Summary The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a novel mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.

The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process.

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Advanced prostate adenocarcinomas enriched in stem-cell features, as well as variant androgen receptor (AR)-negative neuroendocrine (NE)/small-cell prostate cancers are difficult to treat, and account for up to 30% of prostate cancer-related deaths every year. While existing therapies for prostate cancer such as androgen deprivation therapy (ADT), destroy the bulk of the AR-positive cells within the tumor, eradicating this population eventually leads to castration-resistance, owing to the continued survival of AR-/lo stem-like cells. In this study, we identified a critical nexus between p38MAPK signaling, and the transcription factor Forkhead Box Protein C2 (FOXC2) known to promote cancer stem-cells and metastasis. We demonstrate that prostate cancer cells that are insensitive to ADT, as well as high-grade/NE prostate tumors, are characterized by elevated FOXC2, and that targeting FOXC2 using a well-tolerated p38 inhibitor restores epithelial attributes and ADT-sensitivity, and reduces the shedding of circulating tumor cells in vivo with significant shrinkage in the tumor mass. This study thus specifies a tangible mechanism to target the AR-/lo population of prostate cancer cells with stem-cell properties.

LBA4517 Background: A preplanned interim analysis of COU-AA-301 showed that AA, a selective androgen biosynthesis (CYP17) inhibitor, significantly improves OS in mCRPC. This is the first phase III study to prospectively assess CTC as a surrogate biomarker as part of a regulatory qualification process, here using updated OS data. Methods: 1,195 patients (pts) with mCRPC post docetaxel were randomized 2:1 to AA (1 g QD) + P (5 mg BID) (n = 797) or placebo + P (n = 398). CTCs (screening and baseline [BL]; post BL at weeks 4, 8 and 12) were enumerated (cells/7.5 mL) at MSKCC and The ICR using CellSearch and analyzed with other prognostic covariates as dichotomous and continuous variables using updated OS data at 775 events (prior to crossover from placebo to AA). CTC (as part of a biomarker panel - LDH, PSA, Hg, AlkPhos) was examined as a surrogate for OS. Multivariate (Cox model) analyses were conducted. Results: At median follow up (FU) of 20.2 mo, the difference in median OS between the 2 groups improved from 3.9 to 4.6 mo (AA 15.8 mo vs placebo 11.2 mo; HR = 0.74; p < .0001). CTC counts were evaluated in 972 pts at screening and BL, 838 at 4 wks, 783 at 8 wks and 723 pts at 12 wks. High concordance between screening and BL values was observed (r = 0.83). CTC conversion using standard definition for unfavorable (CTC ≥ 5) and favorable (CTC < 5) counts was predictive of OS as early as 4 wks after treatment and its inclusion significantly reduced the treatment effect at all post-treatment time points (HR: from 0.74 to 0.97). A reduced model incorporating CTCs and LDH was developed. Conclusions: The magnitude of the treatment effect of AA on OS increased with longer FU. Using standard definition of CTC conversion, the biomarker panel demonstrated a level of surrogacy for OS by correlating well with survival and in a model-adjusted analysis dramatically attenuating the treatment effect. BL CTCs and CTC conversion, along with LDH, were key predictors of OS. Future trials will further evaluate the CTC-based surrogate developed from COU-AA-301.