ASTRO 2022: Optimal Duration of ADT with Definitive Radiotherapy for Prostate Cancer: An Individual Patient Data (IPD) Meta-Analysis from the International MARCAP Consortium

(UroToday.com) The 2022 American Society for Radiation Oncology (ASTRO) Annual Meeting held in San Antonio, TX between October 23rd and 26th, 2022 was host to a session that addressed studies aimed at improving outcomes for high-risk prostate cancer patients. Dr. Nicholas Zaorsky presented results of a MARCAP meta-analysis evaluating the optimal duration of ADT with definitive radiotherapy for prostate cancer patients.

 

Dr. Zaorsky noted that the ideal duration of concurrent ADT use in patients receiving radiation therapy is currently unknown. The treating physician must balance the improvement in prostate cancer-specific mortality in longer treatment regimens with the subsequent worsening of other-cause mortality rates., Furthermore, other challenges to determining the optimal ADT duration include the variable compliance rates with long-term ADT (<80% in some trials) and the variable ADT durations tested in randomized controlled trials. As such, the authors sought to determine the optimal duration of ADT for men with localized prostate cancer receiving radiotherapy.

 

The authors included individual patient data from 13 RCTs as demonstrated below:

ASTRO 2022 Zaorsky_0 

The authors utilized both the intention to teat analysis and treatment received ADT compliance durations, where data was available. The inverse probability of treatment weighting (IPTW) was performed, adjusting for age, PSA, Gleason score, clinical T-stage, radiotherapy dose, pelvic nodal radiotherapy, and mid-trial enrolment year. The primary endpoint was overall survival. Secondary endpoints included: prostate cancer-specific mortality, other-cause mortality, biochemical recurrence, and distant metastasis-free survival rates.

 

With regards to baseline patient characteristics, Dr. Zaorsky noted that all patients were intermediate (43%) or high risk (57%) patients. Of the 10,266 patients, almost two-thirds received 6 or less months of concurrent ADT.

 

ASTRO 2022 Zaorsky_1 

 

With regards to the primary endpoint of overall survival, adjusted analysis demonstrated that the duration of ADT use with the maximal benefit, in terms of overall survival, was seen with 19.3 months of ADT use. Notably, with longer ADT use, the overall survival benefit is attenuated, perhaps due to an increase in other-cause mortality, such as cardiac deaths.

 

ASTRO 2022 Zaorsky_2 

 

Not surprisingly, prolonged use of ADT was associated with continued improvement is distant metastasis-free and prostate cancer-specific mortality rates, as such outcomes do not directly account for the competing risk of other-cause mortality.

 

ASTRO 2022 Zaorsky_3 

 

 

When other-cause mortality was evaluated in patients receiving concurrent ADT (0 versus 28 months), use of ADT was associated with a 28% increased hazard of other-cause mortality (HR: 1.28, 95% CI: 1.09 – 1.50, p=0.0023).

 

Next, Dr. Zaorsky addressed whether there was an absolute incremental benefit for ADT prolongation per risk group, with respect to the outcome of 10-year distant metastasis rates. As individual patient risk increased from 1 intermediate risk factor to 2+, to NCCN high-risk, to STAMPEDE high risk, there appeared to be increased utility for ADT prolongation. As seen in the figure below, the number needed to treat (NNT) decreased with longer ADT use durations as the risk of metastasis increased in the individual patient risk groups. Dr. Zaorsky suggested that in patients with 2+ intermediate risk factors, 6 months of ADT may be sufficient for some. Conversely in the NCCN high risk group patients, the rates of 10-year DM were only 1.1% with 18 months of ADT. As such, do NCCN high-risk patients need 18 months of ADT. The NRG GU009 study is testing 12 months of ADT in this cohort of patients. Finally, there appeared to be a continuous benefit for ADT prolongation in STAMPEDE high risk patients, as has already been established in multiple previous trials.

 

Dr. Zaorsky concluded his presentation with the following take home messages:

  1. The optimal ADT duration in regards to overall survival is ~19 months when accounting for the majority of non-compliance data available with long-term ADT
    1. Optimal duration for cancer-specific endpoints (BCR, PCSM) is likely indefinite
    2. Longer durations of ADT appear to worsen other-cause mortality
    3. This analysis does not account for quality of life or baseline comorbidity status in determining optimal duration
  2. The absolute incremental benefit varies by baseline risk
    1. Optimal risk models should be utilized to better estimate absolute risk and potential benefit of various durations of ADT (STAR-CAP, Clinico-Genomic Risk Groups, ArteraAI, etc.)

 

Presented by: Nicholas G. Zaorsky, MD, MS, Vice Chair, Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2022 American Society of Radiation Oncology (ASTRO) Annual Hybrid Meeting, San Antonio, TX, Sat, Oct 22 – Wed, Oct 26, 2022.

 

 

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