Digital Pathology-based Artificial Intelligence Biomarker Validation in Metastatic Prostate Cancer.

Background And Objective: Owing to the expansion of treatment options for metastatic hormone-sensitive prostate cancer (mHSPC) and an appreciation of clinical subgroups with differential prognosis and treatment responses, prognostic and predictive biomarkers are needed to personalize care in this setting. Our aim was to evaluate a multimodal artificial intelligence (MMAI) biomarker for prognostic ability in mHSPC.

Methods: We used data from the phase 3 CHAARTED trial; 456/790 patients with mHSPC had evaluable digital histopathology images and requisite clinical variables to generate MMAI scores for inclusion in our analysis.

Association of serum steroids with survival in metastatic hormone-sensitive prostate cancer.

The CHAARTED study showed that adding docetaxel (Doc) to androgen deprivation therapy (ADT) in men initiating treatment for metastatic hormone sensitive prostate cancer (mHSPC) prolongs survival, particularly in high-volume disease. Androgens drive both mHSPC and metastatic castration resistant prostate cancer (mCRPC). Lower nadir serum testosterone (T) concentrations are associated with better outcomes in men treated with ADT for biochemical relapse, while higher androgens at mCRPC are associated with better prognosis and increased benefit from abiraterone.

Molecular Hallmarks of Prostate-specific Membrane Antigen in Treatment-naïve Prostate Cancer.

Background And Objective: We characterized tumor prostate-specific membrane antigen (PSMA) levels as a reflection of cancer biology and treatment sensitivities for treatment-naïve prostate cancer.

Methods: We first correlated PSMA positron emission tomography (PET) maximum standardized uptake values (SUVmax) in primary prostate cancer with tumor FOLH1 (PSMA RNA abundance) to establish RNA as a proxy (n = 55). We then discovered and validated molecular pathways associated with PSMA RNA levels in two large primary tumor cohorts.

Circulating Tumor DNA Assessment for Treatment Monitoring Adds Value to PSA in Metastatic Castration-Resistant Prostate Cancer.

Purpose: Enzalutamide after abiraterone progression is commonly used in metastatic castration-resistant prostate cancer despite a low rate of clinical benefit. Analyzing IMbassador250, a phase III trial assessing enzalutamide with or without atezolizumab after abiraterone, we hypothesized that baseline and early changes in circulating tumor DNA (ctDNA) tumor fraction (TF) may identify patients more likely to exhibit survival benefit from enzalutamide.

Experimental Design: ctDNA was quantified from plasma samples using a tissue-agnostic assay without buffy coat sequencing.

Insulin resistance during androgen deprivation therapy in men with prostate cancer.

Background: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear.

Methods: The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42).

Spatial transcriptomics in cancer research and potential clinical impact: a narrative review.

Spatial transcriptomics (ST) provides novel insights into the tumor microenvironment (TME). ST allows the quantification and illustration of gene expression profiles in the spatial context of tissues, including both the cancer cells and the microenvironment in which they are found. In cancer research, ST has already provided novel insights into cancer metastasis, prognosis, and immunotherapy responsiveness.

Refining Risk Stratification of High-risk and Locoregional Prostate Cancer: A Pooled Analysis of Randomized Trials.

Background And Objective: Radiotherapy (RT) and long-term androgen deprivation therapy (ltADT; 18-36 mo) is a standard of care in the treatment of high-risk localized/locoregional prostate cancer (HRLPC). We evaluated the outcomes in patients treated with RT + ltADT to identify which patients have poorer prognosis with standard therapy.

Methods: Individual patient data from patients with HRLPC (as defined by any of the following three risk factors [RFs] in the context of cN0 disease-Gleason score ≥8, cT3-4, and prostate-specific antigen [PSA] >20 ng/ml, or cN1 disease) treated with RT and ltADT in randomized controlled trials collated by the Intermediate Clinical Endpoints in Cancer of the Prostate group.

Challenges and Opportunities in Establishing Appropriate Intermediate Endpoints Reflecting Patient Benefit: A Roadmap for Research and Clinical Application in Nonmetastatic Prostate Cancer.

Defining meaningful endpoints for research of early-stage high-risk prostate cancer is challenging, with established measures such as overall survival and metastasis-free survival facing limitations related to feasibility and adequate reflection of patient relevance. Developing endpoints must cater to diverse perspectives across scientific, clinical, regulatory, and patient viewpoints. Endpoints such as pathological complete response, no evidence of disease, and prevention of prostate-specific antigen relapse may reflect patient benefit by accounting for diagnostic and treatment burdens.

Patient-reported Quality of Life and Survival Outcomes in Prostate Cancer: Analysis of the ECOG-ACRIN E3805 Chemohormonal Androgen Ablation Randomized Trial (CHAARTED).

Background: Chemohormonal therapy with androgen deprivation therapy and docetaxel (ADT + D) improves overall survival (OS) and quality of life (QOL) at 12 mo versus androgen deprivation therapy (ADT) alone in men with metastatic hormone-sensitive prostate cancer (mHSPC). However, the prognostic role of QOL is unknown in this population.

Objective: To study the relationship between QOL, disease characteristics, and OS in men with mHSPC.

Precision medicine for prostate cancer: An international perspective.

Greater personalization of cancer medicine continues to shape therapy development and patient selection accordingly. The treatment of prostate cancer has evolved considerably since the discovery of androgen deprivation therapy. The comprehensive profiling of the prostate cancer genome has mapped the targetable molecular landscape of the disease and identified opportunities for the implementation of novel and combination therapies.

Multi-institutional Analysis of Metastasis-directed Therapy with or Without Androgen Deprivation Therapy in Oligometastatic Castration-sensitive Prostate Cancer.

Background: Metastasis-directed therapy (MDT) is increasingly being used in oligometastatic castration-sensitive prostate cancer (omCSPC). However, it is currently unclear how to optimally integrate MDT with the standard of care of systemic hormonal therapy.

Objective: To report long-term outcomes of MDT alone versus MDT and a defined course of androgen deprivation therapy (ADT) in omCSPC.

Impact of teratoma on survival probabilities of patients with metastatic non-seminomatous germ cell cancer: Results from the IGCCCG Update Consortium.

Aims: To resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT).

Patients And Methods: Using the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method.

Randomized Phase II Study Evaluating the Addition of Pembrolizumab to Radium-223 in Metastatic Castration-resistant Prostate Cancer.

The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC.

Soil-specific outcomes in the OECD 216 Nitrogen Transformation Test.

The Organisation for Economic Co-operation and Development (OECD) 216 test guideline investigates the impact of agrochemicals on soil nitrogen transformation. After an evaluation of 465 OECD 216 studies, we describe two distinct yet contrasting outcomes in control nontreated samples that are possible in this testing framework, which we term the "rise" (consistent increases in nitrate concentrations throughout the test period) and "dip" (initial decline in nitrate concentration between Days 0-7, followed by a net-generation of nitrate across Days 7-28) responses. We raise significant concerns that control data from standardized, internationally recognized test guidelines can demonstrate such dissimilar patterns.

The influence of soil organic matter content and substance lipophilicity on the toxicity of pesticides to the earthworm Eisenia andrei.

To account for potential differences in bioavailability (and toxicity) due to different soil organic matter (OM) contents in natural and artificial soil (AS), in the current European environmental risk assessment (ERA) a correction factor (CF) of 2 is applied to toxicity endpoints for so called lipophilic pesticides (i.e. log K > 2) generated from laboratory tests with soil invertebrates.

Radiographic Progression-Free Survival and Clinical Progression-Free Survival as Potential Surrogates for Overall Survival in Men With Metastatic Hormone-Sensitive Prostate Cancer.

Purpose: Despite major increases in the longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC), most men still die of prostate cancer. Phase III trials assessing new therapies in mHSPC with overall survival (OS) as the primary end point will take approximately a decade to complete. We investigated whether radiographic progression-free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite future phase III clinical trials.