mCRPC

This review paper highlights the transformative role of PSMA-targeted diagnostics and therapy in prostate cancer management, particularly focusing on 177 Lu-PSMA-617, approved by the FDA and EMA for metastatic castration-resistant prostate cancer (mCRPC) patients post-chemotherapy and ARPI treatment. Originating from the VISION trial's success, this paper navigates the current radioligand therapy (RLT) indications, emphasizing practical patient selection, planning, and treatment execution. It critically examines Lu-PSMA's comparative effectiveness against cabazitaxel and Ra-223, addressing decision-making dilemmas for mCRPC treatments...

Biallelic loss of cyclin-dependent kinase 12 ( CDK12 ) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development-either alone, or in the context of other genetic alterations-and whether CDK12 -mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate...

BACKGROUND: Androgen deprivation therapy (ADT) intensification (ADTi) (i.e., ADT with androgen receptor pathway inhibitor or docetaxel, or both) has significantly improved survival outcomes of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of prior ADTi in the mHSPC setting on the disease presentation and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) is not well characterized. In this study, our objective was to compare the disease characteristics and survival outcomes of patients with new mCRPC with respect to receipt of intensified or nonintensified ADT in the mHSPC setting...

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. The primary endpoint was differences in CD4+ and CD8+ T-cell infiltrate in 8-week versus baseline bone metastasis biopsies; secondary endpoints were safety, radiographic progression-free survival (rPFS), and overall survival (OS)...

BACKGROUND: There are limitations in treating advanced prostate cancer (PC), especially castration-resistant (CR) cases, in renal transplant recipients (RTRs). We describe the case of RTR with metastatic CRPC (mCRPC) treated with docetaxel. CASE REPORT: A 60-year-old man with end-stage renal disease due to autosomal-dominant polycystic kidney disease (ADPKD) underwent living-related kidney transplantation. A year later, he was diagnosed with PC (prostate-specific antigen level: 998 ng/mL)...

PURPOSE: It is estimated that the PTEN tumor suppressor gene is functionally lost in 40%-50% of patients with metastatic castration-resistant prostate cancer (mCRPC). There is limited information on the prognostic significance of PTEN status identified with genomic testing. This real-world cohort study assessed PTEN as a genetic biomarker using data from US-based oncology practices. METHODS: This retrospective real-world cohort study used a deidentified US-based metastatic prostate cancer clinicogenomic database linked to longitudinal clinical data derived from electronic health records...

Aryl hydrocarbon receptor (AhR) is a transcription factor that is primarily known as an intracellular sensor of environmental pollution. After five decades, the list of synthetic and toxic chemicals that activate AhR signaling has been extended to include a number of endogenous compounds produced by various types of cells via their metabolic activity. AhR signaling is active from the very beginning of embryonal development throughout the life cycle and participates in numerous biological processes such as control of cell proliferation and differentiation, metabolism of aromatic compounds of endogenous and exogenous origin, tissue regeneration and stratification, immune system development and polarization, control of stemness potential, and homeostasis maintenance...

BACKGROUND: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. METHODS: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430)...

BACKGROUND: There are no large head-to-head phase 3 clinical trials comparing overall survival (OS) for abiraterone and enzalutamide. This study used Medicare claims data to compare OS in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) who initiated abiraterone or enzalutamide. METHODS: This retrospective analysis of the Medicare database (2009-2020) included adult men with ≥1 claim for prostate cancer, metastatic diagnosis, and no prior chemotherapy or novel hormone therapy who initiated first-line (1L) abiraterone or enzalutamide in the index period (September 10, 2014 to May 31, 2017)...

Prostate Cancer (PCa) easily progress to metastatic Castration-Resistant Prostate Cancer (mCRPC) that remains a significant cause of cancer-related death. Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Proteolysis-targeting chimaera (PROTAC) technology based on Hydrophobic Tagging (HyT) represents an intriguing strategy to regulate the function of therapeutically androgen receptor proteins. In the present study, we have designed, synthesized, and evaluated a series of PROTAC-HyT AR degraders using AR antagonists, RU59063, which were connected with adamantane-based hydrophobic moieties by different alkyl chains...

PURPOSE: Majority of patients with metastatic prostate cancer who receive androgen deprivation therapy and androgen receptor (AR) signaling inhibitors progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI-resistance. This single-arm phase I trial assessed safety and pharmacokinetic feasibility of combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in metastatic castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in refractory mCRPC patients enrolled using 6+3 design...

BACKGROUND: Physiological PSMA expression in the cells of the proximal renal tubules and consecutive radiopharmaceutical binding and retention could potentially lead to radioligand-therapy-induced nephrotoxicity. Thus, patients with metastatic castration-resistant prostate cancer undergo 99m Tc-Mercaptoacetyltriglycine (MAG3) renal scintigraphy to assess kidney function and to exclude renal obstruction as part of their workup for PSMA-targeted radioligand therapy (RLT). 99m Tc-MAG-3 renal scintigraphy often requires an additional visit to the nuclear medicine department and patients spend 30-90 min in the department, which is inconvenient and takes up camera time...

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (177 Lu)-PSMA-617 is the first radioligand therapy to be approved in Canada for use in patients with metastatic castration-resistant prostate cancer (mCRPC). As this treatment represents a new therapeutic class, guidance regarding how to integrate it into clinical practice is needed. This article aims to review the evidence from prospective phase 2 and 3 clinical trials and meta-analyses of observational studies on the use of 177 Lu-PSMA-617 in prostate cancer and discuss how Canadian clinicians might best apply these data in practice...

BACKGROUND: Men with metastatic castration-resistant prostate cancer (mCRPC) have an incurable disease. Along with prolonging life, symptom management is one of the main goals with treatment. This is also important from a palliative care perspective where the life prolonging outcomes should be balanced with quality of life (QoL) in this late phase. It is also essential in symptom management to view different dimensions of symptoms, for example how severe or distressing symptoms are, to support best QoL...

FOXA1 is a pioneer transcription factor that is frequently mutated in prostate, breast, bladder, and salivary gland malignancies. Indeed, metastatic castration-resistant prostate cancer (mCRPC) commonly harbour FOXA1 mutations with a prevalence of 35%. However, despite the frequent recurrence of FOXA1 mutations in prostate cancer, the mechanisms by which FOXA1 variants drive its oncogenic effects are still unclear. Semaphorin 3C (SEMA3C) is a secreted autocrine growth factor that drives growth and treatment resistance of prostate and other cancers and is known to be regulated by both AR and FOXA1...

INTRODUCTION: Anti-osteoclast treatment with denosumab or zoledronate is known to effectively reduce the need for radiotherapy to bone and other skeletal-related events (SREs) in patients with metastatic castration-resistant prostate cancer (mCRPC). In this study, we analyze primary versus secondary initiation of bone-targeting agents (BTAs) relative to first palliative bone radiotherapy in patients dying of mCRPC. METHODS: Provincial administrative databases from Ontario, Canada identified patients with prostate cancer (2007-2018, n = 98 646) who received continuous androgen deprivation therapy (n = 29 453), died of prostate cancer (2013-2018, n = 3864), and received life-prolonging therapy for mCRPC (n = 1850)...

Intermittent docetaxel therapy (IDT) is rarely used nowadays as a treatment option for men with metastatic castration-resistant prostate cancer (mCRPC) because of the widespread availability of androgen receptor axis-targeted therapy, which is less toxic. Therefore, there is limited information available on whether IDT has a clinical benefit in the treatment of men with mCRPC. This report describes the case of a 66-year-old man with a diagnosis of cT2N1M0 prostate cancer who underwent neoadjuvant combined androgen blockade and whole-pelvis radiation therapy...

STUDY AIM: ModraDoc006, an oral formulation of docetaxel, is co-administered with the cytochrome P450-3A4 and P-glycoprotein inhibitor, ritonavir (r): ModraDoc006/r. The preliminary efficacy and safety of oral ModraDoc006/r was evaluated in a global randomized phase II trial and compared to the current standard chemotherapy regimen of intravenous (i.v.) docetaxel and prednisone. METHODS: 103 mCRPC patients, chemotherapy-naïve with/without abiraterone and/or enzalutamide pretreated, with adequate organ function and evaluable disease per RECIST v1...

OBJECTIVE: Radium-223 is a first alpha-emitting radionuclide treatment for metastatic castration-resistant prostate cancer (mCRPC) patients with bone metastases. Although the spread-based bone scan index (BSI) and novel index of the intensity-based two-dimensional total bone uptake (2D-TBU) from bone scintigraphy may provide useful input in radium-223 treatment, they have not been evaluated in detail yet. This study aimed to fill this gap by evaluating BSI and 2D-TBU in patients treated with radium-223...

BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC). METHODS: Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy...