 0815 trial shared during the 2021 ASTRO Annual Meeting.1

“Patients with intermediate-risk prostate cancer we know benefit from both escalation of radiotherapy dose as well as from the addition of androgen suppression. Technically, we still don’t know if we need both,” Daniel Krauss, MD, of the Rose Cancer Treatment Center in Royal Oak, Michigan, said during a presentation of the data. “Previous results have been confounded by heterogenous inclusions criteria that have frequently included high-risk in addition to intermediate-risk patients and noncontemporary radiotherapy techniques.”

The trial aimed to determine if addition of STAD, defined as 6 months of total androgen suppression with a luteinizing hormone-releasing hormone agonist and an antiandrogen, would result in OS improvement in patients with intermediate-risk prostate cancer who were being treated with definitive, dose-escalated radiotherapy.

Eligibility criteria included nonmetastatic, intermediate-risk prostate cancer defined as the presence of 1 or more of the following factors: biopsy with a Gleason score of 7, pretreatment PSA level above 10 ng/mL and up to 20 ng/mL, or clinical stage T2b-T2c disease. Patients positive for all 3 baselines factors who had more than 50% of biopsy cores positive were not eligible for treatment. Stratification was based on number of risk features, comorbidity status, and radiotherapy modality.

Patients (N = 1538) were randomized to dose-escalated radiotherapy alone—which consisted of external beam radiation therapy (EBRT) at 79.2 Gy, EBRT plus a low-dose rate brachytherapy boost, or EBRT plus a high-dose rate brachytherapy boost—or with STAD. The primary end point was OS designed to detect a 3% improvement at 5 years with a 1-side significance level of 0.025 and 85% power, which translates to a 34% reduction in the annual death rate (HR, 0.66). Secondary end points included biochemical failure, local failure, distant metastases, prostate cancer death, non-prostate cancer death, and initiation of salvage therapy.

Patient characteristics were well balanced between the 2 arms with a median patient age of 68 (interquartile range [IQR], 63-72 years), most being White (75%), and having a Zubrod performance status of 0 or 1 (99.9%). Two-thirds of patients each (67%) had 1 intermediate risk factor and an ACE-27 score of 2 or lower. Radiotherapy modality in most cases (89%) was EBRT alone. Baseline PSA was 8.1 ng/mL (range, 5.1-10.6 ng/mL) on average, most patients (92%) had a Gleason score of 7, and nonpalpable T1 disease occurred in the majority of cases (63%).

In all evaluable patients (n = 1492), the median follow-up was 6.2 years. The only factor associated with an increased risk of acute adverse effects (AEs) was being treated in the radiotherapy plus STAD arm (odds ratio [OR], 8.7; 95% CI, 6.85-11.11; P <.001).

“This is largely driven by the known and anticipated [adverse] effects of endocrine therapy for prostate cancer, [such as] endocrine, sexual and reproductive, metabolic/laboratory domains,” Krauss said. “There was a slight increased risk of experiencing a cardiac adverse event [1% vs 0.4%] but the overall rate was low and there was no difference in the rates of [gastrointestinal or genitourinary] adverse events based on whether or not patients received androgen deprivation.”

Of note, Krauss said there was no increased rate of late adverse events associated with androgen deprivation.

Five-year rates of OS were 90% for patients treated with radiotherapy alone versus 91% for those receiving radiotherapy plus STAD. At 8 years, corresponding rates were 79% and 84% with further follow-up failing to show a statistically significant difference in outcomes (P = .22).

In terms of PSA failure, rates were higher for patients on radiotherapy alone at 5 years at 14% vs 8% for those in the radiotherapy/androgen deprivation arm; at 8 years, those rates were 21% and 10% (P <.001). Five- and 8-year rates of distant metastasis in the radiotherapy alone arm were 3.1% and 4.3%, respectively, vs 0.6% and 1.0% (P <.001).

Initiation of salvage therapy occurred in 6.1% of those in the radiotherapy alone arm at 5 years compared with 4.2% with both modalities. At 8-years the corresponding rates of initiation of salvage therapy were 9.8% and 5.3%, respectively (P = .025).

Prostate cancer–specific mortality at 5 and 8 years was 0.9% and 1.6%, respectively, in the radiotherapy alone arm; in the androgen deprivation arm, only 1 event was noted overall (P = .007). No difference was noted for non-prostate cancer–specific mortality (P = .5).

The investigators looked to stratification factors to try and determine which patients were driving differences in PSA failure and distant metastases rates. They determined that all but a small group of patients with a Gleason score of 2 – 6 (8.24%) benefited from the addition of STAD by both outcome measures.

“There was no difference in the patient-reported outcomes in the EPIC urinary or bowel domains, so the administration of this hormonal therapy comes at the cost of approximately 12 months of detriment in the hormone and sexual function domains that resolve with further follow-up,” Krauss said.

Reference

1. Krauss DJ, Karrison TG, Martinez AA, et al. Dose escalated radiotherapy alone or in combination with short-term androgen suppression for intermediate risk prostate cancer: outcomes from the NRG Oncology/RTOG 0815 randomized trial. Int J Radia Oncol Biol Phys. 2021;111(suppl 3):S1. doi:10.1016/j.ijrobp.2021.07.039