Long-term androgen deprivation may improve survival in prostate cancer

1. In a phase III, open-labelled trial of over 340 patients with localized prostate cancer treated with high-dose radiation, long-term androgen deprivation increased biochemical, overall, and metastasis-free survival compared to short-term treatment.

2. The survival benefits were significant for patients with high-risk prostate cancer and less pronounced in intermediate-risk prostate cancer.

Evidence Rating Level: 1 (Excellent)

Study Rundown: A number of large randomized trials have demonstrated that androgen-deprivation therapy (ADT) with concurrent radiation therapy (RT) increases survival compared to RT alone in patients with high-risk and intermediate-risk prostate cancer. However, due to the severe adverse effects of ADT (e.g. depression, metabolic syndrome, and osteoporosis), the optimal length of androgen suppression remains unclear. The purpose of this phase III randomized controlled trial was to compare long-term ADT to short-term treatment in men with localized intermediate or high-risk prostate cancer concurrently receiving modern, high-dose RT. Over 340 prostate cancer patients were randomized to either receive 4 months of ADT with concurrent RT in the short-term arm, or the same with an additional 24 months of ADT in the long-term arm. After a median follow-up time of 63 months, the authors demonstrated that patients randomized to long-term ADT demonstrated a significantly higher rate of 5-year biochemical, metastasis-free, and overall, survival. The survival benefits were more pronounced in patients with high-risk prostate cancer and not as significant in the subgroup of patients with intermediate-risk disease. The results of this trial support the use of long-term ADT with RT in patients with high risk disease. However, although adverse cardiovascular events were reported, rates of depression, gynecomastia, and osteoporosis—which are common quality of life metrics adversely associated with ADT were not reported. Furthermore, additional prospective trials are required to clarify the magnitude of survival benefit in long-term ADT in patients with intermediate risk-prostate cancer.

Click to read the study in The Lancet Oncology

Click to read an accompanying editorial in The Lancet Oncology

Relevant Reading: Androgen Suppression and Radiation vs Radiation Alone for Prostate Cancer: A Randomized Trial

In-Depth [randomized controlled trial]: This was a phase III, open-label, multicenter trial of long- and short-term ADT in localized prostate cancer patients. 355 patients with localized intermediate or advanced prostate cancer were recruited from ten academic hospitals in Spain. Overall, 178 and 177 men were randomly assigned to short-term and long-term ADT with RT, respectively. Patient randomization were matched in terms of patient demographic as well as tumor-related and treatment characteristics. All patients received conformal RT to 76-82 Grey followed by 4 months of goserelin. The long-term ADT cohort then received an additional 24 months of a luteinizing-hormone releasing hormone analogue. At 5-years of follow-up, biochemical disease-free survival (defined as a PSA rise of no more than 2ng/uL over the nadir value) in the high-risk disease subgroup was increased in the long-term ADT compared to short-term ADT (88% vs 76%; HR: 1.91; 95% CI: 0.97-3.77; p=0.054). However, biochemical disease-free survival in the intermediate-risk disease subgroup was equivocal (88% vs 92%; HR 1.82; 95% CI, 0.76-4.33; p=0.174). Similarly, overall survival was improved for high-risk patients treated with long-term ADT compared to short-term ADT (96% vs 82%; HR 3.34; 95% CI, 1.26-9.32; p=0.015), but not for intermediate-risk patients (94% vs 91%; HR 1.67; 95% CI, 0.61-4.60; p=0.318). Metastasis-free survival was also improved for high-risk patients treated with long-term ADT compared to short-term ADT (94% vs 79%; HR 2.27; 95% CI, 1.04-5.01; p=0.041), but not for intermediate-risk patients (94% vs 89%; HR 2.14; 95% CI, 0.81-5.66; p=0.124). Notably, 20% of patients in the long-term ADT group suffered from cardiovascular events compared to 14% in the short-term ADT group.

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