In intermediate-risk prostate cancer, the benefit of androgen-deprivation therapy (ADT) combined with dose-escalated radiotherapy (RT) has been unclear. Several randomized trials have investigated the benefit of adding ADT to definitive RT in men with localized prostate cancer, as well as the benefit of prolonging ADT duration (neoadjuvant, adjuvant). However, the aggregate benefits of these interventions are poorly quantified. Thus, the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was formed to quantify the effects of various treatment intensification strategies. These strategies included adding ADT to RT, extending neoadjuvant ADT before RT, or prolonging adjuvant ADT after RT completion.

With an extensive systematic literature search, the MARCAP Consortium identified 12 high-quality trials with data from nearly 11,000 patients and a median follow-up of 11.4 years that evaluated the use or prolongation of ADT in men with localized prostate cancer treated with definitive RT. Importantly, the authors had access to the individual patient data in each of the 12 trials. Based on these data, they conducted a meta-analysis, and the results were published recently. To evaluate the addition of ADT to RT, they analyzed six trials, which included a total of 5136 patients, with a median follow-up of 12.9 years. The results showed that adding ADT to RT led to a significant improvement in metastasis-free survival (hazard ratio [HR], 0.83; P < 0.0001), corresponding to a 10-year absolute benefit of 8.6%. In addition, the use of ADT also significantly improved biochemical recurrence, distant metastases, and overall survival (OS). Next, the authors evaluated neoadjuvant ADT extension (from 3-4 months to 6-9 months) based on data from three randomized trials that included a total of 2213 patients, with a median follow-up of 10.3 years. This analysis indicated that neoadjuvant ADT extension was not associated with any improvements in metastasis-free survival (HR, 0.95; P = 0.50), biochemical recurrence, or OS. Finally, they evaluated adjuvant ADT prolongation in four randomized trials that included a total of 3774 patients, with a median follow-up of 10.9 years. They found that prolonging adjuvant ADT (from 4-6 months to up to 18-28 months) significantly improved metastasis-free survival (HR, 0.84; P < 0.0001), corresponding to a 10-year absolute benefit of 7.7%. Furthermore, adjuvant ADT prolongation significantly improved OS, biochemical recurrence, and distant metastasis. Of note, the RT dose, patient age or National Comprehensive Cancer Network risk group did not significantly impact the treatment effects of each intensification strategy.

In their conclusions, the MARCAP authors highlighted: “Our findings provide the strongest evidence to date for the routine recommendation of the addition of ADT to radiotherapy for men with intermediate-risk and high-risk prostate cancer, regardless of radiotherapy dose. The findings also suggest that prolonging the adjuvant component of ADT offers a significant benefit, regardless of radiotherapy dose, in men with intermediate-risk and high-risk disease—although the absolute benefit is greater in men with high-risk disease.” They recommend shared decision-making in these cases and note that the incorporation of biomarkers will be crucial for tailored recommendations for ADT duration. In addition, the authors added that neoadjuvant ADT extension “offers no clear benefit” and thus should not be routinely recommended.

Reference:
Kishan AU, et al. Lancet Oncol. 2022 Jan 17. [Online ahead of print]