|
|
|
|
|
|
|
PEER-TO-PEER CLINICAL CONVERSATIONS
|
|
|
|
|
|
|
Practical Approaches to Genetic Testing in Metastatic Hormone-Sensitive Prostate Cancer
|
|
Emmanuel Antonarakis, MD
|
| Emmanuel Antonarakis recommends germline and somatic testing for all metastatic prostate cancer patients. Dr. Antonarakis orders germline testing pre-emptively, reserving genetic counseling for pathogenic variants when first-degree relatives face 50% inheritance risk.
|
|
|
|
|
|
|
|
|
|
|
|
|
Genomic Associations with Phenotypic Heterogeneity in Advanced Prostate Cancer
|
|
Michael Haffner, MD, PhD
|
| Andrea Miyahira hosts Michael Haffner to discuss tumor heterogeneity patterns in lethal prostate cancer. Using University of Washington's rapid autopsy cohort, Dr. Haffner's team analyzed over 630 tumor samples from 52 patients with castration-resistant prostate cancer, applying a four-subtype molecular classification based on androgen receptor/luminal markers and neuroendocrine expression.
|
|
|
|
|
|
|
|
|
|
|
|
|
AR Degraders, T-Cell Engagers, and EZH2 Inhibitors in Prostate Cancer Pipeline
|
|
Maha Hussain, MD, FACP, FASCO
|
| Maha Hussain surveys emerging prostate cancer therapies across disease states. An AR degrader under investigation in a phase 3 study called rechARge showed a median PFS of 16.5 months in chemotherapy-naive mCRPC patients and approximately 5.5 months in those with prior chemotherapy.
|
|
|
|
|
|
|
|
|
|
|
|
| Tumor Suppressor Genes in Prostate Cancer – Currently Prognostic, but Soon to Be Predictive?
|
| Evan Yu, MD
|
| Alterations in the tumor suppressor genes PTEN, TP53, and RB1 define aggressive prostate cancer phenotypes and are well-established prognostic biomarkers, but they are not yet routinely used to guide therapy outside clinical trials. PTEN loss drives PI3K–AKT–mTOR activation and may sensitize to AKT inhibitors and possibly PARP inhibitors; TP53 mutations and RB1 loss accumulate with progression, with combined TP53/RB1 loss marking a highly aggressive, often AR-independent state linked to lineage plasticity and neuroendocrine features.
|
|
|
|
|
|
| Molecular Pathology of Rare Histologic Variants and Treatment-Resistant Lineages of Prostate Cancer - Beyond the Abstract
|
| Ryuta Watanabe, MD, PhD
|
| This review covers rare histologic variants and treatment-resistant lineages of prostate cancer that diverge from conventional acinar adenocarcinoma. Intraductal carcinoma (IDC-P) is a high-risk entity enriched for TP53, RB1, PTEN, and BRCA2 alterations and a hypoxic, immunologically cold microenvironment. Ductal adenocarcinoma is aggressive and often harbors DNA repair defects, while treatment-related neuroendocrine and double-negative prostate cancers are AR-independent, lineage-plastic states driven by TP53/RB1 loss, highlighting the need for integrated molecular and spatial pathology to guide therapy.
|
|
|
|
|
|
| Plasma Epigenomic Profiling Reveals Treatment-Emergent Squamous Transformation in Prostate Cancer - Beyond the Abstract
|
| Rashad Nawfal, MD, Karl Semaan, MD, MS, Jacob E. Berchuck, MD, and Sylvan C. Baca, MD, PhD
|
| This case report demonstrates that plasma epigenomic profiling using cell-free chromatin immunoprecipitation sequencing (cfChIP-seq) can non-invasively detect treatment-emergent squamous transformation in prostate cancer months before histologic confirmation. In a patient with mCRPC who developed squamous cell prostate cancer after Lutetium-PSMA therapy, cfChIP-seq profiling of H3K27ac and H3K4me3 histone modifications revealed dynamic activation of squamous-specific genes and regulatory regions 4 months prior to biopsy-proven diagnosis, with signal declining after initiation of squamous-directed chemoimmunotherapy.
|
|
|
|
|
|
|
|
|
|
|
BCL2 Drives Castration Resistance in Castration-Sensitive Prostate Cancer by Orchestrating Reciprocal Crosstalk Between Oncogenic Pathways - Beyond the Abstract
|
| Rahim Hirani, MS, and Goutam Chakraborty, PhD
|
| This study identifies BCL2 as an early, therapy-induced driver of castration resistance in prostate cancer. Androgen deprivation therapy and androgen receptor signaling inhibitors universally upregulate BCL2 in castration-sensitive disease, creating a reciprocal signaling loop among BCL2, AR, and PI3K/AKT that sustains tumor survival and accelerates progression to castration-resistant prostate cancer.
|
|
|
|
|
|
| Phase 1 Study of QLH12016, an Androgen Receptor PROTAC Degrader in Heavily Pretreated Patients with mCRPC: Safety, Tolerability, and Antitumor Activity
|
| Shun Zhang, PhD
|
| In this phase 1 study of the oral AR PROTAC degrader QLH12016 in 44 heavily pretreated mCRPC patients, the drug was safe and well tolerated with no dose-limiting toxicities, a manageable safety profile, and encouraging activity across doses. QLH12016 produced PSA30/PSA50 responses in 14 and 9 patients, respectively; among those with measurable disease, ORR was 23.5% and DCR 70.6%, with median radiographic PFS of 7.4 months overall and longer rPFS in AR ligand-binding domain wild-type versus mutant subgroups, supporting further development as monotherapy and in combinations.
|
|
|
|
|
|
|
|
|
|
|
