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Urothelial carcinoma (UC) is characterized by expression of a plethora of cell surface antigens, thus offering opportunities for specific therapeutic targeting with use of antibody-drug conjugates (ADCs). ADCs are structured from two major constituents, a monoclonal antibody (mAb) against a specific target and a cytotoxic drug connected via a linker molecule. Several ADCs are developed against different UC surface markers, but the ones at most advanced stages of development include sacituzumab govitecan (IMMU-132), enfortumab vedotin (ASG-22CE/ASG-22ME), ASG-15ME for advanced UC, and oportuzumab monatox (VB4-845) for early UC. Several new targets are identified and utilized for novel or existing ADC testing. The most promising ones include human epidermal growth factor receptor 2 (HER2) and members of the fibroblast growth factor receptor axis (FGF/FGFR). Positive preclinical and early clinical results are reported in many cases, thus the next step involves further improving efficacy and reducing toxicity as well as testing combination strategies with approved agents.

Background: The immune contexture of cancers and the tumor-immune system interplay are becoming increasingly understood. Immunotherapy with checkpoint inhibitors is an established treatment for several cancer types, with PD-L1 immunohistochemical expression as a companion predictive biomarker in some tumors. Checkpoint blockade is not an established treatment for patients with advanced PC (castration-resistant or neuroendocrine); however, platinum compounds have shown activity. The aim of this study was to assess the impact of PD-L1 somatic alterations on clinical response to platinum-based chemotherapy in men with advanced PC. Methods: Records of advanced PC patients from our Precision Medicine cohort who were treated with platinum-containing chemotherapy with available tissue samples and information on known prognostic factors were reviewed. By whole-exome sequencing (WES) we assessed for presence of mutations and copy number alterations in CD274 gene (encoding PD-L1). Kaplan Meier curves, univariable and multivariable Cox regression analyses were used to predict time to PSA progression-free survival (PSA-PFS), radiographic progression-free (rPFS) and overall survival (OS) after platinum chemotherapy initiation. Results: Thirty-one men, median age 69 years (range 50-85), were studied. Eight patients (26%) were NEPC based on histologic features. Nineteen had visceral metastases (16 liver, 11 lung, 1 brain) and 25 had bone metastases. 26 patients received carboplatin, 8 received cisplatin (4 received both sequentially, with initial platinum used for this analysis). Most received platinum in combination with other drugs, most commonly paclitaxel (N=11) and etoposide (N=12). CD274 somatic alterations (mutations or/and copy number changes) were associated with a significantly longer rPFS (median rPFS: 8 months) compared to patients with wild-type PD-L1 (median rPFS: 4 months, P=0.022). PD-L1 alterations were less frequent in patients with bone metastases (2/22 vs 4/9, P=0.043). There was no significant difference in PSA-PFS or OS among patients with PD-L1 wild-type and mutated tumors. On multivariate analysis (adjusted for Gleason score, PSA, alkaline phosphatase, lactate dehydrogenase, hemoglobin, visceral metastases, performance status, use of opioids), PSA (P=0.049) and presence of visceral metastases (P=0.048) were independent prognostic indicators for OS. Conclusions: PD-L1 somatic alterations may confer sensitivity to platinum-based chemotherapy in men with advanced PC who receive platinum-based chemotherapy. Prospective validation studies in such patients are needed to confirm these findings. Citation Format: Panagiotis J. Vlachostergios, Aileen Lee, Charlene Thomas, Priyanka Patel, Amy L. Hackett, Naureen Rashid, Ana M. Molina, David M. Nanus, Himisha Beltran, Scott T. Tagawa. PD-L1 somatic alterations predict sensitivity of advanced prostate cancer patients to platinum-based chemotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B193.