Androgen Receptor Signaling Inhibitors Research Articles

External validation of biomechanical computed tomography for fracture risk classification in metastatic hormone sensitive prostate cancer.

e24077 Background: For men with metastatic hormone-sensitive prostate cancer (mHSPC) on androgen deprivation therapy (ADT), guidelines recommend dual-energy X-ray absorptiometry (DXA) screening to identify fracture risk and benefit from antiresorptive therapy. However, only 8% of men with mHSPC receive routine DXA screening. Biomechanical computed tomography (BCT) is a radiomic technique that measures bone mineral density (BMD) and bone strength from routine staging and surveillance CT scans but has not been validated in mHSPC. Methods: This retrospective cohort study included 99 patients with incident mHSPC beginning ADT (2013-2020) at one academic (n = 70) and one tertiary VA medical center (n = 29) with CT abdomen/pelvis or PET/CT imaging at baseline (within 1 year prior to ADT initiation) and follow-up (1-2 years after ADT initiation). BCT-assessed BMD T-score and femoral strength were calculated from baseline and follow-up CT scans. We evaluated the association between BCT measures and subsequent pathologic and non-pathologic fractures within 3 years following mHSPC diagnosis. Results: Among 99 patients, mean age was 68 years, 48 (48.5%) were White, and 45 (45.4%) were Black. During median follow-up of 19 months, 23 (24%) developed a pathologic and 15 (15%) a non-pathologic fracture. BCT and DXA-assessed femoral-neck BMD T-score were strongly correlated (R2= 0.94, N = 23). Higher BCT-assessed baseline BMD (Odds Ratio [OR] 0.5, p = 0.03) and bone strength (OR 0.57, p = 0.02) were each associated with decreased pathologic fracture (Table). Neither BMD nor bone strength were significantly associated with non-pathologic fracture. BCT identified 10 (10%) men eligible for antiresorptive therapy by established BMD, strength, or FRAX criteria at ADT initiation, 4 (40%) of whom never received it by the end of follow-up. Between baseline and follow-up, both BMD (-0.27) and bone strength (-0.34) decreased among patients who did not receive antiresorptive therapy (n = 76), with no difference in longitudinal change between ADT alone vs with androgen receptor signaling inhibitors. Conclusions: In this diverse, multicenter cohort of men with mHSPC beginning ADT, BCT BMD assessed from routine CT scans strongly correlated with DXA-assessed BMD. BCT measurements predicted subsequent pathologic fracture and identified additional men who would benefit from antiresorptive therapy. BCT may provide a practical method to assess the role for anti-resorptive therapy in patients with mHSPC. [Table: see text]

Prostate cancer public health system database from Brazil: Racial disparities and heterogeneity of treatment interventions to understand evidence-based practice patterns in a large real-world database.

5025 Background: The Brazilian Public National Health System (SUS) provides an opportunity to understand epidemiologic information, treatments, discrepancies in care, and costs of men with prostate cancer (PCa) using a large real-world dataset. This analysis focuses on racial disparities and heterogeneity of specific interventions to understand evidence-based practice patterns in Brazil. Additionally, the dataset can serve as a model for other low-middle income countries (LMIC). Methods: Patients included in the database were those with a diagnosis of PCa receiving care in the SUS from 01/01/2008 to 08/31/2022. Data were analyzed using a proprietary Healthcare Data Science platform offered by TECHTRIALS and included information regarding stage, demographics, cancer-related information, treatment-related information, and resources utilized. Results: 657,609 PCa pts were diagnosed and treated at SUS during the 14.5-year study period of whom 382,263 (58%) were brown/black (non-white) and 262,820 (42%) white. Median age of the population was 72.6 years, and did not vary with race. 26.16% of the pts were diagnosed with stage IV and this was not impacted by race or localization, including state or type of city (capital or not). Rates of radical prostatectomy and radiation utilization were similar between race categories. Additionally, in patients with stage IV disease, rates of systemic therapy utilization including chemotherapy with docetaxel (7.7%), with a tendency to increase use in the last years, and androgen receptor signaling inhibitors (ARSI) with (0.6%) or enzalutamide (0.08%), were low and similar between race categories. Rates of first-generation anti-androgens and estrogens were higher (56%) The total costs of prostate cancer directed care was R$4.31 billions (US$820 millions) and race did not impact total cost of care and cost by procedure or therapy type options. Conclusions: This is one of the largest studies using public health-system databases for Prostate cancer with Real World Data ever published. Race had no impact in presenting stage, treatment received and even in the costs involved. Underutilization of chemotherapy (docetaxel) in a scenario of limiting resources and without the use of new hormonal therapies is a matter of concern, together with an overuse of agents without proven survival advantage. Our data highlights the need for increased access to life prolonging agents for patients with metastatic PCa in the SUS.

A phase Ib/II study of intermittent talazoparib plus temozolomide in patients with metastatic castration-resistant prostate cancer (mCRPC) and no mutations in DNA damage repair (DDR).

e17036 Background: Poly (ADP-ribose) polymerase (PARP) inhibition exhibits an enhanced cytotoxic effect in cancers with DDR alterations, but as monotherapy has little activity for those without DDR defects. A variety of combinatorial methods utilizing PARP inhibitors are under investigation to determine if a multimodal approach could benefit patients without DDR alterations. Supported by pre-clinical models, we hypothesized that the PARP inhibitor talazoparib in combination with the chemotherapy temozolomide could induce DNA damage leading to cell death and tumor response. Methods: This is a single arm Phase 1b/2 study of escalating doses of intermittent talazoparib (Day (D) 1-6) plus temozolomide (D2-8) in 28D cycles in patients with mCRPC without DDR mutations. Patients must have failed at least one androgen receptor signaling inhibitor and may have received chemotherapy in the hormone sensitive setting. Response is determined by a composite endpoint of overall response per RECIST v1.1, PSA50% decline, and CTC conversion from >1 to 0. Pharmacokinetic samples were collected, and the mTPI-2 method was used in escalation. Results: 13 patients were enrolled across 4 dose levels in escalation. The most common adverse events were anemia (any grade (Gr) 31%, Gr3 23%), thrombocytopenia (any Gr 54%, Gr3+ 30.7%), fatigue (Gr≤2, 62%), and nausea (Gr1 46%). There was one patient with a DLT (Gr3 neutropenic fever, Gr4 thrombocytopenia). The identified RP2D was talazoparib 1 mg (D1-6) and temozolomide 75mg/m2 (D2-8). 4 (30.8%) patients met the efficacy endpoint (3 CTC responses, 1 PR, 0 PSA50% decline). While there were no PSA50 responses, 2 (15.4%) patients had a PSA30% decline. Median duration on trial was 20 weeks with 4 (30.8%) patients on trial for ≥6mos, 2 of whom also met the efficacy endpoint. Conclusions: Hematologic toxicity was dose limiting in this combination strategy using intermittent dosing of talazoparib and temozolomide in patients with mCRPC without DDR alterations. A reduction in CTCs to 0 was identified at several dose levels, and PSA30% declines were seen in 2 patients. With identification of the RP2D, enrollment in the Phase 2 study is currently underway. Clinical trial information: NCT04019327 .

Luminal and basal subtyping of circulating tumor cells and influence on outcomes in patients with metastatic castration-resistant prostate cancer.

e17034 Background: Luminal and basal subtyping using PAM50 classifier and the prostate cancer classification system (PCS) have been shown to predict outcomes and treatment response in prostate cancer (PCa). However, these genomic classifiers rely on the acquisition of tumor samples, which are usually not available in patients with metastatic castration resistant PCa (mCRPC). Circulating tumor cells (CTC) are tumors cells shed into bloodstream and can serve as surrogates of tumor. In this study, we aimed to subtype circulating tumor cells with PAM50 and PCS classifiers and evaluate their prognostic performance in mCRPC patients. Methods: A CTC RNA assay was developed by combining NanoVelcro microfluidic system for enriching CTCs and Nanostring nCounter system for PAM50 and PCS profiling of CTCs. The PAM50 and PCS genes were refined through a bioinformatic pipeline to ensure the specific profiling of CTCs. The classification and prognostic performance of the refined CTC-PAM50 and CTC-PCS gene panels were validated in GenomeDx GRID database. For the clinical study, 50 blood samples from mCRPC patients before the initiation of androgen receptor signaling inhibitors (ARSI) (n = 34) or taxanes (n = 16) were analyzed with the CTC RNA assay. Kaplan-Meier analysis and log-rank test were used to evaluate the association between CTC-PAM50/PCS subtypes and survival. Results: The refined CTC-PAM50 (36 genes) and CTC-PCS (40 genes) classifiers retained their original classification and prognostic performance in the GenomeDx GRID cohort. In the clinical study, the CTC RNA assay classified the 50 mCRPC patients into luminal A (n = 14), luminal B (n = 22), and basal (n = 14) by CTC-PAM50 classifier; and PCS1 (n = 5), PCS2 (n = 24), and PCS3 (n = 21) by CTC-PCS classifier. Overall, patients assigned as PCS1 subtype had shorter overall survival than other subtypes (hazard ratio [HR] = 4.8). In addition, basal or PCS1 subtype showed worse biochemical progression free survival than other subtypes (ARSI group: Basal: HR = 2.5; PCS1: HR = 6.9. Taxanes group: Basal: HR = 5.0; PCS1: HR = 7.2). Conclusions: Luminal and basal subtyping of CTCs is prognostic and provides a noninvasive method for molecular profiling mCRPC patients.

PSMA expression and response to 177Lu-PSMA-617 (LuPSMA) in men with vs. without DNA damage repair (DDR) mutations.

5055 Background: LuPSMA, a radioligand targeting the cell surface protein PSMA, is approved for men with PSMA-positive metastatic castration resistant prostate cancer (mCRPC) following an androgen receptor (AR)-signaling inhibitor (ARSI) and docetaxel. DNA damage repair gene (DDR) mutations are common in mCRPC, and given that ionizing radiation induces DNA damage, we hypothesized that the presence of these alterations could associate with improved clinical outcomes to LuPSMA. Data also suggests that the presence of DDR mutations may correlate with PSMA expression, providing further motivation to evaluate if DDR alterations are associated with the clinical activity of LuPSMA. Methods: We abstracted retrospective data from all patients at our center who received at least one cycle of LuPSMA per the FDA label and who had panel-based sequencing performed (e.g. UW-Oncoplex, Foundation One). Patients with somatic or germline alterations in a DDR gene were assigned to the DDR deficient cohort, while patients with somatic testing negative for a DDR gene mutation were assigned to the DDR intact cohort. Mutations in any DDR gene were considered for the purpose of stratifying between genomic subgroups. Differences in baseline PSMA SUVmean and PSA50 responses (i.e. ≥50% decline in PSA) were compared between cohorts. Results: Of 91 patients who received ≥1 cycle of LuPSMA, 54 had genetic testing. 35 (64%) received ≥2 lines of prior ARSI therapy, 30 (56%) received ≥2 lines of prior chemotherapy and 15 (28%) received prior PARP inhibitor. 21 patients had alterations in a DDR gene and the remaining 33 patients had somatic testing without an identifiable DDR mutation. PSMA SUVmean was similar between groups: 8.04 (95% CI: 6.95 - 9.12) (DDR intact) vs. 7.32 (95% CI: 6.23 – 8.41) (DDR deficient), p = 0.37. 7/33 (21%) patients in the DDR intact group achieved PSA50 response compared to 11/21 (52%) in the DDR group (p= 0.018). Survival data is immature but will be presented at the meeting. Rapid autopsy (RA) was performed in one subject with a BRCA2 mutation (baseline PSMA SUVmean 5.6) and immunohistochemistry analysis revealed profound loss of PSMA following progression on LuPSMA. Conclusions: Mutations in DDR genes were associated with a higher PSA50 response rate following LuPSMA compared to patients without a DDR mutation. There was no difference in baseline PSMA expression based on DDR mutational status, suggesting that higher response rates in the DDR cohort may have been mediated primarily by increased sensitivity to ionizing radiation. Evaluation for associations between DDR mutational status and survival endpoints is needed and will require a larger sample size and longer follow up. RA post-LuPSMA revealed loss of PSMA expression, suggesting that antigen loss may be a relevant resistance mechanism. [Table: see text]

A phase 1/2 study of combination olaparib and radium-223 in men with metastatic castration-resistant prostate cancer with bone metastases (COMRADE): A trial in progress.

TPS5110 Background: Radium-223, an α-emitting radioisotope inducing DNA double-stranded breaks leading to cell death has demonstrated improvement in overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. PARP inhibitors prevent the repair of DNA single-stranded breaks and have demonstrated clinical efficacy as monotherapy in mCRPC patients harboring alterations in the homologous recombination repair (HRR) pathway and in combination with androgen receptor signaling inhibitors irrespective of DNA repair mutation status. In preclinical models, PARP inhibitors have shown efficacy as radio sensitizing agents. We designed a phase 1/2 trial to identify the recommended phase 2 dose (RPD2) of olaparib and radium-223 and test the hypothesis that radium-223 + olaparib will demonstrate anti-tumor activity in mCRPC irrespective of homologous recombination repair deficiency (HRD) status (NCT03317392). Methods: This open-label, multicenter, phase 1/2 study evaluates the dosing, safety and efficacy of olaparib with radium-223 in men with mCRPC with bone metastases. The phase 1 component used a 3+3 dose escalation design to determine the olaparib recommended phase 2 dose (RP2D) + fixed dose radium-223 (55 kBq/kg IV every 4 weeks x 6). The phase 1 portion has completed accrual (n = 12) and demonstrated that the RP2D of olaparib is 200 mg by mouth twice daily when combined with standard dose radium-223. The phase 2 component of the study which was activated in 1/2021 is an open-label, randomized trial (1:1) evaluating olaparib + radium-223 compared to radium-223 alone. The inclusion criteria include patients with mCRPC with any number of prior therapy lines for mCRPC and ≥2 bone metastases by imaging and at least 1 lesion which has not been treated with prior radiation. Patients with visceral metastases or malignant lymphadenopathy ( > 4 cm in short diameter) are excluded. The primary endpoint for phase 2 is radiographic progression-free survival (rPFS) per PCWG3 guidelines for bone metastases and RECIST v1.1 for non-bone disease. The integrated biomarker is Oncopanel assay to determine HRR status. A key secondary endpoint will evaluate rPFS in biomarker positive and negative patients. Other secondary endpoints include time to PSA progression, PSA response, time to subsequent therapy, time to first skeletal event, and OS. Exploratory endpoints include WES/WTS of baseline biopsy tissue, assessment of RAD51 IHC and correlation with outcomes, ctDNA assessment and correlation with responses, evaluation of changes in the tumor immune microenvironment, and quality of life assessment. Target accrual is 133 patients. Clinical trial information: NCT03317392 .

Phase I trial of enzalutamide (Enz) plus the glucocorticoid receptor antagonist relacorilant (Rela) for patients with metastatic castration resistant prostate cancer.

5062 Background: Resistance to androgen receptor (AR) targeted therapies is common in mCRPC. Glucocorticoid receptor (GR) expression increases with AR inhibition in patients (pts) and blockade of GR signaling inhibits CRPC growth in preclinical models when combined with AR blockade. We thus conducted a phase I study of the combination of rela and enz in patients with mCRPC. Methods: The study used a 6+3 design to assess safety and pharmacokinetics (PK) of the 2-drug combination. The starting dose of rela 100mg/day was chosen based on current clinical studies indicating this dose was both safe for daily dosing and pharmacologically active and the starting dose for Enz was 120mg based on anticipated drug-drug interactions. Escalating doses of rela were combined with Enz 120 using pre-specified dose escalation rules. An additional 12 patients were to be assessed at the MTD to refine safety and PK profiles. Primary endpoint was safety of the combination and to establish safe and pharmacologically active doses of both agents. Key secondary endpoints were tumor response per RECIST 1.1 criteria and progression-free survival (PFS; defined as either PSA progression, radiographic progression or death). PSA was measured after 12 weeks or at the last time at which PSA data was available, including times <12 weeks. Results: 35 pts were enrolled. Pts had a median age of 74 (range 62-85) and baseline PSA of 89.5 (range 7.3-2391). 100% had prior potent AR signaling inhibitor (abi or enz) with 89% receiving prior enz, 94% prior abi, 83% prior both. 69% of pts received prior docetaxel. Median PSA change was 0.1%. Enz 120mg + Rela 100mg and Enz 120+Rela 150 were found to be safe and tolerable and achieved desirable Enz PK. DLTs were noted in 3 pts at the 200mg Rela dose, which was deemed to have exceeded the MTD, which was thus defined as 150mg Rela+120mg Enz. Most common ≥ grade 3 treatment related adverse events (TRAEs) were fatigue (11% of pts), anemia (9%), abdominal pain (6%) and pericardial effusion (6%). Median PFS was 2.5 months for 21 of 35 evaluable pts. Best response per RECIST 1.1 were Not Evaluable (40%), SD (34%) & PD (26%). No CR or PR were noted. Most common reasons for discontinuation from trial included progressive disease/hospice (82%), AEs (12%), physician discretion (3%) & death (3%). 2 pts remain on trial as of data cutoff (12/31/22). Conclusions: The combination of enzalutamide and relacorilant was safe & largely well tolerated. The majority of pts were discontinued from trial due to progressive disease or hospice. Further analyses of secondary & correlative endpoints such as translational/endocrine biomarkers, GR target gene expression and circulating tumor cells are ongoing. Clinical trial information: NCT03674814 .

Analysis of androgen receptor dynamics through immunofluorescent staining of circulating tumor cells in castration-resistant prostate cancer.

e17021 Background: Prostate adenocarcinomas are initially dependent on the androgen receptor (AR) for growth and proliferation. Androgen synthesis inhibitors and AR antagonists are the most commonly used first line treatments in metastatic prostate cancer, but these agents are not curative and virtually all tumors progress to a castration resistant state often associated with AR amplification (ARamp) and overexpression. Small molecule AR degraders designed to overcome ARamp/overexpression and other AR alterations associated with resistance are now in clinical development. In parallel, it is important to identify and validate biomarkers that predict sensitivity and inform treatment selection. Methods: CTC samples collected at progression from 114 men with metastatic castration resistant prostate cancer were stained for CK, DAPI, CD45, and AR. AR cRatio (ratio between a cell’s immunofluorescent [IF] intensity and the median IF intensity across all cells) was quantified for each CTC. Low-pass whole genome sequencing (lpWGS) was performed on candidate CK-positive (CK+) CTCs to generate copy number profiles. Cohen’s kappa was used to evaluate the relationship between AR copy number and IF at the single cell level. Dynamics in high AR expressing (ARhigh) CTCs were analyzed separately in a longitudinal cohort of patients (n = 18) from whom CTCs were collected at baseline, early on-treatment (4-12 weeks), and at progression on their 1st AR signaling inhibitor (1L-ARSI). Results: lpWGS was performed on 726 CK+ CTCs, of which 23% (170) were ARamp and 27% (195) were ARhigh (AR cRatio ≥ 3). Fifty-six percent (96/170) of CTCs with ARamp were ARhigh. Overall, a fair agreement was observed between AR copy number and IF (76.1% agreement; k = 0.37, 95%CI = 0.29 – 0.44). At baseline prior to 1L-ARSI, the median CK+ CTC burden was 7.9 CTC/mL (IQR: 1.3 – 10.5). One or more ARhigh CTC was detected in 28% (5/18) of patients, but no patient had more than 0.7 ARhigh CTCs per mL of blood. ARhigh CTCs were not observed in early on-treatment samples. At progression, the median CTC burden was 2.3 CTC/mL (IQR: 0.9 – 9.45) and, despite lower CTC burden, the emergence of a substantial (≥1 CTC/mL) ARhigh CTC subpopulation was observed in 17% (3/18) of patients. In samples with ≥1 detected CTC, the mean AR cRatio was 1.106 and 1.777 at baseline and progression, respectively. Conclusions: AR protein can be measured in CTCs with IF staining and is supported by the agreement with data from lpWGS. ARhigh CTC subpopulations can be detected at baseline for 1L-ARSI, but these cells were all cleared from circulation after 4-12 weeks of therapy. In a subset of patients at progression, resistance appears at least partially attributable to selection for ARhigh CTC subclones. [Table: see text]

Validation of an LC-MS/MS method for simultaneous quantification of abiraterone, enzalutamide and darolutamide in human plasma

Currently, several oral androgen receptor signalling inhibitors are available for the treatment of advanced prostate cancer. Quantification of plasma concentrations of these drugs is highly relevant for various purposes, such as Therapeutic Drug Monitoring (TDM) in oncology. Here, we report a liquid chromatography/tandem mass spectrometric (LC–MS/MS) method for the simultaneous quantification of abiraterone, enzalutamide, and darolutamide. The validation was performed according to the requirements of the U.S. Food and Drug Administration and European Medicine Agency. We also demonstrate the clinical applicability of the quantification of enzalutamide and darolutamide in patients with metastatic castration-resistant prostate cancer.

Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo

BackgroundCastration-resistant prostate cancer (CRPC) is currently the main challenge for prostate cancer (PCa) treatment, and there is an urgent need to find novel therapeutic targets and drugs. Prohibitin (PHB1) is a multifunctional chaperone/scaffold protein that is upregulated in various cancers and plays a pro-cancer role. FL3 is a synthetic flavagline drug that inhibits cancer cell proliferation by targeting PHB1. However, the biological functions of PHB1 in CRPC and the effect of FL3 on CRPC cells remain to be explored.MethodsSeveral public datasets were used to analyze the association between the expression level of PHB1 and PCa progression as well as outcome in PCa patients. The expression of PHB1 in human PCa specimens and PCa cell lines was examined by immunohistochemistry (IHC), qRT-PCR, and Western blot. The biological roles of PHB1 in castration resistance and underlying mechanisms were investigated by gain/loss-of-function analyses. Next, in vitro and in vivo experiments were conducted to investigate the anti-cancer effects of FL3 on CRPC cells as well as the underlying mechanisms.ResultsPHB1 expression was significantly upregulated in CRPC and was associated with poor prognosis. PHB1 promoted castration resistance of PCa cells under androgen deprivation condition. PHB1 is an androgen receptor (AR) suppressive gene, and androgen deprivation promoted the PHB1 expression and its nucleus-cytoplasmic translocation. FL3, alone or combined with the second-generation anti-androgen Enzalutamide (ENZ), suppressed CRPC cells especially ENZ-sensitive CRPC cells both in vitro and in vivo. Mechanically, we demonstrated that FL3 promoted trafficking of PHB1 from plasma membrane and mitochondria to nucleus, which in turn inhibited AR signaling as well as MAPK signaling, yet promoted apoptosis in CRPC cells.ConclusionOur data indicated that PHB1 is aberrantly upregulated in CRPC and is involved in castration resistance, as well as providing a novel rational approach for treating ENZ-sensitive CRPC.

SOX2 expression in prostate cancer drives resistance to nuclear hormone receptor signaling inhibition through the WEE1/CDK1 signaling axis

The development of androgen receptor signaling inhibitor (ARSI) drug resistance in prostate cancer (PC) remains therapeutically challenging. Our group has described the role of sex determining region Y-box 2 (SOX2) overexpression in ARSI-resistant PC. Continuing this work, we report that NR3C1, the gene encoding glucocorticoid receptor (GR), is a novel SOX2 target in PC, positively regulating its expression. Similar to ARSI treatment, SOX2-positive PC cells are insensitive to GR signaling inhibition using a GR modulating therapy. To understand SOX2-mediated nuclear hormone receptor signaling inhibitor (NHRSI) insensitivity, we performed RNA-seq in SOX2-positive and -negative PC cells following NHRSI treatment. RNA-seq prioritized differentially regulated genes mediating the cell cycle, including G2 checkpoint WEE1 Kinase (WEE1) and cyclin-dependent kinase 1 (CDK1). Additionally, WEE1 and CDK1 were differentially expressed in PC patient tumors dichotomized by high vs low SOX2 gene expression. Importantly, pharmacological targeting of WEE1 (WEE1i) in combination with an ARSI or GR modulator re-sensitizes SOX2-positive PC cells to nuclear hormone receptor signaling inhibition in vitro, and WEE1i combined with ARSI significantly slowed tumor growth in vivo. Collectively, our data suggest SOX2 predicts NHRSI resistance, and simultaneously indicates the addition of WEE1i to improve therapeutic efficacy of NHRSIs in SOX2-positive PC.

Identification and verification of an ALYREF-involved 5-methylcytosine based signature for stratification of prostate cancer patients and prediction of clinical outcome and response to therapies

ObjectivesDue to the heterogeneity of PCa, the clinical indicators used for PCa can't satisfy risk prognostication and personalized treatment. It is imperative to develop novel biomarkers for prognosis prediction and therapy response in PCa. Accumulating evidence shows that non-mutational epigenetic reprogramming, independent from genomic instability and mutation, serves as a newly added hallmark in cancer progression.MethodsIn this study, we integrated multi-center cohorts (N > 1300) to develop a RNA 5-methylcytosine regulator-based signature, the m5C score. We performed unsupervised clustering and LASSO regression to identify novel m5C-related subtypes and calculate the m5C score. Then we assessed the role of m5C cluster and m5C score in several clinical aspects such as prognosis in various molecular subtypes, responses to chemotherapy, androgen receptor signaling inhibitor (ARSI) therapy and immunotherapy in PCa. Finally, we validated the cancer-promoting performance of ALYREF through clinical data analysis and experiments in vivo and in vitro.ResultsThe investigation revealed that the m5C score could accurately predict the biochemical recurrence (BCR) in different subtypes (the PAM50 subtypes and immunophenotypes) and the responses to chemotherapy, ARSI therapy, and immunotherapy (PD1/PD-L1). A high m5C score indicated a poor BCR prognosis in every subtype of PCa, unfavorable responses in ARSI therapy and immunotherapy (PD1/PD-L1). Moreover, the m5C reader gene termed ALYREF, yielding the highest weighed coefficient, promoted PCa progression through in silico analysis and experimental validations (in vivo and in vitro).ConclusionsThe m5C signature can function in many aspects of PCa, such as the development and prognosis of the disease, and multiple therapy responses. Further, the m5C reader, ALYREF, was identified as a prognostic biomarker and a potential therapeutic target for PCa. The m5C signature could act as a brand-new tool for predicting the prognosis of patients in different molecular subtypes and patients’ therapy responses and promoting customized treatments.

Metastatic prostate cancer management: 20 years of progress

Since 1940, patients with metastatic prostate cancer were given androgen deprivation therapy alone. In 2013, the addition of docetaxel improved progression-free survival and overall survival in patients with metastatic hormone-sensitive prostate cancer. 1 Gravis G Fizazi K Joly F et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013; 14: 149-158 Summary Full Text Full Text PDF PubMed Scopus (528) Google Scholar , 2 Sweeney CJ Chen YH Carducci M et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015; 373: 737-746 Crossref PubMed Scopus (1831) Google Scholar After 2013, the combination of abiraterone acetate plus prednisolone with androgen deprivation therapy increased overall survival, as did the addition of other androgen receptor signalling inhibitors (such as enzalutamide or apalutamide) to standard androgen deprivation therapy. 3 James ND de Bono JS Spears MR et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017; 377: 338-351 Crossref PubMed Scopus (1091) Google Scholar , 4 Davis ID Martin AJ Stockler MR et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019; 381: 121-131 Crossref PubMed Scopus (734) Google Scholar , 5 Chi KN Chowdhury S Bjartell A et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021; 39: 2294-2303 Crossref PubMed Scopus (124) Google Scholar In 2022, the triple combination of androgen deprivation therapy, docetaxel, and abiraterone or darolutamide showed improved overall survival compared with androgen deprivation therapy plus docetaxel. 6 Fizazi K Foulon S Carles J et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022; 399: 1695-1707 Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar , 7 Smith MR Hussain M Saad F et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022; 386: 1132-1142 Crossref PubMed Scopus (153) Google Scholar Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocolEnzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Full-Text PDF Open Access

Comparison of prostate-specific antigen response in patients with metastatic castration-sensitive prostate cancer initiated on apalutamide or abiraterone acetate: A retrospective cohort study.

Deep prostate-specific antigen (PSA) response (≥90% reduction in PSA [PSA90]) is an important early response indicator of radiographic progression-free survival and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC). This study compared PSA90 responses by 6 months between patients with mCSPC at first use of apalutamide or abiraterone acetate, both androgen receptor signaling inhibitors. Clinical data from 77 community urology practices in the United States were analyzed. Patients with mCSPC were classified into treatment cohorts based on their first filled prescription (index date) for apalutamide or abiraterone acetate on or after September 17, 2019 (approval date of apalutamide for mCSPC). Patients were followed from the index date until the earliest of index treatment discontinuation, treatment switch, end of clinical activity, or end of data availability (September 17, 2021). Inverse probability of treatment weighting (IPTW) was used to ensure similarity in distribution of baseline characteristics between cohorts. PSA90 was defined as the earliest attainment of ≥90% reduction in PSA relative to baseline (most recent value within 13 weeks pre-index). Time to PSA90 between cohorts was compared by weighted Kaplan-Meier analysis and with Cox proportional hazards models. A total of 364 patients treated with apalutamide and 147 treated with abiraterone acetate met the study criteria. Patient characteristics were well balanced after IPTW. By 6 months post-index, patients initiated on apalutamide were 53% more likely to achieve PSA90 than those initiated on abiraterone acetate (P = 0.016). Similar results were observed by 9 and 12 months post-index (both P ≤ 0.019). The median time to PSA90 was 3.5 months for the apalutamide cohort and not reached for the abiraterone acetate cohort. In real-world patients with mCSPC, significantly more patients achieved PSA90 with apalutamide than with abiraterone acetate, and this response was achieved earlier with apalutamide.

Advances in preclinical models of prostate cancer for research discovery.

There is longstanding interest in the role of androgens in the aetiology of prostate cancer, one of the most common malignancies worldwide. In this review, we reflect on the ways that knowledge of prostate development and hormone action have catalysed advances in the management of patients with prostate cancer. The use of hormone therapies to treat prostate cancer has changed significantly over time, including the emergence of androgen receptor signalling inhibitors (ARSI). These compounds have improved outcomes for patients with castration-resistant prostate cancer, which was once considered 'androgen-independent' but is clearly still driven by androgen receptor signalling in many cases. There is also a need for new therapies to manage neuroendocrine prostate cancer, which is not responsive to hormonal agents. One of the major gaps is understanding how treatment-induced neuroendocrine prostate cancer emerges and whether it can be re-sensitised to treatment. Patient-derived models, including patient-derived xenografts (PDXs), will be instrumental in facilitating future discoveries in these areas. Developments in the use of PDXs have been fostered by lessons from the field of endocrinology, such as the role of stroma and hormones in normal and developmental tissues. Thus, there is ongoing reciprocity between the discoveries in endocrinology and advances in prostate cancer research and treatment.

Attainment of early, deep prostate-specific antigen response in metastatic castration-sensitive prostate cancer: A comparison of patients initiated on apalutamide or enzalutamide.

Deep prostate-specific antigen (PSA) response, defined as a ≥90% decline in PSA (PSA90), is an important early response indicator for achieving radiographic progression-free and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with a next-generation androgen signaling inhibitor (ASI), such as apalutamide or enzalutamide. The objective of this study was to compare deep PSA response among patients with mCSPC newly initiated on apalutamide or enzalutamide. Clinical data from 69 community urology practices in the United States were evaluated. Patients with mCSPC were classified into cohorts based on their first dispensation (index date) for apalutamide or enzalutamide and were followed until the earliest of treatment discontinuation, initiation of a new next-generation androgen receptor signaling inhibitor, end of clinical activity (including death), or end of data availability (03/05/2021). Inverse probability of treatment weights (IPTW) were used to reduce baseline confounding. PSA90 was defined as the earliest ≥90% PSA decline relative to baseline PSA. The proportion of patients achieving PSA90 and time to PSA90 were reported using weighted Kaplan-Meier analysis and weighted Cox proportional hazards models, respectively. The apalutamide and enzalutamide cohorts comprised 186 and 165 patients, respectively. Patient characteristics were generally well balanced after IPTW. By 6 months, patients initiated on apalutamide had a 56% greater likelihood of attaining PSA90 than those initiated on enzalutamide (P = 0.014). This result remained significant through the end of the observation period. The median time to achieving PSA90 was 3.1 months with apalutamide and 5.2 months with enzalutamide. This real-world study demonstrated that apalutamide initiation is associated with a significantly higher likelihood of achieving ≥90% reduction in PSA as compared to initiation of enzalutamide. Moreover, this deep PSA response was observed to occur earlier with apalutamide treatment than with enzalutamide.

The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer.

Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A and KDM5 in androgen signalling in PCa. Our findings support the further development of KDM1A and KDM5B inhibitors to treat advanced PCa. Further work is now required to confirm the therapeutic feasibility of combined inhibition of KDM1A and KDM5B as a novel therapeutic strategy for targeting AR positive CRPC.

Abstract CT121: ARX517, an anti-PSMA ADC targeting mCRPC resistant or refractory to standard therapies: A phase 1 dose escalation and dose expansion study (ARX517-2011, NCT04662580)

Abstract Background: Targeted therapies against prostate-specific membrane antigen (PSMA) have exhibited promising antitumor activity in prostate cancer. With the FDA’s approval of (177) Lu-PSMA-617, PSMA has been validated as a target to treat metastatic castration-resistant prostate cancer (mCRPC). ARX517 is an antibody-drug conjugates (ADC) composed of a fully humanized anti-PSMA mAb site-specifically conjugated to AS269, a potent tubulin inhibitor, yielding a drug-to-antibody (DAR) ratio of 2. After binding to PSMA on the surface of cancer cells, ARX517 is internalized and delivers a cytotoxic payload which inhibits tubulin polymerization and induces cellular apoptosis. ARX517’s site-specific linkage, stable conjugation chemistry, and non-cleavable linker exhibit a homogenous drug-antibody-ratio, mAb-like biophysical properties, and exceptional stability. Therefore, ARX517 promotes highly specific tumor cell apoptosis with minimal off-target bystander activity. Trial Design: The Phase 1 study’s dose escalation and dose expansion evaluates the safety, pharmacokinetics, and preliminary evidence of anti-tumor activity of ARX517 in adults with mCRPC. Patients must have mCRPC which is resistant or refractory to standard therapies, including androgen receptor signaling inhibitors, and show disease progression by Prostate Cancer Working Group 3 (PCWG3) criteria. All patients must have adequate organ function and brain metastases must be radiographically stable. Ascending dose levels of ARX517 administered as a single agent will use an i3+3 design in the dose escalation phase. During the dose expansion phase, ARX517 will be administered at the recommended phase 2 dose (RP2D) or maximum tolerated dose (MTD). Exploratory pharmacodynamic assessment includes PSMA-PET/CT imaging. The total number of subjects is dependent on the number of ascending doses and cohort size before dose expansion. Status: ARX517-2011 began enrolling patients in July 2021. With no dose limiting toxicities through dose level 6 (2.0 mg/kg Q3W), dose escalation remains ongoing. As of January 2023, the APEX-01 study is currently enrolling in cohort 7 (2.4 mg/kg) of dose-escalation. Dose expansion will start after RP2D or MTD. Citation Format: John Shen, Richard Pachynski, Luke Nordquist, Nabil Adra, Mehmet Bilen, Rahul Aggarwal, Zachary Reichert, Michael Schweizer, Dong Xu, Manan Patel, Jin Zhang, Wenge Shi, Darryl Z. L'Heureux, Scott Tagawa. ARX517, an anti-PSMA ADC targeting mCRPC resistant or refractory to standard therapies: A phase 1 dose escalation and dose expansion study (ARX517-2011, NCT04662580) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT121.

Health-related quality of life in patients with metastatic hormone-sensitive prostate cancer treated with androgen receptor signaling inhibitors: the role of combination treatment therapy.

While the addition of androgen receptor signaling inhibitors (ARSIs) to androgen deprivation therapy (ADT) results in better of overall survival in patients with metastatic hormone-sensitive prostate cancer (mHSPC), information regarding health related quality of life (HR-QoL) is sparse. We aimed at summarizing current evidence on the impact of ARSIs on HR-QoL. We performed a systematic review of the published literature on PubMed/EMBASE, Web of Science, SCOPUS, and the Cochrane libraries between January 2011 and April 2022. We included only phase III randomized controlled trials (RCT), which were selected according to the PRISMA guidelines. We aimed at evaluating differences in HR-QoL, assessed by validated patient reported outcomes instruments. We analyzed global scores and sub-domains such as sexual functioning, urinary symptoms, bowel symptoms, pain/fatigue, emotional and social/family wellbeing. We reported data descriptively. Six RCTs were included: two used enzalutamide with ADT as intervention arms (ARCHES, ENZAMET); one used apalutamide with ADT (TITAN); two abiraterone acetate and prednisone (AAP) with ADT (STAMPEDE, LATITUDE); and one darolutamide with ADT (ARASENS). Enzalutamide or AAP with ADT increase overall HR-QoL in comparison with ADT alone, ADT with first generation nonsteroideal anti-androgens or ADT with docetaxel, whereas apalutamide and darolutamide with ADT maintain HR-QoL similarly to ADT alone or ADT with docetaxel, respectively. Time to first deterioration of pain was longer with combination therapy with enzalutamide, AAP or darolutamide, but not with apalutamide. No worsening of emotional wellbeing was reported from the addition of ARSIs to ADT than ADT alone. The addition of ARSIs to ADT in mHSPC tends to increase overall HR-QoL and prolong time to first deterioration of pain/fatigue compared with ADT alone, ADT with first generation nonsteroideal anti-androgens, and ADT with docetaxel. ARSIs show a complex interaction with remaining HR-QoL domains. We advocate a standardization of HR-QoL measurement and reporting to allow further comparisons.

A prognostic signature consisting of N6-methyladenosine modified mRNAs demonstrates clinical potential in prediction of biochemical recurrence and guidance on precision therapy in prostate cancer

Novel biomarkers are urgently needed to improve the prediction of clinical outcomes and guide personalized treatment for prostate cancer (PCa) patients. However, the role of N6-methyladenosine (m6A) modifications in PCa initiation and progression remains largely elusive. In our study, we collected benign Prostate Hyperplasia (BPH), localized PCa, and metastatic PCa samples from patients and performed methylated RNA immunoprecipitation sequencing (MeRIP-Seq) to map m6A-methylated mRNAs. Furthermore, we developed a prognostic signature based on 239 differentially methylated RNAs and the TCGA-PRAD dataset, which can be used to calculate an m6A-modified mRNA (MMM) score for a PCa patient, validated by independent multi-center cohorts. Our findings revealed that differential m6A modifications were positively correlated with altered expressions of mapped m6A-modified mRNAs. Higher MMM scores were associated with shorter times to biochemical recurrence (BCR) in PCa patients, and the MMM scoring system outperformed three well-established signatures in nine independent validation cohorts, as demonstrated by Kaplan-Meier survival analysis, C-index and ROC. Patients who did not respond to androgen receptor signaling inhibitor (ARSI) therapy and immunotherapy were found to have high MMM scores. Two hub genes, TLE1 and PFKL, were confirmed to have m6A sites through MeRIP-qPCR, and their knockdown promoted PCa cell invasion. Bioinformatics analysis of single-cell databases identified cell types with high transcript abundance levels of these two genes. In summary, our study is the first to perform transcriptome-wide m6A mapping in prostate tissues. The translational potential of a prognostic signature, comprising m6A-methylated mRNAs, in predicting clinical outcomes and therapy responses for PCa patients, is demonstrated.