Androgen Receptor Pathway Inhibitors Research Articles

Adjuvant and salvage radiotherapy after neoadjuvant therapy and radical prostatectomy for high-risk localized prostate cancer.

We sought to describe patterns of delivery of adjuvant (aRT) and salvage RT (sRT) in patients who underwent RP after receiving neoadjuvant androgen receptor pathway inhibitor (ARPI) before radical prostatectomy (RP) for high-risk localized prostate cancer (HRLPC). Two hundred eighteen patients treated on phase 2 neoadjuvant trials between 2006 and 2018 at two academic centers were evaluated. aRT and sRT were defined as receipt of RT with a PSA of ≤0.1or >0.1 ng/mL, respectively. Primary outcomes were biochemical recurrence (BCR), defined as time from aRT/sRT to a PSA rising to >0.1 ng/mL, and metastasis-free survival (MFS) after RT. Twenty-three (11%) and 55 (25%) patients received aRT and sRT respectively. Median PSA at start of aRT and sRT was 0.01and 0.16 ng/mL, and median duration from RP to RT was 5 and 14 months, respectively. All aRT patients had NCCN high-risk disease, 30% were pN1and 43% had positive surgical margins; 52% had prostate bed RT. Fifty-one percent of sRT patients had biopsy Gleason 9-10, 29% were pT2and 9% had positive surgical margins; 63% had RT to the prostate bed/pelvis. At a median follow-up of 5.3 and 3.0 years after aRT and sRT, 3-year freedom from BCR was 55% and 47%, and 3-year MFS was 56% and 53%, respectively. aRT was infrequently used in patients who received neoadjuvant ARPI before RP for HRLPC. Outcomes of aRT and sRT were similar but generally poor. Studies evaluating intensified systemic therapy approaches with postoperative RT in this high-risk population are needed.

Glucocorticoid treatment influences prostate cancer cell growth and the tumor microenvironment via altered glucocorticoid receptor signaling in prostate fibroblasts

Despite significant therapeutic advances in recent years, treatment of metastatic prostate cancer (PCa) remains palliative, owing to the inevitable occurrence of drug resistance. There is increasing evidence that epithelial glucocorticoid receptor (GR) signaling and changes in the tumor-microenvironment (TME) play important roles in this process. Since glucocorticoids (GCs) are used as concomitant medications in the course of PCa treatment, it is essential to investigate the impact of GCs on stromal GR signaling in the TME. Therefore, general GR mRNA and protein expression was assessed in radical prostatectomy specimens and metastatic lesions. Elevated stromal GR signaling after GC treatment resulted in altered GR-target gene, soluble protein expression, and in a morphology change of immortalized and primary isolated cancer-associated fibroblasts (CAFs). Subsequently, these changes affected proliferation, colony formation, and 3D-spheroid growth of multiple epithelial PCa cell models. Altered expression of extra-cellular matrix (ECM) and adhesion-related proteins led to an ECM remodeling. Notably, androgen receptor pathway inhibitor treatments did not affect CAF viability. Our findings demonstrate that GC-mediated elevated GR signaling has a major impact on the CAF secretome and the ECM architecture. GC-treated fibroblasts significantly influence epithelial tumor cell growth and must be considered in future therapeutic strategies.

Treatment-Related Cognitive Impairment in Patients with Prostate Cancer: Patients' Real-World Insights for Optimizing Outcomes.

Cognitive impairment (CI) is an issue that needs to be at the forefront of unmet healthcare needs in patients with prostate cancer (PCa) as it can negatively impact quality of life during long-term care. CI in patients with prostate cancer is thought to be influenced by treatment, androgen deprivation therapy (ADT), and novel androgen receptor (AR) pathway inhibitors in particular; however, current understanding is limited on how treatment affects cognition. Additionally, the experience of patients with CI who are receiving PCa treatment is not well understood or represented in clinical literature, which is a barrier to optimal patient outcomes in managing prostate cancer treatment-related cognitive impairment (PCa-TRCI). To help understand the patient journey and elucidate management gaps in PCa-TRCI, an international roundtable of healthcare provider and patient panelists was convened. The panelists focused on four key topic areas: (1) the patient experience when afflicted with, or at risk of, PCa-TRCI, (2) the physical, emotional, and social impact of CI on patients' quality of life (QoL), (3) the challenges that patients with PCa-TRCI face, and their impact on clinical decision-making, and (4) ways in which managing PCa-TRCI should evolve to improve patient outcomes. The purpose of the roundtable was to include patients in a direct discussion with healthcare providers (HCPs) regarding the patient journey and highlight real-world evidence of areas where patient outcomes could be improved in the absence of clinical evidence. The resulting discussion highlighted important healthcare gaps for patients with, and at risk of, PCa-TRCI and offered potential solutions as a roadmap to effective medicine.

Perceptions of emerging PARP inhibitor (PARPi) data among practicing oncologists in prostate cancer.

546 Background: Studies suggest that PARPi agents work best in cancers, including metastatic castration-resistant prostate cancer (mCRPC), that have mutations in DNA repair pathways regulated by homologous recombination repair ( HRR) genes . The first PARPis for prostate cancer (olaparib for HRR-mutated and rucaparib for BRCA-mutated CRPC) were approved in 2020. Two recent trials, TALAPRO-2 and PROpel, evaluate PARPis plus an androgen receptor pathway inhibitor for patients both with and without genetic mutations were presented at ASCO GU 2023. This study aimed to determine oncologists’ perceptions of these new data. Methods: In April 2023, US-based oncologists were invited to attend one of two meetings to discuss data from ASCO GU 2023. Demographics were collected in an online survey, and perceptions of the TALAPRO-2 and PROpel trials were captured via audience response system technology at the meetings. Results: Across the two meetings, 115 oncologists were surveyed; 99 oncologists (86%) indicated that they manage patients with prostate cancer. Of these, 74% reported that they either very often or always test for HRR mutations, and the majority are testing at initial diagnosis of metastatic disease. Prior to reviewing trial updates, 84% of oncologists reported olaparib as their preferred PARPi, and the top factors driving their preferences are efficacy (83%) and safety/tolerability (63%). Perceptions of the trial updates are reported in Table 1. A subset of oncologists were also asked their treatment preferences for patients with mCRPC before and after the trial updates. Altogether, there was a 41% increase in physicians who would use talazoparib plus enzalutamide in an ATM-mutated patient after progression on docetaxel. They were also more likely to report (35%) a preference for this combination for a BRCA1-mutated patient after progression on abiraterone acetate. Additionally, there was a 27% increase in physicians who would use olaparib plus abiraterone acetate in an HRR-wild type patient after enzalutamide. Conclusions: Overall, these data show that clinical updates regarding PARPi agents have an impact on practicing oncologists. However, further exploration of genetic testing practices among oncologists and the impact of emerging data on real-world practice is needed.[Table: see text]

Impact of Initial Timing of Metastatic Disease on Survival in Patients With Newly Diagnosed Metastatic Castration-Resistant Prostate Cancer Treated With Androgen Receptor Pathway Inhibitors.

Patients with synchronous (de novo) metastatic castration-sensitive prostate cancer appear to have worse survival outcomes and shorter time to develop castration resistance than patients with metachronous disease. However, the impact of synchronous metastasis on outcomes in metastatic castration-resistant prostate cancer (mCRPC) setting is unknown in patients without prior exposure to androgen receptor pathway inhibitors (ARPIs). In this study, we assessed the impact of initial timing of metastasis (synchronous vs metachronous) on survival outcomes of patients with new-onset mCRPC in a real-world population treated with first-line abiraterone or enzalutamide. Data were collected retrospectively from 323 patients with a confirmed diagnosis of mCRPC who received ARPIs as first-line therapy and had no prior exposure to ARPIs. The study endpoints were progression-free survival and overall survival. The results showed that median overall survival was significantly shorter in patients with synchronous disease than those with metachronous disease (26 vs 38.7 months, HR 1.42, 95% CI 1.09-1.86, P = .011). However, there was no difference in median progression-free survival. The initial presentation with synchronous metastasis remained an independent factor associated with shorter OS in the multivariable analysis. These hypothesis-generating data, after external validation, may have implications in patient counseling, prognostication, and design of future clinical trials in the new-onset mCRPC setting.

Development of Novel Models of Aggressive Variants of Castration-resistant Prostate Cancer

BackgroundGenomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models. ObjectiveTo develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy. Design, setting, and participantsNEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models. Outcome measurements and statistical analysisRelationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test. Results and limitationsOur PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity. ConclusionsOur models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms. Patient summaryIn this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).

Survival Trend in Individuals With De Novo Metastatic Prostate Cancer After the Introduction of Doublet Therapy

Recently, life-prolonging treatments for patients with advanced prostate cancer have been introduced in clinical practice. To investigate if the introduction of doublet therapy is associated with changes in survival on a population-basis. This nationwide population-based cohort study used data from the Prostate Cancer data Base Sweden from 2008 to 2020. Men registered with de novo metastatic castration-sensitive prostate cancer (mCSPC) were included. The proportion of men with mCSPC who received doublet therapy, ie, androgen deprivation therapy plus androgen receptor pathway inhibitor drugs or chemotherapy was assessed. Standardized overall survival, taking age, comorbidity, and cancer characteristics into consideration, was estimated by use of a parametric survival model. A total of 11 382 men were included in this study (median [IQR] age, 74.0 [68-81] years). There was a shift toward less advanced prostate cancer during the study period with a decrease in median (IQR) prostate-specific antigen at diagnosis in men with mCSPC from 145 (39-571) ng/mL to 107 (27-426) ng/mL. Upfront treatment with doublet therapy in these men simultaneously increased from 1% (7 of 991) in 2016 to 44% (402 of 922) in 2020. The adjusted 5-year overall survival increased from 26% (95% CI, 25%-28%) from 2008 to 2012 to 35% (95% CI, 31%-40%) from 2017 to 2020. During the first 5 years after diagnosis, there was an increase in mean survival of 6 months, from 2.7 (95% CI, 2.6-2.8) years from 2008 to 2012 to 3.2 (95% CI, 3.1-3.1) years from 2017 to 2020. In parallel with improvements in treatment of advanced prostate cancer, a clinically meaningful increase in mean survival was observed in men with de novo mCSPC in Sweden between 2008 and 2020 in this study.

Cardiovascular Adverse Events Associated With New-Generation Androgen Receptor Pathway Inhibitors (ARPI) for Prostate Cancer: A Disproportionality Analysis Based on the FDA Adverse Event Reporting System (FAERS).

The potential cardiovascular adverse events associated with new-generation androgen receptor pathway inhibitors (ARPI) in the treatment of prostate cancer remain unclear. We aimed to assess the pharmacovigilance (PV), reporting rate, severity, and reaction outcomes of major adverse cardiovascular events (MACE) related to new-generation ARPI for prostate cancer reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed reports of cardiovascular adverse events associated with drug therapy for prostate cancer submitted to FAERS between January 2014 and December 2022. Three primary new-generation ARPIs were identified: abiraterone acetate, enzalutamide, and apalutamide. Our primary composite endpoint was the PV of MACE caused by ARPIs in the treatment of prostate cancer, and the secondary endpoint was PV of other cardiovascular events. The software implemented was STATA 17.0 MP. A total of 278,031 suspected drug-adverse event pairs related to drug treatment in patients with prostate cancer were identified, of which 10,861 reports were cardiovascular events, including 5800 reports of MACE and 5061 reports of other cardiovascular events. The majority of these cardiovascular adverse event reports came from the United States (36.6%) and were mostly older men (age 76.0 ± 8.6 years). Compared with enzalutamide, the constituent ratio of MACE caused by abiraterone acetate and apalutamide was significantly increased, but the incidence of severe MACE decreased significantly. The PV signal regarding MACE was detected in abiraterone acetate and apalutamide but not in enzalutamide. Abiraterone acetate and apalutamide presumably are associated with a higher risk of MACE than enzalutamide in new-generation ARPI for prostate cancer. More extensive prospective studies and more extended follow-up periods need to confirm this further.

LBA86 Androgen receptor pathway inhibitors or taxanes for patients with metastatic castration-resistant prostate cancer: A direct comparison in ProBio, a randomized, outcome-adaptive, biomarker-driven platform trial

LBA86 Androgen receptor pathway inhibitors or taxanes for patients with metastatic castration-resistant prostate cancer: A direct comparison in ProBio, a randomized, outcome-adaptive, biomarker-driven platform trial

PSMA PET/CT for Response Assessment and Overall Survival Prediction in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors.

We aimed to evaluate the role of prostate-specific membrane antigen (PSMA) PET/CT for response assessment and outcome prediction in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor pathway inhibitors (ARPIs), including abiraterone acetate or enzalutamide. Methods: We retrospectively analyzed 30 ARPI-treated mCRPC patients who underwent 68Ga-PSMA-11 PET/CT within 8 wk before (baseline) and 12 ± 4 wk after treatment initiation. Total PSMA tumor volume was calculated using the fixed threshold method (SUV ≥ 3). Patients were categorized as PSMA responders (PSMA-Rs) or PSMA nonresponders (PSMA-NRs) on the basis of both European Association of Urology/European Association of Nuclear Medicine (EAU/EANM) criteria and Response Evaluation Criteria in PSMA PET/CT (RECIP) 1.0. PSMA-R included patients with a complete response, a partial response, or stable disease, and PSMA-NR included those with progressive disease. On the basis of prostate-specific antigen (PSA), patients were classified as biochemical responders if PSA decreased by at least 50% and as nonresponders if it did not. The Φ-coefficient was used to evaluate the correlation of PSMA- and PSA-based responses. Survival analysis was performed using the Cox regression hazard model and the Kaplan-Meier method. Predictive accuracy was tested for both response criteria. Results: On the basis of PSMA PET/CT, 13 (43%) patients were PSMA-NR according to the EAU/EANM criteria and 11 (37%) patients were PSMA-NR according to RECIP 1.0. Significant correlations were observed between PSMA- and PSA-based responses for both criteria (Φ = 0.79 and 0.66, respectively). After a median follow-up of 25 mo (interquartile range, 21-43 mo), the median overall survival was significantly longer for PSMA-R than PSMA-NR (54 vs. 22 mo) for both the EAU/EANM criteria and RECIP 1.0, with hazard ratios of 6.9 (95% CI, 1.9-26; P = 0.004) and 5.6 (95% CI, 1.69-18.26, P = 0.005), respectively. No significant difference in predictive accuracy was found between the 2 criteria (C-index, 0.79 vs. 0.76, respectively, P = 0.54). Flare phenomena at the second PSMA PET study were not observed in our cohort. Conclusion: Our results demonstrate that PSMA PET/CT is a valuable imaging biomarker for response assessment and overall survival prediction when performed at 3 mo after ARPI treatment initiation in mCRPC patients. Both proposed PSMA response criteria (EAU/EANM and RECIP 1.0) seem to perform equally well. No PSMA flare was observed. Prospective validation of these findings is strongly needed.

Effect of Concomitant Medications on Treatment Response and Survival in De Novo Metastatic Prostate Cancer: Secondary Analysis of the LATITUDE Study

It is unclear whether exposure to commonly prescribed medications influences survival and treatment response in patients with de novo high-risk metastatic prostate cancer (mPCa) treated with androgen receptor pathway inhibitors (ARPIs). We performed a secondary analysis of the LATITUDE trial to determine whether receipt of concomitant medications influenced the effect of abiraterone acetate and prednisone, in addition to androgen deprivation therapy (ADT), on overall survival (OS) and prostate cancer-specific mortality (PCSM) in patients with de novo mPCa. We focused on 7 commonly prescribed classes of medications: metformin, statins, proton pump inhibitors (PPIs), cyclooxygenase 2 (COX-2) inhibitors, aspirin, acetaminophen, and NSAIDs (nonselective COX inhibitors). To account for multiple testing, a two-sided p < 0.0024 was set as the threshold for statistical significance. Overall, 1135 patients were eligible. There was some evidence of a differential treatment effect from abiraterone among patients who received concomitant NSAIDs (hazard ratio [HR] for OS: 0.54; 95% CI: 0.42-0.70) versus those who did not (HR: 0.74; 95% CI: 0.60-0.91), though this did not reach significance (interaction p = 0.05). A similar non-significant finding of heterogeneity of effect from abiraterone was noted among patients who received concomitant aspirin (HR for OS: 0.93 [0.63-1.36]) versus those who did not (HR: 0.61 [0.51-0.73]) (interaction p = 0.04). Receipt of NSAIDs was independently associated with a significantly inferior OS (HR: 1.37 [1.15-1.62]; p < 0.001) and higher relative incidence of PCSM (sHR: 1.47 [1.21-1.78]; p < 0.001). This exploratory analysis did not find statistically significant evidence of differences in treatment effects from ADT plus abiraterone in de novo high-risk mPCa based on the receipt of concurrent medications. The receipt of NSAIDs was independently associated with increased PCSM and inferior OS.

Exosomal miR-222-3p contributes to castration-resistant prostate cancer by activating mTOR signaling.

Despite the clinical benefits of androgen deprivation therapy, most patients with advanced androgen-dependent prostate cancer (ADPC) eventually relapse and progress to lethal androgen-independent prostate cancer (AIPC), also termed castration-resistant prostate cancer (CRPC). MiRNAs can be packaged into exosomes (Exos) and shuttled between cells. However, the roles and mechanisms of exosomal miRNAs involved in CRPC progression have not yet been fully elucidated. Here, we find that miR-222-3p is elevated in AIPC cells, which results in remarkable enhancement of cell proliferation, migration, and invasion ability. Furthermore, Exos released by AIPC cells can be uptaken by ADPC cells, thus acclimating ADPC cells to progressing to more aggressive cell types in vitro and in vivo through exosomal transfer of miR-222-3p. Mechanistically, Exos-miR-222-3p promoted ADPC cells transformed to AIPC-like cells, at least in part, by activating mTOR signaling through targeting MIDN. Our results show that AIPC cells secrete Exos containing miRNA cargo. These cargos can be transferred to ADPC cells through paracrine mechanisms that have a strong impact on cellular functional remodeling. The current work underscores the great therapeutic potential of targeting Exo miRNAs, either as a single agent or combined with androgen receptor pathway inhibitors for CRPC treatment.

Impact of androgen receptor alterations on cell-free DNA genomic profiling on survival outcomes in metastatic castration-resistant prostate cancer.

Androgen receptor (AR) gene alterations, as detected by circulating tumor cell-free DNA (cfDNA) genomic profiling, have been shown to emerge after a variable duration of androgen signaling inhibition. AR alterations were associated with inferior outcomes on treatment with androgen receptor pathway inhibitors (ARPI) in the first line metastatic castration-resistant prostate cancer (mCRPC) setting in a phase 2 trial. Here in, we assessed the impact of these AR alterations on survival outcomes in a real-world patient population of mCRPC experiencing disease progression on an ARPI. In this IRB-approved retrospective study, consecutively seen patients with a confirmed diagnosis of mCRPC, with disease progression on a treatment with ARPIs in the first line mCRPC setting, with no prior exposure to an ARPI in the castration sensitive setting, and with available cfDNA profiling from a CLIA certified laboratory were included. Patients were categorized based on AR status: wild-type (ARwt ) or alteration-positive (AR+ ). The objective was to correlate overall survival (OS) after disease progression on the first-line ARPI with the presence or absence of AR alterations. Kaplan-Meier and Cox Regression Tests were used as implemented in R-Studio (v.4.2). A total of 137 mCRPC patients were eligible: 69 with ARwt versus 68 with AR+ . The median OS posttreatment with the first ARPI was significantly higher for ARwt than AR+ patients (30.1 vs. 15.2 mos; p < 0.001). Of 108 patients who received a subsequent line of therapy, 63 received an alternate ARPI (AR+ 39 vs. 24 ARwt ), while 20 received a taxane-based therapy (11 AR+ vs. 9 ARwt ). Among patients receiving an alternate ARPI, AR+ had numerically shorter OS (16.8 vs. 30.4 mos, p = 0.1). Among patients receiving taxane-based regimens, the OS was not significantly different between AR+ and ARwt (14.5 vs. 10.1 mos, p = 0.18). In this real-world study, mCRPC patients with AR alterations on cfDNA had inferior OS after disease progression on the first ARPI, compared to those who did not, and may impact outcomes on a subsequent ARPI but not on subsequent taxane-based therapy received. By providing survival estimates for patients with or without AR alterations, our data may aid in patient counseling, prognostication, treatment decision, and for designing future clinical trials in this setting.

BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype

Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events impact prognosis and/or treatment response is vital for optimising clinical outcomes. Targeted sequencing was performed on 407 plasma samples from 375 men with mCRPC. Using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay, pathogenic alterations in 152 key genes (including 27 DDR-related genes) were assessed, as was the presence and mechanisms of biallelic loss in BRCA2. At least one DDR alteration was present in 34.5% (129/375) of patients (including monoallelic alterations). The most frequently altered DDR genes were BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%) and BRCA1 (3%). Patients with BRCA alterations, especially BRCA2, had significantly worse progression-free survival (PFS) (Hazard ratio (HR) 3.3 [95% CI 1.9-6.0]; Cox regression p<0.001), overall survival (HR 2.2 [95% CI 1.1-4.5]; Cox regression p=0.02) and PSA response rates to androgen receptor (AR) pathway inhibitors (32% vs 60%, chi-square p=0.02). BRCA-deficient tumours were also enriched for alterations within multiple genes including in the AR and PI3K pathways. Zygosity of BRCA2 alterations had no discernible impact on clinical outcomes, with similarly poor PFS for monoallelic vs biallelic loss (median 3.9 months vs 3.4 months vs copy neutral 9.8 months). These data emphasise that the BRCA genes, in particular BRCA2, are key prognostic biomarkers in mCRPC. The clinical utility of BRCA2 as a marker of poor outcomes may, at least in cfDNA assays, be independent of the zygosity state detected. Enrichment of actionable genomic alterations in cfDNA from BRCA-deficient mCRPC may support rational co-targeting strategies in future clinical trials. Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.

ASCL1 is activated downstream of the ROR2/CREB signaling pathway to support lineage plasticity in prostate cancer

Lineage plasticity is a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors potentially lead to the accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. However, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identifies ROR2 as the top upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem-cell-like and neuronal networks. Mechanistically, ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.

Race and Treatment Outcomes in Patients With Metastatic Castration-Sensitive Prostate Cancer

Black patients present with more aggressive disease and experience higher mortality than White patients with prostate cancer. Race and social determinants of health influence prostate cancer-specific mortality and overall survival (OS); however, in a previous trial, Black patients did not have inferior outcomes compared with White patients, possibly because of equitable access to care available in a clinical trial setting. To compare differences in survival outcomes of patients with metastatic castration-sensitive prostate cancer (mCSPC) by race in a phase 3 trial with a large proportion of Black patients. This secondary analysis of patient-level data of a prospective phase 3 randomized clinical trial included patients with newly diagnosed mCSPC enrolled between March 1, 2013, and July 15, 2017. Analysis was conducted between December 2022 and February 2023. Patients receiving androgen deprivation therapy were randomized (1:1) to receive either orteronel 300 mg orally twice daily (experimental group) or bicalutamide 50 mg orally daily (control group). OS, with progression-free survival (PFS) as a secondary end point. Among 1313 participants, 135 (10%) identified as Black and 1077 (82%) as White, with an equal racial distribution between groups. Black patients were younger (median [IQR] age, 65.8 [60-70] vs 68.4 [62.5-74.1] years; P = .001) and had a higher median (IQR) baseline prostate-specific antigen response rate than White patients (54.7 [19.8-222.0] vs 26.7 [9.2-96.0] ng/mL; P < .001). At a median follow-up of 4.9 years, Black and White patients had similar median PFS (2.3 years; 95% CI, 1.8-1.4 years vs 2.9 years; 95% CI, 2.5-3.3 years; P = .71) and OS (5.5 years; 95% CI, 4.8-NR vs 6.3 years; 95% CI, 5.7-NR; P = .65). The multivariable analysis confirmed similar PFS and OS after adjusting for known prognostic factors. No interaction between race and treatment was observed. In this secondary analysis of a randomized clinical trial studying androgen deprivation therapy with first- or second-generation androgen receptor pathway inhibitors, both Black and White patients demonstrated similar OS and PFS. Equitable access to care may reduce historical differences in outcomes between Black and White patients with advanced prostate cancer. ClinicalTrials.gov Identifier: NCT01809691.

A Multivalent Peptoid Conjugate Modulates Androgen Receptor Transcriptional Activity to Inhibit Therapy-resistant Prostate Cancer.

Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance due to ongoing AR expression and function. To counter this, we developed a new approach to modulate the AR and inhibit castration-resistant prostate cancer (CRPC) using multivalent peptoid conjugates (MPC) that contain multiple copies of the AR-targeting ligand ethisterone attached to a peptidomimetic scaffold. Here, we investigated the antitumor effects of compound MPC309, a trivalent display of ethisterone conjugated to a peptoid oligomer backbone that binds to the AR with nanomolar affinity. MPC309 exhibited potent antiproliferative effects on various enzalutamide-resistant prostate cancer models, including those with AR splice variants, ligand-binding mutations, and noncanonical AR gene expression programs, as well as mouse prostate organoids harboring defined genetic alterations that mimic lethal human prostate cancer subtypes. MPC309 is taken up by cells through macropinocytosis, an endocytic process more prevalent in cancer cells than in normal ones, thus providing an opportunity to target tumors selectively. MPC309 triggers a distinct AR transcriptome compared with DHT and enzalutamide, a clinically used antiandrogen. Specifically, MPC309 enhances the expression of differentiation genes while reducing the expression of genes needed for cell division and metabolism. Mechanistically, MPC309 increases AR chromatin occupancy and alters AR interactions with coregulatory proteins in a pattern distinct from DHT. In xenograft studies, MPC309 produced significantly greater tumor suppression than enzalutamide. Altogether, MPC309 represents a promising new AR modulator that can combat resistant disease by promoting an AR antiproliferative gene expression program.

Survival outcomes of real world patients with metastatic hormone-sensitive prostate cancer who do not achieve optimal PSA response with intensified androgen deprivation therapy with docetaxel or androgen receptor pathway inhibitors.

In patients with metastatic hormone-sensitive prostate cancer (mHSPC) undergoing intensified androgen deprivation therapy (ADT), not achieving an optimal PSA response, defined as PSA nadir >0.2 ng/ml (PSAsubOR) has been associated with worse survival outcomes in clinical trials (1)(10)(11). Here, we externally evaluate, the impact of optimal PSA response on survival outcomes in these patients and provide absolute PFS and OS measures in those with PSAsubOR in the context of ADT intensification in real world setting. In this retrospective study, all consecutive patients with mHSPC who underwent intensified ADT treated at our institution, and whose outcomes data were available, were included. We classified patients based on their PSA nadir on treatment: those with a on treatment PSAOR (PSA nadir ≤0.2 ng/ml) versus PSAsubOR. A total of 205 patients were eligible: 136 (66.3%) patients achieved PSAOR versus 69 (33.7%) patients had PSAsubOR. Patients who experienced a PSAOR had significantly improved PFS and OS from the start of intensified ADT versus who did not: PFS was not reached (NR) versus 11 months (hazard ratio (HR) 0.20, P < 0.001) and OS was NR versus 38.9 months (HR 0.21, P < 0.001). Survival outcomes were poor with PSAsubOR regardless of intensification with docetaxel or an ARPI (absolute PFS and OS measures for each group are provided in the text). Our study is the first to explore the negative impact of PSAsubOR in patients with mHSPC undergoing intensified ADT in the real-world setting, and is the first to provide absolute PFS and OS in patients with PSAsubOR receiving ADT intensification with ARPIs or docetaxel outside of clinical trial setting. These data will aid with prognostication, patient counseling, and for designing future clinical trials for patients with PSAsubOR.

Hospitalizations Among Veterans Treated for Metastatic Prostate Cancer With Abiraterone or Enzalutamide

BackgroundAbiraterone and enzalutamide are second generation androgen receptor pathway inhibitors (ARPIs) used to treat advanced or metastatic prostate cancer. Without head-to-head comparative studies identifying 1 agent as preferred initial therapy, physician preferences guide initial ARPI choice. This study compares hospitalizations among patients treated initially with abiraterone versus enzalutamide. Patients and MethodsUnited States veterans treated with abiraterone or enzalutamide between May 13, 2011 and December 31, 2019; then compared hospitalization rate during first treatment with ARPI in the Veterans Healthcare Administration. Baseline incidence rate of hospitalization was determined from data 1 year prior to ARPI. Incidence Rate Difference (IRD) was calculated using χ2 test and difference in IRD using Poisson Regression. Results19,775 veterans were identified; 13,527 (68.4%) were initially treated with abiraterone and 6248 (31.6%) initially with enzalutamide. The enzalutamide cohort was older (75.8 vs. 74.5 years, P < .001) and had higher baseline comorbidities at ARPI initiation (4.4 vs. 4.0, P < .001). Patients were treated with enzalutamide longer than abiraterone (median 9.0 vs. 8.0 months, P < .001). Total hospitalizations increased from 465 per 1000 person-years in the year prior to treatment with abiraterone to 567 during treatment. Total hospitalizations increased from 417 per 1000 person-years in the year prior to treatment with enzalutamide to 430 during treatment. Total rate of hospitalization increased 22% for abiraterone compared to a 3% increase for enzalutamide in the 12 months after ARPI initiation (P < .0001). Abiraterone was associated with greater increase in rates of acute heart failure, atrial fibrillation, acute kidney injury, urinary tract infections, sepsis, and pneumonia. ConclusionBy comparing the rate of hospitalization before vs. during treatment, real world analyses identified a 22% versus 3% increase in hospitalizations with abiraterone compared to enzalutamide respectively, despite being used in a younger population with less comorbid disease. Abiraterone was also associated with higher risk of infections, a novel finding.

Feasibility of home-based exercise training during adjuvant treatment for metastatic castrate-resistant prostate cancer patients treated with an androgen receptor pathway inhibitor (EXACT)

BackgroundExercise is an effective adjuvant therapy that can alleviate treatment-related toxicities for men with prostate cancer (PC). However, the feasibility of delivering exercise training to men with advanced disease and the wider impact on clinical outcomes remain unknown. The purpose of the EXACT trial was to determine the feasibility and effects of home-based exercise training in men with metastatic castrate-resistant prostate cancer (mCRPC).MethodsPatients with mCRPC receiving ADT + an androgen receptor pathway inhibitor (ARPI) were prescribed 12 weeks of home-based, remotely monitored, moderate intensity, aerobic and resistance exercise. Feasibility was assessed using recruitment, retention and adherence rates. Safety and adverse events were monitored throughout, with functional and patient-reported outcomes captured at baseline, post-intervention and at 3-month follow-up.ResultsFrom the 117 screened, 49 were deemed eligible and approached, with 30 patients providing informed consent (61% recruitment rate). Of those who consented, 28 patients completed baseline assessments, with 24 patients completing the intervention and 22 completing follow-up (retention rates: 86% and 79% respectively). Task completion was excellent throughout, with no intervention-related adverse events recorded. Self-reported adherence to the overall intervention was 82%. Exercise training decreased mean body mass (−1.5%), improved functional fitness (> 10%) and improved several patient-reported outcomes including clinically meaningful changes in fatigue (p = 0.042), FACT-G (p = 0.054) and FACT-P (p = 0.083), all with moderate effect sizes.ConclusionHome-based exercise training, with weekly remote monitoring, was feasible and safe for men with mCRPC being treated with an ARPI. Given that treatment-related toxicities accumulate throughout the course of treatment, and as a result, negatively impact functional fitness and health-related quality of life (HRQoL), it was positive that exercise training improved or prevented a decline in these clinically important variables and could better equip patients for future treatment. Collectively, these preliminary feasibility findings support the need for a definitive, larger RCT, which downstream may lead to the inclusion of home-based exercise training as part of adjuvant care for mCRPC.