Validation of the Decipher Genomic Classifier in Patients receiving Salvage Radiotherapy without Hormone Therapy after Radical Prostatectomy – An Ancillary Study of the SAKK 09/10 Randomized Clinical Trial

The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase 3 trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy.
Patients and Methods

A clinical grade whole-transcriptome assay was performed on RP samples obtained from patients enrolled in SAKK 09/10, a phase 3 trial of 350 men with biochemical recurrence post-radical prostatectomy randomized to 64Gy vs. 70Gy without concurrent hormonal therapy or pelvic nodal radiotherapy (RT). A pre-specified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, post-radical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks.

The analytic cohort of 226 patients was representative of the overall trial, with median follow-up of 6.3 years (IQR 6.1-7.2). GC (high vs. low-intermediate) was independently associated with biochemical progression (subdistribution hazard ratio [sHR] 2.26 [95% CI 1.42-3.60], p<0.001), clinical progression (HR 2.29 [95% CI 1.32-3.98], p=0.003), and use of hormone therapy (sHR 2.99 [95% CI 1.55-5.76], p=0.001). GC high patients had 5-year freedom from biochemical progression of 45% vs. 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower vs. higher GC scores.

This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. This data confirms the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting.

Highlights
•  Decipher identifies patients at highest risk of progression who may require treatment intensification
•  Decipher defines subgroups associated with improved outcomes when treated with very early SRT compared to late SRT
•  Transcriptomic profiling can guide personalized management of SRT timing and the addition of systemic therapy

Pra AD, Ghadjar P, Hayoz S, Liu VYT, Spratt DE, Thompson DJS, Davicioni E, Huang HC, Zhao X, Liu Y, Schär C, Gut P, Plasswilm L, Hölscher T, Polat B, Hildebrandt G, Müller AC, Pollack A, Thalmann GN, Zwahlen D, Aebersold DM, Validation of the Decipher Genomic Classifier in Patients receiving Salvage Radiotherapy without Hormone Therapy after Radical Prostatectomy – An Ancillary Study of the SAKK 09/10 Randomized Clinical Trial, Annals of Oncology (2022), doi: https:// doi.org/10.1016/j.annonc.2022.05.007.
© 2022 Published by Elsevier Ltd on behalf of European Society for Medical Oncology.
Corresponding author:
Dr. Alan Dal Pra Department of Radiation Oncology University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center 1475 NW 12th Ave, Miami, FL 33136, United States of America +1 305 689 0608; +1 305 689 0930 (fax) 
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