Stahlfeld, Charlotte N.

Abstract Background Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. Methods This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. Results Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node–only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. Conclusions Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

Abstract Purpose: Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody–drug conjugates (ADC). Experimental Design: TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2–positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2–targeting agents in a mouse xenograft model generated from prostate cancer cell lines. Results: We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti–TROP-2 agents in vivo. Conclusions: These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC.

5060 Background: Tumor-associated calcium signal transducer 2 (TROP-2, TACSTD2) is a transmembrane glycoprotein that is highly expressed in many epithelial cancers. Overexpression of TROP-2 is postulated to mediate cancer cell growth, invasion, and is associated with more aggressive disease. TROP-2 has emerged as a therapeutic target for antibody-drug conjugates in clinical trials including sacituzumab govitecan and DS-1062. Here, we evaluated the expression of TROP-2 in tumor biopsies and circulating tumor cells (CTCs) in men with metastatic castration resistant prostate cancer (mCRPC) to evaluate TROP-2 as a clinically relevant target. Methods: RNA-seq data from the SU2C-PCF database and PROMOTE clinical trial (NCT#01953640) was assessed for TACSTD2 and androgen receptor (AR) splice variant ( AR_V7/AR_V9) expression. Prostate cancer ChIP-seq data was analyzed to identify binding of the AR to the TROP-2 promoter. EpCAM and TROP-2 captured CTCs were isolated from patients with mCRPC using the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform and assessed for splice variant, neuroendocrine (NE), and AR-regulated gene signatures, in addition to CTC enumeration and TROP-2 protein expression. Results: TROP-2 expression was detectable in 90% of patients, in both bone and visceral metastatic biopsies (SUC2-PCF). Although TROP-2 low biopsies were infrequent (10%), 58% of these samples showed high levels of NE markers, as compared with 5% in all other patients. In the PROMOTE study, elevated TROP-2 gene expression was significantly higher in biopsies with high AR_V7 expression than in those with low (p = 0.04) or negative (p <.01) AR_V7 expression. ChIP-seq data demonstrated binding of AR at the TROP-2 promoter as well as at a potential enhancer site upstream, suggesting that TROP-2 expression can be regulated by AR activity. Splice variants and NE gene signatures were expressed in CTCs captured with both EpCAM and TROP-2, although markedly different gene expression profiles between EpCAM and TROP-2 CTCs were observed in a subset of patients with neuroendocrine prostate cancer. Detection of AR_V7 from TROP-2 CTCs corresponded to shorter overall survival in 20 patients with mCRPC. TROP-2 protein expression was identified on EpCAM captured CTCs, although patients exhibited a wide degree of both intra- and inter-patient heterogeneity. Conclusions: Our findings demonstrate that TROP-2 is highly expressed in mCRPC, and is reduced in a subset of patient tumors expressing neuroendocrine markers. In the PROMOTE clinical trial with abiraterone acetate, TROP-2 AR variant expression correlated with increased TROP-2 expression. Binding of the AR to the TROP-2 promoter and potential enhancer was observed in prostate cancer cell lines and biopsies. These results indicate TROP-2 is a high value a biomarker and therapeutic target mCRPC.