Prostate Cancer Foundation

The 30th Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held at the Omni La Costa Resort in Carlsbad, CA, from October 26 to 28, 2023. A hybrid component was included for virtual attendees. The Annual PCF Scientific Retreat is a leading international scientific conference focused on pioneering, unpublished, and impactful studies across the spectrum of basic through clinical prostate cancer research, as well as research from related fields with significant potential for improving prostate cancer research and patient outcomes. The 2023 PCF Retreat concentrated on key areas of research, including: (i) the biology of cancer stem cells and prostate cancer lineage plasticity; (ii) mechanisms of treatment resistance; (iii) emerging AI applications in diagnostic medicine; (iv) analytical and computational biology approaches in cancer research; (v) the role of nerves in prostate cancer; (vi) the biology of prostate cancer bone metastases; (vii) the contribution of ancestry and genomics to prostate cancer disparities; (viii) prostate cancer 3D genomics; (ix) progress in new targets and treatments for prostate cancer; (x) the biology and translational applications of tumor extracellular vesicles; (xi) updates from PCF TACTICAL Award teams; (xii) novel platforms for small molecule molecular glues and binding inhibitors; and (xiii) diversity, equity and inclusionstrategies for advancing cancer care equity. This meeting report summarizes the presentations and discussions from the 2023 PCF Scientific Retreat. We hope that sharing this information will deepen our understanding of current and emerging research and drive future advancements in prostate cancer patient care.

215 Background: A missense-encoding germline polymorphism in the HSD3B1 gene has been shown to result in adrenal-permissive (c.1100 C, p.367 Thr) or adrenal-restrictive (c.1100 A, p.367 Asn) phenotypes with respect to androgen synthesis from adrenal precursors, and the adrenal-permissive variant is associated with inferior outcomes to hormonal therapies. However, the tumoral characteristics (somatic alteration landscape, transcriptome, immune-cell composition) of prostate cancers that arise in the context of these germline genotypes are unknown. Methods: We utilized the Caris Life Sciences (Phoenix, AZ) database to study the relationship between germline HSD3B1 c.1100 genotypes and somatic tumoral characteristics in 5,421 prostate cancer biopsies. Germline HSD3B1 status was inferred using variant allele frequencies (VAFs) derived from tumor DNA sequencing: c.1100C VAF of 0% defined the AA genotype, VAF of 40-60% defined the AC genotype, and VAF of 100% defined the CC genotype. Each HSD3B1 genotype was interrogated for its associated mutational landscape (by exome sequencing) and tumor transcriptome (by RNA-seq); immune-cell subsets were explored using the quanTIseq deconvolution algorithm. Results: The prevalence of the HSD3B1 c.1100 AA genotype (restrictive–homozygous) was 54.4%, AC (heterozygous) was 34.2%, and CC (permissive–homozygous) was 11.4%. Liver/lung metastases had the highest prevalence of the CC genotype (14.2%), while lymph node metastases had the lowest (10.9%). Among the AR-associated genes, compared to the AA genotype, the CC genotype had greater frequency of TMPRSS2-ERG fusions (35.5% vs 29.7%, P<0.01), AR-V7 (17.2% vs 14.7%, P=0.17), and mRNA expression of AR (median 124 vs 115 TPM, P=0.01), HOXB13 (37 vs 34 TPM, P=0.08) and KLK2 (490 vs 448 TPM, P=0.12); there were no associations with SPOP or FOXA1 mutations or expression. Outside of AR pathways, the MAPK activation signature was higher in the CC relative to the AA genotype (0.27 vs -0.04 MPAS, P=0.01). When examining immune-cell subsets and immunotherapy targets, the CC genotype unexpectedly showed higher CD276 ( B7-H3) expression (30 vs 27 TPM, P<0.01), higher dendritic cells ( P=0.02) and T-regs ( P=0.03), and lower neutrophils ( P=0.10) compared to the AA genotype. Conclusions: The homozygous adrenal-permissive HSD3B1 variant (c.1100 CC) is associated with distinct tumoral features characterized by elevated AR signaling and MAPK activation. It is also associated with a unique immune-cell regulatory landscape, with higher B7-H3 expression, increased intratumoral dendritic cells and decreased immunosuppressive neutrophils. This distinct molecular landscape of HSD3B1 c.1100 CC–associated prostate cancers warrants special therapeutic considerations, including possibly using B7-H3–targeted therapies.

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.

This cohort study examines the associations of multiple social risk factors with mortality risk among patients newly diagnosed with cancer in the US.

Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain. To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021. High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01). These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.