6 - Evaluation of PAM50 Molecular Subtypes in Post-Prostatectomy Salvage Radiotherapy: An NRG Oncology-RTOG 0534 Analysis
Presenter(s)
P. T. Tran1, M. Johnson2, J. Proudfoot3, E. Davicioni3, A. Dal Pra4, J. Simko5, O. Mohamad6, S. G. Zhao7, C. Maher8, A. G. Martin9, A. G. Balogh Jr10, H. Lukka11, J. M. Michalski12, M. Duclos13, H. Campbell14, R. J. Lee15, K. S. Roof16, T. G. Karrison17, P. L. Nguyen18, and A. Pollack4; 1Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 2Veracyte, San Diego, CA, 3Veracyte, Inc., South San Francisco, CA, 4Department of Radiation Oncology, University of Miami/Sylvester Comprehensive Cancer Center, Miami, FL, 5UCSF, San Franscico, CA, 6American University of Beirut, Beirut, TX, Lebanon, 7UT MD Anderson Cancer Center, Houston, TX, 8Washington University, St. Louis, MO, 9CHU de Québec – Université Laval, Québec, QC, Canada, 10University of Calgary, Calgary, AB, Canada, 11Juravinski Cancer Centre, Hamilton, ON, Canada, 12Washington University School of Medicine, St. Louis, MO, 13McGill University Health Centre, Montreal, QC, Canada, 14Dalhousie University, Halifax, NS, Canada, 15Intermountain Medical Center, Murray, UT, 16SERO, Huntersville, SC, 17NRG Oncology SDMC, Philadelphia, PA, 18Mass General Brigham Cancer Institute, Boston, MA
Purpose/Objective(s): The three-arm randomized NRG/RTOG 0534 SPPORT trial (n=1792) examined treatment intensification on the outcome of men treated with salvage radiotherapy (SRT) for a detectable PSA. The arms were prostate bed RT (PBRT) alone (Arm 1), PBRT + short term androgen deprivation therapy (STADT; Arm 2), and PBRT + STADT + pelvic lymph node RT (PLNRT; Arm 3). With treatment intensification in Arms 2 and 3, there were significant incremental gains in the freedom from progression (FFP) endpoint, but not metastasis free-survival (MFS) with 8 yr median follow-up; although metastatic events were reduced with intensification. The PAM50 genomic classifier categorizes prostate cancers into luminal A (LumA), luminal B (LumB) and basal cell subtypes with LumB tumors found to benefit most from postoperative ADT. We hypothesized that PAM50 LumB tumors are a predictive biomarker of response to postoperative ADT.
Materials/Methods: Prospectively collected prostatectomy tissue was profiled for clinical-grade whole-transcriptomes from samples passing quality control to assign PAM50 LumB (vs not-LumB) subtype. This National Clinical Trials Network (NCTN)-approved integrated biomarker pre-specified statistical plan included the secondary objective of validating the predictive nature of PAM50 LumB for ADT use. The protocol FFP endpoint included biochemical (nadir+2 ng/mL) failure, clinical failure, or death from any cause. MFS included distant metastasis or death from any cause. Multivariable (MVA) Cox models adjusted for age, treatment arm, race, seminal vesicle involvement, Gleason grade group (1-3 vs 4-5), pre-SRT PSA and stage.
Results: PAM50 subtype scores were obtained for 709 patients (median follow-up 7.9 yr), with 215 in Arm 1, 247 in Arm 2, and 247 in Arm 3. The arms were balanced for key covariates. There were 226 FFP and 136 MFS events. On MVA, the PAM50 LumB subtype was prognostic for FFP (HR 1.33, 95% CI 1.02-1.74, p = 0.03) and MFS (HR 1.52, 95% CI 1.08-2.14, p = 0.02). Adding STADT ± PLNRT to PBRT resulted in a greater benefit in patients with PAM50 LumB subtype than non-LumB subtype, with a 5-yr FFP absolute benefit of 31% vs. 10% in PAM50 LumB vs non-LumB patients, respectively, with a significant treatment interaction (p-int = 0.01). In patients treated with STADT ± PLNRT + PBRT, the 10-yr MFS absolute benefit was 20% vs -3% in PAM50 LumB v non-LumB patients, respectively, with a significant treatment interaction (p-int = 0.05).
Conclusion: In this randomized phase 3 trial, PAM50 LumB subtype was both prognostic and predictive of benefit from postoperative ADT-based treatment intensification. LumB tumors have increased proliferative and androgen receptor signaling, providing a mechanistic rationale for their preferential response to ADT. These findings support molecular subtyping to personalize salvage radiotherapy strategies for localized prostate cancer.