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Metastatic and high-risk localized prostate cancer respond to hormone therapy but outcomes vary. Following a pre-specified statistical plan, we used Cox models adjusted for clinical variables to test associations with survival of multi-gene expression-based classifiers from 781 patients randomized to androgen deprivation with or without abiraterone in the STAMPEDE trial. Decipher score was strongly prognostic (p-5) and identified clinically-relevant differences in absolute benefit, especially for localized cancers. In metastatic disease, classifiers of proliferation, PTEN or TP53 loss and treatment-persistent cells were prognostic. In localized disease, androgen receptor activity was protective whilst interferon signaling (that strongly associated with tumor lymphocyte infiltration) was detrimental. Post-Operative Radiation-Therapy Outcomes Score was prognostic in localized but not metastatic disease (interaction p=0.0001) suggesting the impact of tumor biology on clinical outcome is context-dependent on metastatic state. Transcriptome-wide testing has clinical utility for advanced prostate cancer and identified worse outcomes for localized cancers with tumor-promoting inflammation.

Purpose To develop nomograms that predict the detection of clinically significant prostate cancer at diagnostic biopsy based on multiparametric prostate MRI (mpMRI), serum biomarkers, and patient clinicodemographic features. Materials and Methods Nomograms were developed from a cohort of biopsy-naïve men presenting to our 11-hospital system with a PSA of 2-20ng/mL who underwent pre-biopsy mpMRI from March 2018-June 2021 (n = 1494). The outcomes were the presence of clinically significant and high-grade prostate cancer (defined as ≥ GG2 [Grade Group 2] and ≥ GG3 prostate cancer, respectively). Using significant variables on multivariable logistic regression, individual nomograms were developed for men with PSA, % free PSA, or prostate health index (PHI) when available. The nomograms were both internally validated and evaluated in an independent cohort of 366 men presenting to our hospital system from July 2021-February 2022. Results 1031 of 1494 men (69%) underwent biopsy after initial evaluation with mpMRI, 493 (47.8%) of whom were found to have ≥ GG2 PCa, and 271 (26.3%) were found to have ≥ GG3 PCa. Age, race, highest PIRADS score, prostate health index (PHI) when available, % free PSA when available, and PSA density were significant predictors of ≥ GG2 and ≥ GG3 PCa on multivariable analysis and were used for nomogram generation. Accuracy of nomograms in both the training cohort and independent cohort were high, with areas under the curves (AUC) of ≥ 0.885 in the training cohort and ≥ 0.896 in the independent validation cohort. In our independent validation cohort, our model for ≥ GG2 prostate cancer with PHI saved 39.1% of biopsies (143/366) while only missing 0.8% of csPCa (1/124) with a biopsy threshold of 20% probability of csPCa. Conclusions Here we developed nomograms combining serum testing and mpMRI to help clinicians risk stratify patients with elevated PSA of 2-20ng/mL who are being considered for biopsy. Our nomograms are available at https://rossnm1.shinyapps.io/MynMRIskCalculator/ to aid with biopsy decisions.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel's discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.

INTRODUCTION AND OBJECTIVES Checkpoint blockade targeting PD-1 or CTLA-4 works by fundamentally different mechanisms (with CTLA-4 inhibition acting at secondary lymphoid organs for activation of naïve T cells, and PD-1 interactions being regulated at the tissue / tumor level to effect T cells already exposed to antigen). The efficacy and toxicity profile of anti-PD-1/PD-L1 and anti-CTLA-4 therapies also differ greatly, with PD-1/PD-L1 therapy having relatively low toxicity. In both humans and animal models, PD-1 directed therapy for prostate cancer had not been shown to be efficacious. Here we investigate combinatorial strategies to augment the effect of PD-1 therapy in a mouse model. METHODS Immuno-competent FVB mice were bilaterally implanted with Myc-CAP cells to form isogenic grafts. Four weeks after tumor introduction tumors were treated with either 10mg/kg of anti-PD-1 therapy alone or in combination with cryotherapy to one tumor. In a separate experiment, the same paradigm was followed but mice were pre-treated with 25mg/kg of Degarelix after palpable tumors were seen (followed by cryotherapy and anti-PD1). Finally, we performed a similar set of experiments but in the presence or absence of pretreatment with epigenetic modifiers (5-azaccytidine and Entinostat). RESULTS Therapy with anti-PD1 or anti-PD1 combined with cryotherapy marginally and insignificantly increased mouse survival and time to logarithmic tumor growth. Addition of neoadjuvant androgen deprivation significantly increased median survival (from 40 days to 60 days, p

INTRODUCTION AND OBJECTIVES B7-H3 (CD276), part of the B7 superfamily, has been shown to play an immunomodulatory role, however its regulation, receptor and mechanism of action remain unclear. Protein levels of B7-H3 have been previously shown to relate to prostate cancer outcomes and currently, humanized monoclonal antibodies are being developed for clinical use (MGA271, Macrogenics). Here we use genomic expression data to examine the relationship of B7-H3 to prostate cancer outcomes, and molecular subtypes and explore its relationship to other gene sets and pathways. METHODS Prostatectomy tissue from 905 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Kruskal-Wallis tests were used to identify significant associations of B7-H3 expression with clinico-pathologic variables, and survival analysis was used to evaluate the prognostic value of B7-H3. Pearson’s correlation analyses were also performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy of promoter regions was derived in silico from chromosomal immune- precipitation (ChIP) data. RESULTS B7-H3 expression was positively associated with Gleason score (p < 0.01) and tumor stage (p < 0.01). High B7-H3 expression also correlated with the development of metastasis and prostate cancer specific mortality (HR of 3.4 and 2.4 respectively, p < 0.05 for both), but this was not significant on multi-variable analysis. B7-H3 was positively associated with ERG+ disease (n = 670, r = 0.85, p < 0.05) and AR expression (n = 670, r = 0.46, p < 0.001). B7-H3 was found to be one of the most correlated genes with AR (95th percentile) and ChIP analysis revealed androgen dependent AR binding upstream of B7-H3. Gene set enrichment analysis demonstrated a positive correlation with androgen signaling and a negative correlation with the defensins reactome (FDR

Context Prostate biopsy (PB) represents the gold standard method to confirm the presence of cancer. In addition to traditional random or systematic approaches, a magnetic resonance imaging (MRI)–guided technique has been introduced recently. Objective To perform a systematic review of complications after transrectal ultrasound (TRUS)–guided, transperineal, and MRI-guided PB. Evidence acquisition We performed a systematic literature search of Web of Science, Embase, and Scopus databases up to October 2015, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Complications and mortality following random, systematic, and image-guided PBs were reviewed. Eighty-five references were included. Evidence synthesis The most frequent complication after PB was minor and self-limiting bleeding (hematuria and hematospermia), regardless of the biopsy approach. Occurrence of rectal bleeding was comparable for traditional TRUS-guided and image-guided PBs. Almost 25% of patients experienced lower urinary tract symptoms, but only a few had urinary retention, with higher rates after a transperineal approach. Temporary erectile dysfunction was not negligible, with a return to baseline after 1–6 mo. The incidence of infective complications is increasing, with higher rates among men with medical comorbidities and older age. Transperineal and in-bore MRI–targeted biopsy may reduce the risk of severe infectious complications. Mortality after PB is uncommon, regardless of biopsy technique. Conclusions Complications after PB are frequent but often self-limiting. The incidence of hospitalization due to severe infections is continuously increasing. The patient's general health status, risk factors, and likelihood of antimicrobial resistance should be carefully appraised before scheduling a PB. Patient summary We reviewed the variety and incidence of complications after prostate biopsy. Even if frequent, complications seldom represent a problem for the patient. The most troublesome complications are infections. To minimize this risk, the patient's medical condition should be carefully evaluated before biopsy.