Authors:
 Peter H. J. Slootbeek*, Iris S.H. Kloots, Inge M. van Oort, Winald R. Gerritsen, Jack A. Schalken, Marjolijn Ligtenberg, Katrien Grunberg, Leonie I. Kroeze, Haiko J. Bloemendal, Niven Mehra
 
 
 Affiliations:
 Radboudumc
 
 
 Abstract Body:
 "Background
 Prostate cancer (PCa) is the second leading cancer related cause of death in men worldwide. Lethality particular occurs following diagnosis of metastatic castration-resistant PCa (mCRPC), with a median survival approximating 36 months. With mCRPC being molecular heterogeneous, identification of actionable targets, in a timely fashion, and matching to targeted and immunotherapies could impact patient (pt) outcome. This study describes the experiences with routine genetic profiling, and discussion of mCRPC pts in a molecular tumor board (MTB) at a tertiary referral center in the Netherlands. 
 Methods
 Pts with mCRPC underwent next-generation sequencing (NGS) of tumour tissue at the Radboudumc in the period between 1-1-2017 and 1-1-2020. Archived or fresh tumour material was targeted or whole-genome sequenced. The pathogenicity of all possibly consequential alterations was reassessed in the MTB. Pathogenic and likely pathogenic actionable alterations were matched to targeted agents in clinical trials such as the Drug Rediscovery Protocol (DRUP) trial with 14 collaborating pharmaceutical companies and 25 different treatments, or to compassionate use. As there was no access yet to specific PI3K-targets, PTEN-targeted advices were disregarded in results of this study.
 Results
 Out of the 277 molecularly profiled mCRPC pts, 215 (78%) were discussed in at least one MTB-meeting. At the time of initial MTB discussion, the median age was 68 years (interquartile range [IQR]: 62-73 years) and received two lines of therapy in CRPC setting. Median time from first CRCP therapy until initial discussion was 12 months (IQR: 1-28 months). An advice for a genetically-matched therapy outside of standard of care, was given to 102 patients (47%), of which 61 pts actually started with their advised therapy. Classes of agents most commonly matched to actionable alterations were PARP inhibitors (N=74), programmed death-(ligand) 1 inhibitors (N=21), tyrosine kinase inhibitors (N=19), monoclonal antibodies (N=5). Reason for a patient not initiating the advised cancer therapy was frequently deterioration of performance status. Those with an actionable target that initiated therapy showed a longer survival (median 18 vs. 6 months, P<0,001) compared to those that did not, with analyses not corrected for disbalance in patient characteristics. Retrospective assessment with today’s availability of targeted agents identified 170 (61%) patients with a potentially druggable aberration. The most commonly detected druggable alterations were in PTEN (28%) and BRCA2 (9%), with most common altered druggable pathways being PI3K (36%) and DNA damage repair (27%). 
 Conclusion
 Almost half of mCRPC pts had an actionable alteration with high proportion of pts initiating a proposed genetically-matched therapy in a tertiary referral center. PCa pts are underrepresented in MTBs and based on this data and available literature is unjustified. In conclusion, availability of NGS and discussion in an MTB broadens treatment allocation and trial inclusion, and crucial for moving precision oncology forward."
 
 
 Funding Acknowledgments:
 The study was funded by the Radboudumc, Nijmegen, the Netherlands. WGS was made available through the Hartwig Medical Foundation
 
 
 Corresponding Author Email:
 Peter.Slootbeek@radboudumc.nl
 
 
 Conflict of Interest:
 Niven Mehra: Advisory role (compensated and institutional): ‘Roche, MSD, BMS, Bayer, Astellas and Janssen’. Research support (institutional): ‘Astellas, Janssen, Pfizer, Roche and Sanofi’ Genzyme. Travel support: ‘Astellas, MSD’.

Role of routine referral to molecular tumor boards and their role in delivering precision medicine to patients with metastatic castration-resistant prostate cancer