Androgen Receptor Pathway Inhibitors Research Articles

Current Systemic Therapy in Men with Metastatic Castration-Sensitive Prostate Cancer.

This review aims to explore the evolving landscape of treatments available for metastatic castration-sensitive prostate cancer (mCSPC) patients. In less than a decade, evidence was chronologically provided that (1) systemic treatment intensification with docetaxel improves outcomes, including survival, in men with mCSPC, (2) then that these outcomes are also improved when a second-generation androgen receptor pathway inhibitor (ARPI) is combined with androgen deprivation therapy (ADT), and (3) using a "triplet systemic therapy," which consists in the combination of ADT, an ARPI and docetaxel, further improves outcomes, including survival. Radiotherapy to the prostate combined with ADT alone is now recommended in men with low-volume mCSPC. Combining prostate radiotherapy and intensified systemic treatment including abiraterone may be synergistic as suggested in the PEACE-1 trial. Also, the role of metastases-directed local therapies (mostly stereotactic radiotherapy) is currently being assessed in phase 3 trials. Finally, the integration of biomarkers (e.g. BRCA2 gene alterations, PTEN loss, PSMA expression) for decision making is not currently established, though trials are also currently underway. Importantly, most evidence currently available was obtained in men with de novo metastases, while for those with metastatic relapse after definitive local treatment, the role of treatment intensification is less well established. Treatment intensification is nowadays the standard of care for patients with de novo mCSPC as it leads to outcomes improvement, including survival, and the standard of care is evolving almost on a yearly basis.

Genomic profiling and clinical utility of circulating tumor DNA in metastatic prostate cancer: SCRUM-Japan MONSTAR SCREEN project

BackgroundCirculating tumor DNA (ctDNA) testing has emerged as a novel tool for cancer precision medicine. This study investigated the genomic profiling and clinical utility of ctDNA in metastatic prostate cancer.MethodsThis is a nation-wide prospective observational study. Patients treated with systemic treatment for metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) were included. ctDNA was analyzed using FoundationOne Liquid®CDx at enrollment. In a subset of patients, ctDNA after disease progression and tissue prior to the initiation of treatment were examined using FoundationOne Liquid®CDx and FoundationOne®CDx, respectively.ResultsThe frequency of AR alterations and homologous recombination repair (HRR) defect was higher in mCRPC compared with mCSPC. Tumor mutational burden was correlated between tissue and ctDNA at pre-treatment, as well as ctDNA between at pre-treatment and at post-treatment. Patients with HRR defect were associated with shorter time to castration resistance in androgen deprivation therapy/combined androgen blockade, but not in androgen receptor pathway inhibitor, compared with patients without HRR defect in mCSPC. Time to treatment failure in patients with AR amplification or AR mutation was shorter compared with patients without AR alterations in mCRPC.ConclusionsThis study revealed valuable findings for the clinical care of metastatic prostate cancer. Especially, predictive factors such as HRR defect in mCSPC should be validated in the future.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Combined therapy targeting AR and EZH2 curbs castration-resistant prostate cancer enhancing anti-tumor T-cell response.

Aim: Castration-resistant prostate cancer (CRPC) eventually becomes resistant to androgen receptor pathway inhibitors like enzalutamide. Immunotherapy also fails in CRPC. We propose a new approach to simultaneously revert enzalutamide resistance and rewire anti-tumor immunity. Methods: We investigated in vitro and in subcutaneous and spontaneous mouse models the effects of combining enzalutamide and GSK-126, a drug inhibiting the epigenetic modulator EZH2. Results: Enzalutamide and GSK-126 synergized to reduce CRPC growth, also restraining tumor neuroendocrine differentiation. The anti-tumor activity was lost in immunodeficient mice. Indeed, the combination treatment awoke cytotoxic activity and IFN-γ production of tumor-specific CD8+ T lymphocytes. Conclusion: These results promote the combination of enzalutamide and GSK-126 in CRPC, also offering new avenues for immunotherapy in prostate cancer.

Abstract 2560: Genomic biomarkers of survival in patients (pts) with metastatic castrate-sensitive prostate cancer (mCSPC) undergoing androgen deprivation therapy (ADT) intensification (ADTi)

Abstract Background: ADTi with androgen receptor pathway inhibitors (ARPI) with or without docetaxel improves survival outcomes in pts with mCSPC. Even with ADTi, 20% of these pts progress within a year and experience poor overall survival (OS). Identifying baseline genomic biomarkers predicting poor survival outcomes in pts receiving ADTi remains an unmet need. Methods: In this IRB-approved retrospective study, pts with a new diagnosis of mCSPC who underwent comprehensive genomic profiling of primary prostate tissue or metastatic site or cell-free DNA and treated with ADTi (ADT with ARPI or docetaxel) were included. Genomic alterations with an incidence &amp;gt; 5% were included in the analysis. Study endpoints: progression-free survival (PFS) was defined from the start of therapy for mCSPC to progression (per PCWG-2) or death from any cause. OS was defined from the start of therapy for mCSPC to the date of death from any cause or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for age at mCSPC diagnosis, disease volume (high vs. low), Gleason score (≥ 8 vs. &amp;lt; 8), Log2PSA at baseline, and initial timing of metastasis (de novo vs. non de novo). A subgroup analysis by intensification treatment received (ARPI vs. docetaxel) was also performed. Missing baseline characteristics such as volume of disease, Gleason score, and Log2PSA were multiply imputed on 50 chained equations using “mice” package in R. All the analyses were done using R version 4.3.1. Results: A total of 289 pts were included in the study. The baseline characteristics of the cohort will be presented in the meeting. The alterations included in the analysis were TP53 (31.8%), TMPRSS2 (30.4%), PTEN (17%), APC (10.4%), SPOP (9%), RB1 (6.2%), BRCA2 (5.2%), and CDK12 (5.2%). In the multivariable analysis, TP53 (HR 1.87, 95% CI 1.29-2.72, p = 0.001), RB1 (HR 2.56, 95% CI 1.45-4.53, p = 0.001), PTEN (HR 1.77, 95% CI 1.15-2.72, p = 0.009), and BRCA2 (HR 2.68, 95% CI 1.47-4.89, p = 0.002) were associated with significantly shorter PFS while TP53 (HR 1.78, 95% CI 1.1-2.88, p = 0.019), RB1 (HR 4.78, 95% CI 2.53-9.02, p &amp;lt; 0.001), and PTEN (HR 2.37, 95% CI 1.37-4.1, p = 0.003) were associated with significantly worse OS. Results of the subgroup analysis by intensification treatment (ARPI vs. docetaxel) will also be presented in the meeting. Conclusions: In this real-world study, we identified genomic biomarkers that could be associated with shorter PFS and OS in pts with mCSPC treated with ADTi. Upon external validation, these results may aid in developing a clinical-genomic risk stratification model, patient counseling, and treatment selection. Citation Format: Arshit Narang, Georges Gebrael, Chadi Hage Chehade, Nicolas Sayegh, Yeonjung Jo, Beverly Chigarira, Nishita Tripathi, Ayana Srivastava, Clara Tandar, Benjamin L. Maughan, Umang Swami, Neeraj Agarwal. Genomic biomarkers of survival in patients (pts) with metastatic castrate-sensitive prostate cancer (mCSPC) undergoing androgen deprivation therapy (ADT) intensification (ADTi) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2560.

Abstract 3812: Treatment guideline concordance for patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the United States in IRONMAN, the International Registry for Men with Advanced Prostate Cancer

Abstract Background: Treatment intensification strategies with an androgen receptor pathway inhibitor (ARPI) and/or docetaxel chemotherapy in addition to androgen deprivation therapy (ADT) are guideline recommended treatment options for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Prevalence of guideline concordant care for mHSPC patients in the US and its changes over time are not well characterized. Methods: The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is a prospective cohort study of patients with newly diagnosed mHSPC and castration-resistant prostate cancer (CRPC). Therapies are captured by site personnel and by directly capturing data from treating physicians via physician questionnaires (PQ). We included all US patients with mHSPC enrolled from 2018 to January 1, 2023 with a completed PQ at enrollment. We examined patient characteristics, first-line treatments for mHSPC, and guideline concordance of first-line treatments. Guideline concordance was defined as a treatment regimen listed in the first National Comprehensive Cancer Network guidelines version for the year prior to treatment. Patients enrolled in clinical trials were excluded from analysis of treatment guideline concordance. Results: Among the 636 US participants with mHSPC, physicians completed PQs for 458 participants (72%). Participants had a median age of 68 years (interquartile range 62 - 75). Three hundred eight (78%) were White, 72 (18%) were Black, 13 (3%) were other races/ethnicities: 65 did not report race. First-line treatment for mHSPC based on the PQ was most commonly ADT + ARPI (59%) followed by ADT + docetaxel (17%), ADT monotherapy (14%), ADT + first-generation antiandrogen (3%), ADT + ARPI + docetaxel (3%), and other treatments (5%). Overall, 384 (86%) participants received first-line treatment that was guideline concordant at the time of treatment. Treatment guideline concordance was highest in 2018 (99%) when ADT monotherapy was considered as guideline concordant but then decreased to 80% in 2019 and remained largely stable from 2019 to 2022 (85%). Overall, rates of guideline concordance were similar when stratified by race (88% for White patients vs 85% for Black patients), age (90% for patients &amp;lt;65 years old vs 85% for patients ≥65 years old), and treatment at a Comprehensive Cancer Center (CCC) (87% at CCC vs 86% at non-CCC). Conclusion: Among patients with mHSPC treated in the US at 38 cancer centers, proportions of guideline concordant first-line treatment were high and remained stable over time, despite changes in approved therapies. Future efforts to understand reasons for treatment decisions will be important to better understand the relatively uncommon situations in which guidelines and actually received treatments differ for patients with mHSPC. Citation Format: Hannah Dzimitrowicz McManus, Lauren Howard, Kerri-Anne Crowell, Terry Hyslop, Jake Vinson, Dana E. Rathkopf, Philip Kantoff, Lorelei A. Mucci, Daniel George, Konrad Stopsack. Treatment guideline concordance for patients with metastatic hormone-sensitive prostate cancer (mHSPC) in the United States in IRONMAN, the International Registry for Men with Advanced Prostate Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3812.

Abstract 6586: ORIC-944, a potent and selective allosteric PRC2 inhibitor with best-in-class properties, demonstrates combination synergy with AR pathway inhibitors in prostate cancer models

Abstract Polycomb repressive complex 2 (PRC2) dysregulation occurs in multiple tumor types and is associated with poor prognosis in patients with prostate cancer. In patients treated with androgen receptor pathway inhibitors (ARPI), emergence of tumor cell plasticity is associated with resistance to therapy. Dysregulation of epigenetic reprogramming factors, including PRC2, creates an environment that is permissive for such lineage plasticity. Inhibition of the PRC2 complex therefore may provide an opportunity to overcome or prevent the emergence of plasticity in prostate cancer. Notably, emerging clinical trial data has demonstrated the potential of ARPI and PRC2 inhibitor combination therapy to improve outcomes in patients with metastatic prostate cancer. PRC2 tri-methylates histone H3 at lysine 27 (H3K27me3), leading to long-term transcriptional silencing, a key mechanism regulating cellular functions such as cell growth and differentiation. Three core subunits comprise PRC2: the catalytic subunit enhancer of zeste homolog 2 (EZH2), suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). EED is essential for the histone methyltransferase activity of PRC2. First-generation PRC2 inhibitors, which target EZH2, exhibit poor drug properties, drug-drug interaction liabilities and short half-life requiring twice daily dosing at high doses in patients. We developed a second generation PRC2 inhibitor, ORIC-944, an allosteric inhibitor of PRC2 that binds the EED subunit. ORIC-944 is a potent, highly selective, orally bioavailable inhibitor with best-in-class properties. ORIC-944 demonstrated single agent tumor growth inhibition in a spectrum of in vivo prostate cancer models, including AR-positive, AR-mutant, ARv7, ARPI-responsive and ARPI-resistant models. In vitro analysis of the combination of ARPIs and ORIC-944 showed synergy in multiple prostate cancer cells, utilizing BLISS and other quantitative methods. In vivo studies revealed that ORIC-944 demonstrated increased efficacy in combination with ARPI, consistent with the in vitro synergy. RNA-seq analysis of transcriptional changes induced by ORIC-944 provided mechanistic insight into the role of PRC2 in prostate cancer lineage plasticity and combination response. These results position ORIC-944 as a best-in-class PRC2 inhibitor for evaluation in combination with ARPI in patients with metastatic prostate cancer. A phase 1b trial of ORIC-944 is ongoing (NCT05413421). Citation Format: Anneleen Daemen, Natalie Yuen, Amber Wang, Aleksandr Pankov, Livia Ulicna, Chelsea Chen, Frank L. Duong, Jason Long, Matthew A. Marx, James G. Christensen, Lori S. Friedman, Melissa R. Junttila. ORIC-944, a potent and selective allosteric PRC2 inhibitor with best-in-class properties, demonstrates combination synergy with AR pathway inhibitors in prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6586.

Abstract 2639: Combined therapy targeting AR and EZH2 restrains the growth of castration resistant prostate cancer by enhancing antitumor T cell response

Abstract Castration resistant prostate cancer (CRPC) is a fatal disease. Androgen receptor pathway inhibitors, like enzalutamide, are initially effective but resistance eventually occurs, often associated to the emergence of aggressive neuroendocrine variants (NEPC). Even immunotherapy induced limited results in prostate cancer, governed by an immunosuppressive microenvironment. Therefore, effective therapies are needed. We here investigate in preclinical models a new approach aimed to revert castration resistance and simultaneously turn the immune milieu from “cold” to “hot”, through the combination between enzalutamide and the drug GSK-126, which inhibits the epigenetic modulator EZH2. We show that enzalutamide and GSK-126 can synergize to restrain the growth of CRPC in vitro and in vivo. Moreover, this therapeutic combination efficiently reduced NEPC differentiation, in both subcutaneous and autochthonous in vivo models, increasing the rate of cured mice with regressed lesions. The antitumor efficacy observed in immunocompetent mice bearing subcutaneous syngeneic CRPC tumors was lost in immunodeficient mice, indicating a contribution of immune cells. Additional experiments in the TRAMP spontaneous mouse model revealed that the combination of enzalutamide and GSK-126 significantly induced cytotoxic activity and IFNγ production by tumor-specific CD8+ T cells, otherwise tolerant, and increased IL-17 production by CD4+ T cells. The two drugs did not directly modulate T cell activity in vitro, suggesting the importance of microenvironment accomplices in triggering these effects. These results promote the combined use of enzalutamide and GSK-126 to restrain CRPC growth and NEPC differentiation, and, simultaneously, to awake antitumor T cell response, opening new possibilities for immunotherapy in prostate cancer. Citation Format: Irene Fischetti, Botti Laura, Roberta Sulsenti, Valeria Cancila, Claudia Enriquez, Renata Ferri, Marco Bregni, Filippo Crivelli, Claudio Tripodo, Mario P. Colombo, Elena Jachetti. Combined therapy targeting AR and EZH2 restrains the growth of castration resistant prostate cancer by enhancing antitumor T cell response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2639.

Abstract 1493: Secretory function of neuroendocrine-like prostate cancer cell enhances therapy resistance and metastatic potential of adjacent adenocarcinoma

Abstract Background: Castration-resistant prostate cancer (CRPC) is advanced non curable disease associated with poor prognosis and survival n patients. Androgen receptor pathway inhibitors (ARSIs) are used to treat advanced prostate cancer, but in majority of patients it progresses by developing resistance to AR-directed therapies and is referred to as CRPC. Adenocarcinoma cells in CRPC tumor often undergoes lineage switch and become neuroendocrine-like cancer cells (NEPC) with small-cell histology, characterized by the loss of Tp53 and Rb1 genes. NEPC cells are frequently present as scattered foci along with prostatic adenocarcinomas and are secretory in nature. Objective: The primary objective is to determine how these NEPC cells influence surrounding adenocarcinoma and aids in disease progression. Methods: We performed Mass spec and cytokine array experiments from NEPC conditioned media to determine its secretory phenotype. We orthotopically implanted NEPC and adeno cells in the nude mice and performed colony formation assay on flow sorted adeno cells from the tumor. We also checked the effect of NEPC on the adeno cells and TME components. Results: Our analysis of the RNA-seq data from SU2C-PCF cohort and NE-like cells revealed that functions related to secretion were significantly enriched in NE-like PCa. NE-like cells gain the ability to secrete neuropeptides, growth factors, and cytokines to establish cell-cell communication. This secretory function is tightly regulated by the Neuropilin2 (NRP2) axis. We studied for the effect of NE-like cells on the adenocarcinoma cells in the mice tumor model and found that the presence of NE-like cells facilitated the adenocarcinoma cells to acquire aggressive characteristics. This could be due to both direct and/or through the modulation of the tumor microenvironment (TME). The direct effect could be by enhancing the therapy resistant ability of the surrounding adenocarcinoma, and the indirect effect is through the tumor microenvironment especially through neurons and macrophages that promote metastatic potential. Conclusions: Overall, our results prove that NE-like cancer cells influence the adjacent adenocarcinoma cells directly by making them resistant to treatment and indirectly make them more metastatic by utilizing macrophage-neuron axis. Citation Format: Juhi Mishra, Sanika Bodas, Sreyashi Bhattacharya, Dipanwita Das, Sheeraz UnNazir, Samikshan Dutta, Kaustubh Datta. Secretory function of neuroendocrine-like prostate cancer cell enhances therapy resistance and metastatic potential of adjacent adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1493.

Abstract 466: microRNA regulators of neuroendocrine differentiation in metastatic castration-resistant prostate cancer

Abstract Therapy-induced neuroendocrine prostate cancer (NEPC), an extremely aggressive variant of castration-resistant prostate cancer (CRPC), is increasing in incidence with the widespread use of highly potent androgen receptor (AR)-pathway inhibitors (APIs) via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED). The molecular basis of NED is not completely understood leading to a lack of effective molecular markers for its diagnosis. We hypothesized that alterations in key miRNAs drive NED, leading to lineage switching and emergence of NEPC. The aims of our study are: (i) identify key miRNA alterations that occur as PCa cells undergo neuroendocrine differentiation; (ii) develop a miRNA-based classifier for predicting/diagnosing NEPC; (iii) understand the functional role of key miRNA alterations. To systematically investigate the key miRNAs alterations driving therapy induced NED, we performed small RNA-NGS in a retrospective cohort of human metastatic CRPC clinical samples + PDX models with adenocarcinoma features (CRPC-adeno) vs those with neuroendocrine features (CRPC-NE). Further, with the application of machine learning algorithms to sequencing data, we trained a ‘miRNA classifier’ that could robustly classify ‘CRPC-NE’ from ‘CRPC-Adeno’ cases. The performance of classifier was validated in additional cohorts of mCRPC patients acquired from independent sites by employing single model prediction algorithm. We further sought to understand the functional role of these miRNAs by overexpessing in PCa cell lines followed by functional assays. In vivo xenograft studies were performed using PC3 cells overexpressing miR-28/control miRNA. We demonstrate for the first time, that lineage switching to NE states is accompanied by key miRNA alterations. Our analysis, measured using receiver operating characteristic (ROC) curves, demonstrated an area under the curve (AUC) value of 0.8318, confirming the robustness of our classifier in distinguishing CRPC-NE from CRPC-Adeno. Furthermore, we identified a select group of 5 miRNAs that were pivotal in distinguishing between these two prostate cancer subtypes. We focused on miR-28-3p, little studied miRNA in prostate cancer. Our in vitro and in vivo data with prostate cancer cell lines and xenograft model suggests that miR-28-3p acts as a tumor suppressor miRNA in advanced stage prostate cancer. We further found mesenchymal gene Vimentin to be a direct miR-28-3p target. We propose that loss of miR-28-3p promotes epithelial-to-mesenchymal transition (EMT), thereby favoring NED. Our study has important clinical implications and transformative potential as our 'miRNA classifier' can be used as a molecular tool to stratify mCRPC patients into those with/without NED and guide treatment decisions. Further, we identify novel miRNA NED drivers that can be exploited for NEPC therapeutic targeting. Citation Format: Diana Asante, Sandip Nathani, Tae Jin Lee, Ashok Sharma, Sharanjot Saini. microRNA regulators of neuroendocrine differentiation in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 466.

Efficacy of Poly(ADP-ribose) Polymerase Inhibitors by Individual Genes in Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer: A US Food and Drug Administration Pooled Analysis.

We performed a pooled analysis of multiple trials of poly(ADP-ribose) polymerase inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) to investigate the efficacy of PARPi in each individual homologous recombination repair (HRR) mutated (m) gene. We pooled patient-level data from trials of PARPi in mCRPC that reported mutation status in individual HRR genes. Any HRR gene with available data across all the randomized trials of PARPi in first-line mCRPC was selected. The hazard ratios (HRs; 95% CI) for radiographic progression-free survival (rPFS; by blinded independent review) and overall survival (OS) of a PARPi plus an androgen receptor pathway inhibitor (ARPI) relative to placebo plus an ARPI in the pool of three randomized trials in first-line mCRPC were calculated using Kaplan-Meier estimates and a Cox proportional hazards model. In ATMm (N = 268), rPFS HR was 1.05 (0.74 to 1.49) and OS HR was 1.18 (0.82 to 1.71). In BRCA1m (N = 64), rPFS HR was 0.51 (0.23 to 1.1) and OS HR was 0.74 (0.34 to 1.61). In BRCA2m (N = 422), rPFS HR was 0.31 (0.23 to 0.42) and OS HR was 0.66 (0.49 to 0.89). In CDK12m (N = 164), rPFS HR was 0.50 (0.32 to 0.80) and OS HR was 0.63 (0.39 to 0.99). In CHEK2m (N = 172), rPFS HR was 1.06 (0.67 to 1.66) and OS HR was 1.53 (0.95 to 2.46). In PALB2m (N = 41) rPFS HR was 0.52 (0.23 to 1.17) and OS HR was 0.78 (0.34 to 1.8). In this pooled analysis, benefit from PARPi appeared greatest for patients with BRCA1m, BRCA2m, CDK12m, and PALB2m. Given limitations of this exploratory analysis, the apparent lack of benefit from PARPi in patients with CHEK2m or ATMm should be further explored in future clinical trials.

177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: A Review of the Evidence and Implications for Canadian Clinical Practice.

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (177Lu)-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 177Lu-PSMA-617 in prostate cancer and discuss how Canadian clinicians might best apply these data in practice. The selection of appropriate patients, the practicalities of treatment administration, including necessary facilities for treatment procedures, the assessment of treatment response, and the management of adverse events are considered. Survival benefits were observed in clinical trials of 177Lu-PSMA-617 in patients with progressive, PSMA-positive mCRPC who were pretreated with androgen receptor pathway inhibitors and taxanes, as well as in taxane-naïve patients. However, the results of ongoing trials are awaited to clarify questions regarding the optimal sequencing of 177Lu-PSMA-617 with other therapies, as well as the implications of predictive biomarkers, personalized dosimetry, and combinations with other therapies.

A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer.

Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC). Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed. In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion. Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.

Instrumental activities of daily living in older patients with metastatic prostate cancer: results from the meet-URO network ADHERE prospective study

Instrumental activities of daily living (IADL) are significant health indicators closely related to executive functions and able to detect mild cognitive impairment. A decline in IADL usually precedes ADL limitation, including taking medications, and may therefore predict a cognitive decline. We aimed to investigate the association of patients’ IADL score with other clinical factors, with a particular focus on the presence of a caregiver, and the impact on adherence to androgen receptor pathway inhibitors (ARPIs) and survival outcomes within the Meet-URO 5—ADHERE study. It was a large prospective multicentre observational cohort study monitoring adherence to ARPIs in 234 metastatic castrate-resistant PC (mCRPC) patients aged ≥ 70. We observed an association between impaired IADL and lower geriatric G8 scores (p < 0.01), and lower adherence to ARPIs whether assessed by pill counting (p = 0.01) or self-reported by the patient himself (p = 0.03). The combination of an IADL < 6 and the absence of a caregiver resulted in a significantly high risk of non-adherence to the ARPIs at the multivariable analysis (HR 9.23, 95% confidence interval 2.28–37.43, p = 0.01). IADL alongside the geriatric G8 scales represent essential tools to identify frail and less auto-sufficient patients who are extremely vulnerable particularly if not supported by a caregiver and have the highest risk of nonadherence to ARPIs.

Care Pathway at a Cancer Center for the Administration of Radiometabolic Therapy with 177Lu-PSMA in Patients with Metastatic Castration-resistant Prostate Cancer.

To present a clinical care model for the administration of 177Lu-labeled prostate-specific membrane antigen (PSMA) in radiometabolic therapy for metastatic castration-resistant prostate cancer (mCRPC) at the National Cancer Institute (NCI) of Bogotá, Colombia. A care model was designed for patients with mCRPC based on the VISION study, a prospective, phase III, multicenter, open-label, randomized study in patients with positive 68Ga-PSMA positron emission tomography/computed tomography who had progressed to taxane and androgen therapy, to receive 177Lu-PSMA-617 combined with the best standard of care vs. the best standard of care alone. The care pathway provided to patients was developed by the Nuclear Medicine Group of the NCI and is the result of adjustments and improvements in the care process and the updating of the literature. A systematic and efficient care model was formalized and implemented for the administration of 177Lu-PSMA therapy in patients with mCRPC who had previously been treated with at least one androgen receptor pathway inhibitor and one or two taxane regimens, with evidence of disease progression. An optimized process of care based on the determinants of clinical outcomes was developed for patients who received this type of radiometabolic therapy.

Biochemically recurrent prostate cancer in the era of EMBARK and PSMA PET imaging: everything has changed, except the patients.

Patients with biochemically recurrent prostate cancer (BCR) after unsuccessful curative therapies frequently have an indolent and asymptomatic disease course for years. There are no prospective data showing that treating BCR improves overall survival despite new imaging strategies and emerging therapeutic data. Managing BCR requires a unique perspective in oncology that balances toxicities and disease kinetics. Prostate specific membrane antigen (PSMA) imaging is now widely available and can define subclinical disease in patients with BCR who otherwise have negative CT and bone scans, but limited data exists showing that treating PSMA-positive disease has long term impact. A phase 3 trial demonstrated that the androgen receptor pathway inhibitor enzalutamide either alone or with androgen deprivation therapy (ADT) was superior in delaying metastasis, relative to ADT alone. Survival benefits from this study remain unknown. BCR is a heterogeneous population where overtreatment may present greater risk to patients than a disease course that is often indolent. Management of BCR should be individualized based on disease kinetics. Given the unique biology of BCR, future therapeutic research should emphasize an approach that alters disease trajectory without accompanying side effects and should explore options beyond ADT-based strategies.

Niraparib and Abiraterone Acetate (Akeega)

&#x0D; CADTH recommends that Akeega be reimbursed by public drug plans for the first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) if certain conditions are met.&#x0D; Akeega should only be covered to treat patients with mCRPC who have BRCA mutations, have not been treated with an androgen receptor pathway inhibitor (ARPi) for earlier stages of prostate cancer, and have not received treatments that affect the entire body for mCRPC (except for treatments of less than 4 months with abiraterone acetate and prednisone) or a poly-(ADP-ribose) polymerase inhibitor (PARPi) for mCRPC. Moreover, patients should be in relatively good health.&#x0D; Akeega should only be reimbursed if it is prescribed by a clinician with expertise in treating prostate cancer with systemic anticancer therapy and if the cost of Akeega is reduced. Akeega should not be reimbursed when used in combination with other anticancer drugs.&#x0D;

Olaparib (Lynparza)

&#x0D; CADTH recommends that Lynparza, in combination with abiraterone and prednisone or prednisolone, should be reimbursed by public drug plans for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) if certain conditions are met.&#x0D; Lynparza should only be covered to treat patients with mCRPC who have BRCA mutations, who have not been treated with an androgen receptor pathway inhibitor (ARPi), who have not been treated with a poly-(ADP ribose) polymerase (PARP) inhibitor for mCRPC, and who have not been treated with a CYP-17 inhibitor for mCRPC for more than 4 months. Also, the patients should be in relatively good health.&#x0D; Lynparza, in combination with abiraterone and prednisone or prednisolone, should only be reimbursed if it is prescribed by a clinician with expertise in treating prostate cancer with systemic anticancer therapy and if the costs of both Lynparza and abiraterone are reduced.&#x0D;

A real-world observational study characterizing patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) treated with or without androgen receptor pathway inhibitors (ARPIs).

59 Background: mCSPC treatment is rapidly evolving with androgen deprivation therapy (ADT) plus ARPIs viewed as the standard of care for most pts. Data are needed to understand the real-world characteristics and treatment patterns of mCSPC (PC) pts in this dynamic field. This study aimed to define clinical features of mCSPC pts, estimate the proportion of pts receiving ARPIs, and evaluate clinical and demographic features associated with ARPI use. Methods: This retrospective cohort study used data from electronic health records and administrative databases in the province of Alberta, Canada. All newly diagnosed metastatic PC pts between 2017-2020 were identified. Pts were considered to have mCSPC if they initiated ADT within 30 days prior to, or at any time after diagnosis. ARPI exposure was defined as receiving ARPI within 180 days of initiating ADT. ARPI-naïve pts may have received ADT alone or other non-ARPI therapy (i.e., docetaxel) within 180 days of initiating ADT. Multivariable logistic regression was used to evaluate pt characteristics related to the receipt of ARPI. Overall survival (OS) was defined as the date of diagnosis to death from any cause or last known contact. Results: Of the 976 mCSPC pts identified, 33.5% received an ARPI. In ARPI exposed pts, the median time from ADT to ARPI start was 7.9 weeks and median time on ARPI was 13.1 months (mos). In multivariable analyses, ARPI use was associated with younger pt age, more recent diagnosis, fewer comorbidities, a higher metastatic burden, treatment centre, referral to a medical oncologist, and prior local therapy (all p&lt;0.05). The median time to next therapy was 24.6 mos (95%CI=19.5-33.0) vs. 18.5 mos (95%CI+16.9-21.1), and median OS was 38.5 mos (95%CI=32.8-NA) vs. 34.2 mos (95%CI=33.3-38.8) for APRI exposed vs. ARPI-naive pts, respectively (p=0.03). Conclusions: This study identified factors associated with ARPI use in mCSPC, potentially allowing targeted efforts to improve ARPI uptake for pts in whom use is low. These findings are important as they reflect outcomes seen in real world pts.

Optimal sequential therapy for metastatic castration-resistant prostate cancer after androgen receptor pathway inhibitors in the up-front era.

168 Background: The optimal sequential therapy for metastatic castration-resistant prostate cancer (mCRPC) following the use of up-front androgen receptor pathway inhibitors (ARPIs) for metastatic hormone-sensitive prostate cancer (mHSPC) is still unclear. Methods: A total of 220 patients who received systemic therapy for de novo mHSPC at Nagoya University Hospital and its affiliated institutions between 2014 and 2022 were included in the study. Patients who received up-front therapy with ARPI as first-line therapy for mHSPC, followed by ARPI as primary therapy for mCRPC were defined as the AA group, followed by docetaxel (DOC) as primary therapy for mCRPC were defined as the AD group. On the other hand, the vAA group was defined as patients who received androgen deprivation therapy alone or combined androgen blockade as “vintage” first-line therapy for mHSPC, followed by two consecutive ARPIs as sequential therapy for mCRPC, and the vAD group was defined as patients who received ARPI followed by DOC as sequential therapy for mCRPC. Patient characteristics and progression-free survival (PFS) of the second agent after the first ARPI were compared in each group. Results: We identified 14 patients in the AA group, 16 in the AD group, 84 in the vAA group, and 59 in the vAD group. There were no differences in patient background such as initial PSA, Gleason score, and metastatic burden between the groups, while patient age was lower in the AD and vAD groups compared to the AA and vAA groups. The PFS of the second agent in the AA group was significantly shorter than that in the vAA group (median, 6.8 vs. 1.9 months; hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.25-0.87; p=0.017). In contrast, there was no significant difference in PFS of the second agent in the vAD and AD groups (median, 7.0 vs. 4.0 months; HR, 0.63; 95%CI, 0.29-1.34; p=0.235). Conclusions: The effect of each agent after ARPI therapy in the UP-FRONT era may be poorer than that in the VINTAGE era. In the setting after up-front ARPI, sequential therapy with DOC may be more appropriate than sequential therapy with ARPI.