JAMA Oncology: High-dose radiotherapy for high-risk prostate cancer, what is the optimal duration of ADT?

The optimal/minimum duration of androgen deprivation therapy (ADT) in high-dose radiotherapy for high-risk prostate cancer remains controversial
.

A recent study published in the journal JAMA ONCOLOGY suggests that high-dose external radiation therapy (EBRT) ± brachytherapy (BT) is significantly associated with optimal duration of ADT
.

The optimal duration of ADT therapy for high-risk prostate cancer remains to be confirmed
.

Radiation therapy and long-term ADT are effective standard regimens for the treatment of high-risk prostate cancer
.

Based on the results of four clinical studies, the current NCCN guidelines recommend: for high-risk prostate cancer, 18-36 months of EBRT is recommended; for patients receiving EBRT combined with brachytherapy (EBRT + BT), the NCCN guidelines believe that 12 months is more appropriate (Based on the ASCENDE-RT trial)
.

However, this treatment duration has not been confirmed by randomized controlled studies
.

Due to adverse events, many patients in the real world are receiving ADT for shorter than expected durations.
Based on this situation and the lack of duration data to guide EBRT+BT treatment decisions, the researchers conducted this study to confirm Optimal ADT duration threshold associated with improved distant metastasis-free survival (DMFS) in high-risk prostate cancer patients
.

Study Methods This study included 3 cohorts: 1 retrospective cohort and 2 randomized controlled study cohorts
.

This retrospective cohort included patients with NCCN-defined high-risk prostate cancer (physical examination-determined clinical T stage 3 or 4, initial PSA level >20 ng/mL, Gleason class 4 or 5) at 16 referral centers, from 2000 to Patients treated with high-dose EBRT or EBRT+BT during 2014
.

Two RCT cohorts included 384 (1051 total) patients in the RADAR study and 91 (352 total) patients in the DART study, respectively
.

The RADAR study included patients with clinical T2b4 or cT2a disease and Gleason grade 2 or higher disease, and all high-risk (as defined by the NCCN) patients receiving 74Gy EBRT or EBRT+BT were included in this study
.

The DART study included patients with clinically staged T1c-T3b localized prostate cancer, classified by the NCCN as intermediate to high risk, and with a PSA level below 100 ng/mL
.

This study included high-risk patients who received 28 months of ADT
.

The primary endpoint was DMFS, which has been shown to be a surrogate study endpoint for overall survival (OS), and the secondary outcome was OS
.

Main Results A total of 2935 patients were included in the study, with a median age of 69 years
.

The median duration of EBRT and EBRT+BT patients in the retrospective cohort was 6.
4 and 7.
1 years, respectively
.

When the cohort was divided into three groups (ADT treatment duration <6, 6-18 months, and >18 months), the study found a correlation between the type of treatment and the effect of ADT duration on DMFS and OS
.

Further analysis found no association between 6-18 months of ADT treatment with DMFS (HR=0.
90) or OS (HR=0.
90) in patients receiving EBRT compared with patients <6 months
.

However, compared with <6 months of ADT treatment (DMFS HR=0.
44, P < 0.
001; OS HR=0.
45, P < 0.
001) and 6 to 18 months of ADT treatment (DMFS HR=0.
49, P < 0.
001; OS HR=0.
50 , P < 0.
001), 18 months or more of ADT treatment was associated with improved DMFS and improved OS
.

In contrast, in patients receiving EBRT + BT, duration of ADT 6-18 months was associated with improved DMFS (HR=0.
34, P<0.
001) and OS ( HR=0.
30, P<0.
001) correlation
.

ADT for 18 months or more was associated with improved DMFS and improved OS compared with <6 months of treatment (DMFS HR=0.
42, P<0.
001; OS HR=0.
43, P<0.
001)
.

However, compared with 6-18 months of treatment, 18 months or more of ADT treatment was not associated with improved DMFS (HR=1.
23, P=0.
17), but was significantly associated with worse OS (HR=1.
44, P=0.
03)
.

Adjusted DMFS curves were further analyzed to quantify the continuous nonlinear relationship between ADT duration and DMFS
.

As shown in Figure 1 below, the optimal duration of ADT was 26.
3 months and 12 months for patients receiving EBRT and EBRT+BT, respectively
.

Figure 1 Optimal ADT Duration in Patients Receiving EBRT±BT Retrospective Cohort vs.
RADAR Cohort Based on analysis of retrospective cohort groups (EBRT and EBRT+BT), investigators hypothesized that extending ADT from 6 to 18 months would improve DMFS in EBRT+BT (non-EBRT) patients
.

We further analyzed data from the RADAR study receiving 74 Gy EBRT or EBRT+RT to assess the association of 18- and 6-month ADT with DMFS and OS
.

Median follow-up was 10 and 11 years in the EBRT group (n = 181) and the EBRT+BT group (Table 1)
.

In all patients, ADT at 18 and 6 months was not associated with improvement in DMFS (HR=0.
75, P=0.
07) or OS (HR=0.
75)
.

Subgroup analysis showed that in patients receiving EBRT, prolonged ADT did not significantly improve DMFS (HR=1.
01) or OS (HR=0.
88)
.

In patients receiving EBRT+BT, prolonged ADT significantly improved DMFS (HR=0.
56, P=0.
01), but not OS outcomes (HR=0.
61, P=0.
06)
.

Table 1 RADAR and DART cohorts Patient and treatment characteristics Based on retrospective data, the investigators further hypothesized that ADT durations beyond 18 months would improve DMFS and OS in patients receiving high-dose EBRT
.

The investigators further performed a meta-analysis of data on patients who received 28 months of ADT in the DART trial versus 6 or 18 months in the RADAR trial
.

The median follow-up of the 91 patients in DART was 5.
4 years, patient characteristics are shown in Table 1, and adjusted survival curves are shown in Figure 2
.

Figure 2 Correlation of ADT duration with DMFS and OS Compared with 6 months of ADT, patients who received 28 months of ADT had improved DMFS and OS (DMFS HR=0.
37, P=0.
01; OS HR= 0.
30, P = 0.
03)
.

Compared with 18 months, receiving ADT at 28 months was also associated with improved DMFS (HR=0.
37, P=0.
01), and OS (HR=0.
34, P=0.
049)
.

Among patients receiving high-dose EBRT, the 5-year DMFS rates of patients receiving 28 months, 18 months, and 6 months of ADT were 93.
5%, 76.
7%, and 79.
6%, respectively
.

The 5-year OS rates of patients who received 28 months, 18 months, and 6 months of ADT were 96%, 87.
3%, and 90.
6%, respectively
.

CONCLUSIONS: For patients receiving high-dose EBRT, results from all 3 cohorts suggest that the optimal duration of ADT may be more than 18 months
.

Based on a retrospective analysis, for patients receiving EBRT+BT, the optimal duration of ADT may be <18 months
.

Investigators will conduct further studies to elucidate whether biomarkers help to select optimal ADT duration
.

Currently, meta-analyses from individual studies can provide guidance on optimal ADT duration
.

References Kishan AU, Steigler A, Denham JW, et al.
Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts .
JAMA Oncol.
Published online January 20, 2022.
doi:10.
1001/jamaoncol.
2021.
6871Review: XY Typesetting: XY Execution: LR