1103 - Genomic Predictors of Response to Metastasis Directed Therapy with or without Androgen Deprivation Therapy

P. Sutera¹, K. Van der Eecken², Y. Song³, A. C. Shetty⁴, A. Hakansson⁵, E. Davicioni⁶, S. Verbeke⁷, J. Van Dorpe⁸, V. Fonteyne⁹, B. DeLaere¹⁰, L. Hathout¹¹, R. D. Ennis¹¹, S. K. Jabbour¹², Z. H. Rana¹³, J. K. Molitoris¹³, A. P. Kiess¹⁴, D. Song¹, P. T. Tran¹⁵, P. Ost⁹, and M. P. Deek¹²; ¹Johns Hopkins University School of Medicine, Baltimore, MD, ²Ghent University, Ghent, Belgium, ³Department of Radiation Oncology, Division of Translational Radiation Sciences, University of Maryland Baltimore, School of Medicine,, Baltimore, MD, ⁴University of Maryland, Baltimore, MD, ⁵Veracyte, San Diego, CA, ⁶Veracyte Inc., San Diego, CA, ⁷Department of Pathology, Ghent University Hospital, Ghent, Ghent, Belgium, ⁸Department of Pathology, Ghent University Hospital, Ghent, Belgium, ⁹Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium, ¹⁰Department of Human Structure and Repair Ghent University, Ghent, Belgium, ¹¹Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, ¹²Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, New Brunswick, NJ, ¹³Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, ¹⁴Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, ¹⁵Johns Hopkins University, School of Medicine, Baltimore, MD

Purpose/Objective(s): Oligometastatic castration-sensitive prostate cancer (omCSPC) is a state of limited metastatic disease that may behave more akin to locoregional rather than systemic disease. Several randomized studies have demonstrated metastasis-directed therapy (MDT) alone improves progression-free survival (PFS) over observation, but androgen deprivation therapy (ADT) represents a standard of care for metastatic CSPC. How to best integrate combinations of MDT and ADT remain unknown. Here we attempt to evaluate whether a high-risk (HiRi) mutational signature can provide discriminative information regarding the added benefit of ADT to MDT. Materials/

Methods: We performed a multi-institutional retrospective analysis of patients with omCSPC who underwent DNA panel sequencing treated with SABR with or without a defined course of ADT. Our primary endpoints included time to biochemical progression (ttBP) and distant metastasis free survival (DMFS) calculated from the end of treatment. Patients were classified according to the presence of a HiRi mutational signature defined as pathogenic alterations in either TP53, BRCA1/2, ATM, and Rb1. Survival analysis was performed using the Kaplan Meier method, stratified by treatment type or HiRi mutation status, and compared using the log-rank test. Interaction terms were calculated for endpoints of interest. All analyses were conducted using R.
Results: 144 patients were included (91 treated with MDT alone and 53 with MDT + ADT). Median ADT length was 6 months (range, 1 – 24.3 months). The use of concurrent ADT was associated with improved median ttBP of 23.3 months (95% CI, 18 months – not reached) vs 13.9 months (95% CI, 11 – 17.2 months, p = 0.03) and DMFS of 25.8 months (95% CI, 21.4 months – NR) vs 19 months (95% CI, 14.7 – 26.3 months, p = 0.05). In patients with a HiRi mutation (n=45), the addition of ADT was associated with significantly longer median ttBP of 23.3 months (95% CI, 20.9 months – NR) vs 8.8 months (95% CI, 6.8 – 12.1 months, p = <0.001) but not in patients without a HiRi mutation 18.4 months (95% CI, 16.8 – NR) vs 17.2 months (95% CI, 14.1 – 26.6 months, p = 0.48). Concurrent ADT was similarly associated with improved DMFS in patients with a HiRi mutation with median of 25.8 months (95% CI, 21.4 months – NR) vs 10.7 months (95% CI 5.6 – 19.0 months, p = 0.003) but not patients without a HiRi mutation with median NR (95% CI, 18 months – NR) vs 24.2 months (95% CI, 17.1 – 30.8 months, p = 0.31). The p-interaction value was significant for ttBP (0.02) but not DMFS (0.24).
Conclusion: The addition of ADT to MDT improves outcomes in unselected patients with omCSPC however appears to provide the greatest benefit to patients with a genetic alteration in TP53, BRCA1/2, ATM, or Rb1. These results may be used to provide predicative information for treatment intensification in omCSPC and should be validated in a prospective randomized setting.