Meta-Analysis Finds Adding ADT to EBRT Extends Survival in Localized Prostate Cancer

William C. Jackson, MD

External beam radiotherapy (EBRT) plus androgen deprivation therapy (ADT) showed superior overall survival (OS) compared with EBRT plus a brachytherapy boost (BT) in men with intermediate- and high-risk prostate cancer, according to findings from a network meta-analysis that were published in the Journal of Clinical Oncology.

Study investigators pooled data from 9 randomized trials. Six trials compared EBRT with or without ADT (n = 4663), and 3 studies compared EBRT with or without BT (n = 718) in this patient population. Results showed that the addition of ADT to EBRT improved OS (HR, 0.71; 95% CI, 0.62-0.81), whereas adding BT to EBRT did not lead to a significant improvement in OS (HR, 1.03; 95% CI, 0.78-1.36). In the network meta-analysis, EBRT plus ADT showed a significant improvement in OS versus EBRT plus BT (HR, 0.68; 95% CI, 0.52-0.89). Additionally, Bayesian modeling demonstrated an 88% probability that EBRT plus ADT resulted in superior OS compared with EBRT plus BT.

“In our analysis of men with intermediate- or high-risk prostate cancer, the addition of ADT to EBRT seems to improve survival, whereas the addition of a brachytherapy boost did not, and this remained true on meta-analysis,” lead study author William C. Jackson, MD, of University of Michigan, and co-investigators wrote. “Our findings demonstrate that there is a high probability that EBRT plus ADT provides superior OS compared with EBRT plus a brachytherapy boost in men with intermediate- and high-risk prostate cancer. Our study suggests that ADT should not be omitted on the basis of available evidence in men with intermediate- or high-risk prostate cancer receiving EBRT plus a brachytherapy boost.”

Each trial had published data on biochemical recurrence-free survival (bRFS) and OS between January 1980 and June 2018.

The data that were compiled included the years the trial accrued, median follow-up, patient age, National Comprehensive Cancer Network (NCCN) risk group, clinical T stage, pretreatment prostate-specific antigen (PSA), Gleason score, duration of ADT if administered, and HRs with 95% confidence intervals for bRFS and OS.

The median follow-up of the trials that assessed EBRT with or without ADT was 114 months versus 110.3 months in those that assessed EBRT with or without BT.

Patients had a median age of 70.1 and 67.8 years, respectively.

In the trials that assessed EBRT with or without ADT, 15% of patients had low-risk disease, 42% had intermediate-risk disease, and 41% had high-risk disease. In the trials that assessed EBRT with or without BT, 1% of patients had low-risk disease, 34% had intermediate-risk disease, and 63% had high-risk disease.

The majority of patients (78%) in the EBRT/ADT trials had clinical T1 to T2 prostate cancer and 22% had T3 prostate cancer. Similarly, 70% of patients in the EBRT/BT trials had T1 to T2 prostate cancer, and 30% had T3 disease.

Gleason scores varied between arms. In the EBRT/ADT trials, 50% of patients had a Gleason score of 6, 34% had a score of 7, and 14% had scores between 8 and 10. In the EBRT/BT trials, Gleason scores were 19%, 47%, and 29%, respectively.

The median pretreatment PSA level was 14.6 ng/mL in the patients who received EBRT with or without ADT versus 16.0 ng/mL in those who received EBRT with or without BT.

In the meta-analysis, the Cochran’s Q test for heterogeneity revealed that EBRT plus ADT was not significant versus EBRT alone, after adjusting for ADT duration. Additionally, EBRT plus BT was not significant versus EBRT alone prior to adjusting for ADT duration (Cochran’s Q = 2.61; P = .3).

Using the calculated HR of 0.68, the 10-year cumulative incidence of overall mortality was 28% for EBRT plus ADT compared with 41% for EBRT plus BT.

“Given the estimated magnitude of the OS benefit of EBRT plus ADT compared with EBRT plus a brachytherapy boost, we estimated the number of men that would be required to be randomly assigned between these 2 treatments to have 80% power to detect an OS benefit of this magnitude in an attempt to inform future clinical trial design,” Jackson and co-investigators wrote. “Assuming an α of 0.05, an estimated 832 men would need to be randomly assigned to have 80% power to demonstrate a statistically significant difference in OS between these two treatment modalities, assuming a 20% event rate.”

Bayesian modeling further revealed that EBRT alone resulted in a 27% probability of superior OS compared with 30% and 90% for EBRT plus BT and EBRT plus ADT, respectively. These data, which were determined using surface under the cumulative ranking curve, demonstrated that ERBT plus ADT had an 87% probability of leading to superior OS compared with EBRT alone and EBRT plus BT.

“Our findings suggest that the addition of ADT provides a greater oncologic benefit than a brachytherapy boost,” Jackson and co-investigators wrote. “Thus, if a brachytherapy boost is to be used for intermediate- or high-risk disease, our data suggest that the addition of ADT is required to prevent inferior survival compared with EBRT with ADT alone. On the basis of our findings, there is currently insufficient evidence to support the omission of ADT in men with intermediate- or high-risk prostate cancer treated with any form of definitive radiation therapy, including brachytherapy.”

Notably, these findings contrast other retrospective and observational studies which suggest that adding ADT to EBRT does not result in a survival benefit for patients. Instead, the literature suggests that omitting ADT and giving concurrent EBRT plus BT can spare patients ADT or shorten the duration of ADT.

“Our data question the validity of this practice and suggest that the use of EBRT plus ADT provides a high probability of superior OS in comparison with EBRT plus a brachytherapy boost without ADT,” Jackson and co-investigators wrote.

Limitations of this meta-analysis include limited sample sizes from the randomized trials, the inability to control for the radiation dose patients received, the inability to compare the treatment-related toxicity between EBRT plus ADT and EBRT plus BT, and the inability to assess the impact of ADT or BT on distant metastases.

“Randomized trials are needed if the omission of ADT is to be recommended with EBRT and a brachytherapy boost. Future trials comparing ADT and brachytherapy boost should include patient-reported quality of life as a secondary outcome,” concluded Jackson and co-investigators.

Reference:

Jackson WC, Hartman HE, Dess RT, et al. Addition of androgen-deprivation therapy or brachytherapy boost to external beam radiotherapy for localized prostate cancer: a network meta-analysis of randomized trials [published online ahead of print May 12, 2020]. J Clin Oncol. doi:10.1200/JCO.19.03217