Androgen Receptor Signaling Inhibitors Research Articles

Apalutamide, Darolutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC): A Critical Review.

Simple SummaryApalutamide, darolutamide and enzalutamide are androgen-receptor signaling inhibitors proved to be useful in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Although computed tomography and bone scans have been used to identify patients with nmCRPC in pivotal trials, currently, novel imaging techniques are widely used to stage patients, and they can detect metastases in many men with nmCRPC who are negative to conventional imaging. This review aims at discussing the role of apalutamide, darolutamide and enzalutamide in nmCRPC and the clinical implications of novel imaging techniques during treatment choice. Nonmetastatic castration-resistant prostate cancer (nmCRPC) represents a condition in which patients with prostate cancer show biochemical progression during treatment with androgen-deprivation therapy (ADT) without signs of radiographic progression according to conventional imaging. The SPARTAN, ARAMIS and PROSPER trials showed that apalutamide, darolutamide and enzalutamide, respectively, prolong metastasis-free survival (MFS) and overall survival (OS) of nmCRPC patients with a short PSA doubling time, and these antiandrogens have been recently introduced in clinical practice as a new standard of care. No direct comparison of these three agents has been conducted to support treatment choice. In addition, a significant proportion of nmCRPC on conventional imaging is classified as metastatic with new imaging modalities such as the prostate-specific membrane antigen positron emission tomography (PSMA-PET). Some experts posit that these “new metastatic” patients should be treated as mCRPC, resizing the impact of nmCRPC trials, whereas other authors suggest that they should be treated as nmCRPC patients, based on the design of pivotal trials. This review discusses the most convincing evidence regarding the use of novel antiandrogens in patients with nmCRPC and the implications of novel imaging techniques for treatment selection.

Feasibility of home-based exercise training in men with metastatic castration-resistant prostate cancer.

Home-based training increases accessibility to exercise and mitigates the side effects of hormone therapy for prostate cancer (PC). However, it is unknown if men with more advanced disease are willing to partake in such interventions. To determine the feasibility of a home-based exercise intervention in men with metastatic castration-resistant prostate cancer (mCRPC). mCRPC patients on androgen receptor signaling inhibitors (ARSI) were prescribed a 12-week, home-based exercise intervention using resistance bands and walking. Feasibility was assessed using recruitment, retention, adherence, and outcome capture. Physiological changes and patient reported outcomes were assessed before and after the intervention. Of the 62 referrals, 47 were eligible with 22 men performing baseline testing (47% recruitment rate) and 16 completing the intervention (73% retention). Task completion was >86% for all physiological tests. Walking adherence was 80% and resistance training was 63%, the latter falling short of the study target (75%). Training increased thigh muscle cross-sectional area by 22%, time to exhaustion by 19% (both p < 0.05) and peak oxygen uptake by 6% (p = 0.057). Improvements in short physical performance battery scores and 400 m walk demonstrated moderate effect sizes that did not reach significance. Home-based exercise is feasible during ARSI treatment for mCRPC. Greater endurance capacity and localized hypertrophy appear as the primary improvements following training. These preliminary findings suggest home-based training may increase exercise accessibility, with important lessons that will inform subsequent trials investigating the efficacy of home-based exercise interventions during mCRPC.

A randomized controlled trial comparing changes in fitness with or without supervised exercise in patients initiated on enzalutamide and androgen deprivation therapy for non-metastatic castration-sensitive prostate cancer (EXTEND).

Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSI) are associated with deleterious physical effects, which exercise may mitigate; however, exercise has never been studied in patients initiating treatment with ADT and an ARSI. Our objective was to determine whether supervised exercise prior to and during initial therapy could mitigate adverse effects of ADT plus enzalutamide. We conducted a single center trial in patients with recurrent prostate cancer treated with ADT and enzalutamide. We randomized 26 patients to 16 weeks of supervised exercise (aerobic and resistance), starting 4 weeks before initiation of ADT and enzalutamide, or usual care. The primary endpoint was change in peak oxygen uptake (VO2peak) as a measure of cardiorespiratory fitness (CRF). Secondary endpoints were functional capacity, maximal strength, body composition, patient-reported outcomes, safety, and feasibility. Analysis of covariance was used to compare outcomes for groups at Week 17 adjusted for baseline values. The usual care group (N = 13) showed declines from baseline to week 17 in both absolute CRF (-0.31 L/min, -10.9%; p < 0.01) and relative CRF (-3.2 mL/kg/min, -8.9%; p = 0.04); worse fatigue (p = 0.01); and worse quality of life (p = 0.01). At week 17, the exercise group (N = 13) demonstrated improved absolute CRF (between-group change +0.20 L/min, p = 0.05), leg strength (+48.6 kg, p < 0.01) and functional capacity (+21.0 m, p = 0.01) at week 17. This is the first randomized controlled trial demonstrating a clinically significant decline in CRF in patients initiating ADT and enzalutamide. We show the effectiveness of short-term supervised exercise to mitigate declines in absolute CRF, and improve maximal leg strength and functional capacity. NCT02256111.

Phase I/II trial of pembrolizumab and AR signaling inhibitor +/- 225Ac-J591 for chemo-naive metastatic castration-resistant prostate cancer (mCRPC).

TPS216 Background: The role of immune checkpoint inhibition (ICI) in prostate cancer remains undefined outside of the subset with mismatch repair. Several studies have suggested that ICI combined with androgen receptor signaling inhibitors (ARSI) or kinase inhibitors may result in improved and/or more durable response in a proportion of men with mCRPC. While not yet proven, addition of external beam radiation to ICI may improve outcomes (for instance Kwon et al Lancet Oncol 2014, Fizazi K et al, Eur Urol 2020). PSMA targeted therapy with 177Lu-PSMA-617 improves survival in men with CRPC, has been combined with ICI in early phase studies, and we have previously demonstrated the benefit of PSMA targeted therapy using radiolabeled mAb J591. PSMA-targeted alpha-emitters have a very high potency and the potential to generate immune response. Based upon i) ARSI may increase PSMA expression, ii) ARSI may radiosensitize tumors, iii) ARSI resistance may lead to increased PD-L1 expression, and iv) alpha emitters may generate an immune response, we hypothesize that the addition of an alpha-emitting radionuclide (225Ac) targeting prostate cancer (i.e PSMA+ tumors targeted with J591) will lead to double-stranded DNA breaks, cell death, and subsequent release of neoantigens, and thus will increase the response proportion to pembrolizumab plus ARSI resulting in more durable response. Methods: Key eligibility criteria include progressive mCRPC by PCWG3 on at least 1 prior AR pathway inhibitor and no prior chemotherapy for mCRPC. A phase I dose-finding study will first test safety of the triplet combination of pembrolizumab, an ARSI of physician choice, and 2 different doses of 225Ac-J591 (one with minimal and one with moderate single-agent toxicity). Following determination of the optimal dose, a randomized phase II trial will treat subjects with a fixed dose of pembrolizumab 400 mg every 6 weeks (for up to 2 years) plus a standard ARSI (until progression or intolerance) with or without 225Ac-J591. The primary endpoint of the study will test the hypothesis that the addition of a PSMA-targeted alpha emitter increases the composite of RECIST measurable disease, PSA, and CTC count response to immuno-hormonal therapy with 90% power. Key secondary clinical endpoints include 1-year progression-free survival, duration of response, and overall survival. Exploratory objectives include assessment of immunogenic cell death, immune serologic and host microbiome changes, plasma ctDNA, serial PSMA PET, and patient reported outcomes (FACT-P, BPI, EQ-5D-5L). The phase I portion of this DOD-funded study was activated in summer 2021 with the randomized phase II portion expected to open at PCCTC sites in 2022. Clinical trial information: NCT04946370.

Association of circulating tumor cell RB1 loss RNA signature with outcomes and immune phenotypes in men with mCRPC.

139 Background: Androgen receptor signaling inhibitors (ARSi) are a mainstay for patients with metastatic castration-resistant prostate cancer (mCRPC). However, patient response is heterogeneous and the molecular underpinnings of ARSi resistance are not well elucidated. Methods: We performed transcriptome analysis of circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMC) in the context of PROPHECY, a prospective clinical trial of men (n = 118) with mCRPC treated with abiraterone (Abi) or enzalutamide (Enza). We obtained CTCs at baseline (before treatment) and at the time of progression on Abi/Enza, performed a comprehensive transcriptomic analysis of CTC patient samples (n = 40) and correlated with clinical outcomes to identify mechanisms of ARSi resistance. In addition, we also performed a transcriptomic analysis of matching peripheral blood mononuclear cells (PBMCs) in order to uncover potential involvement of the circulating immune macroenvironment (CIME) in ARSi resistance. The proportional hazard model was used to determine the prognostic significance of these signatures in predicting overall survival (OS) and progression-free survival (PFS). Results: CTC RNA-sequencing identified that RB loss concurrently with enhanced E2F signaling transcriptional networks were associated with intrinsic ARSi resistance. Using single sample GSEA (ssGSEA) score, we identified that the RB/E2F common signature at baseline was associated with short PFS (median PFS = 6.5 months) and OS (median OS = 24.5 months) (hazard ratio (HR) = 3.5; 95% CI 1.5-8.2) in men with mCRPC. We further developed a BRCA loss transcriptional signature which we validated in the SU2C mCRPC patient cohort, by showing that BRCA loss transcriptional network reflected BRCA genomic alterations as it was significantly enriched in the SU2C BRCA-altered patients vs unaltered patients. Generating BRCA loss ssGSEA scores in the PROPHECY cohort we observed that patients with high BRCA loss scores at baseline experienced shorter OS (HR = 2.42; 95% CI = 1-5.9). Through the comparison of CTC transcriptomic profiles at progression with baseline, we identified an inflammatory response signature in CTCs which was significantly associated with acquired ARSi resistance. Transcriptomic analysis of matching PBMCs identified enrichment of inflammasome gene signatures indicative of activated innate immunity at progression, with concurrent downregulation of CD8 T and NK cells. Importantly, CTC gene signatures of RB loss/E2F signaling had a significant positive association with this CIME signatures. Conclusions: Taken together, these data demonstrate that liquid biopsy transcriptomics of both tumor cells and immune cells can identify molecular pathways associated with clinical ARSi resistance paving the way for treatment optimization and the development of novel precision therapies in patients with mCRPC.

A randomized mCRPC phase 2b study of the BET bromodomain inhibitor (BETi) zen-3694 and enzalutamide vesus enzalutamide.

TPS201 Background: Androgen receptor signaling inhibitors (ARSI), such as enzalutamide (Enza), and abiraterone (Abi), are standard therapies for metastatic hormone-sensitive and metastatic castration-resistant prostate cancer (mHSPC, mCRPC). Patients who respond to the initial ARSI are frequently prescribed a second ARSI upon progression. However, a suboptimal response to first line ARSI, including the ̃ 20% treated with an ARSI for mHSPC who progress within 12 months of treatment initiation, may enrich for cancers harboring AR-independent mechanisms of resistance including treatment-emergent neuroendocrine prostate cancer (t-NEPC). Recently, BETi have been shown pre-clinically to block the neuroendocrine prostate cancer lineage plasticity program through modulating E2F1, a transcription factor involved in stemness and cell differentiation. Prior results from a mCRPC Ph. 1b/2a trial of ZEN-3694+ Enza support this notion, as lower AR transcriptional activity in baseline tumor biopsies was associated with longer radiographic progression-free survival (rPFS). Additionally, mCRPC patients who were primary refractory to first-line abiraterone had prolonged rPFS with ZEN-3694 + Enza, suggesting that the patients with primary resistance may benefit from the combination. To test this hypothesis, a Ph. 2b randomized trial has been initiated, enriching for mCRPC with suboptimal response to first-line ARSI. Methods: This is a multi-national, open-label, randomized, two cohort, Ph. 2b study of ZEN-3694 + Enza vs. Enza in mCRPC patients who have progressed on Abi (NCT04986423). Cohort A (N = 150): Patients with poor response to Abi defined either as progression in &lt; 12 months or failure to achieve PSA nadir of 0.2 ng/mL while taking Abi in HSPC setting, or progression in &lt; 6 months and/or failure to achieve a PSA50 response while taking Abi in the CRPC setting. Cohort B (N = 50): Patients who responded to Abi, defined as &gt; 12 months duration without progression while on Abi in the HSPC setting and achieving a nadir PSA &lt; 0.2 ng/mL, or &gt; 6 months duration without progression while on Abi in the CRPC setting and confirmed PSA50 response. The primary endpoint is radiographic progression-free survival (rPFS) by blinded independent central review (BICR) in Cohort A evaluated by PCWG3. Key secondary endpoints include rPFS by BICR for Cohorts A + B, PFS by investigator assessment, overall survival, PSA50 response rate, objective response rate by RECIST 1.1, and patient-reported health status and quality of life, evaluated in Cohorts A, and Cohorts A + B together. The trial, conducted in collaboration with Newsoara is expected to enroll 200 participants, and the first patient was dosed in October 2021. Astellas is providing the enzalutamide for this study. Clinical trial information: NCT04986423.

Association of changing bone metastatic (mets) patterns with dynamics of circulating tumor DNA (ctDNA) in metastatic castration-resistant prostate cancer (mCRPC).

152 Background: Accurate monitoring response of bone mets to treatment is an active need for mCRPC patients (pts). Recently, ctDNA has been showed as an early biomarker efficacy of androgen receptor signaling inhibitor (ARSI) therapy for mCRPC ( Conteduca, Br J Cancer 2020). In this study, we aimed to reveal if ctDNA analysis can permit more reliable prediction of bone mets burden and radiographic progression disease (PD). Methods: In a biomarker study (REC 2192/2013), targeted next generation sequencing was performed to assess ctDNA fraction. Radiographic evidence of bone disease was documented by conventional imaging according to PCWG3 criteria ( Scher, J Clin Oncol 2018), and was classified on the basis of mets number (≤5, 6 -19, ≥20) in oligometastatic (O), diffuse (D), and widespread (W), respectively. Associations were explored both through uni/multivariate logistic regressions. Results: Serial plasma samples and radiographic scans on ARSI treatment were prospectively collected from 73 CRPC with bone mets. Median age was 74 years [interquartile range (IQR) 69-79]. Bone mets patterns were significantly associated with median baseline ctDNA level (O = 0.16, D = 0.33, and W = 0.46, p 0.0003). Similar results were reported on treatment and at PD (p 0.0003 and p 0.0007, respectively). In 24 pts with a progressive worsening of bone mets pattern (O→D→W) compared to pts with no change in bone mets pattern on ARSI, we observed an early meaningful ctDNA rise with a % ctDNA variation from baseline to 3 month therapy of 150.6% (IQR 104.9-210.7) vs 11.1% (IQR 0-36.6), p &lt; 0.0001. Univariate analysis showed that early ctDNA rise was significantly associated with radiographic progression free/overall survival (rPFS/OS): hazard ratio (HR) 2.06, 95% confidence interval (CI) 1.30-3.27, p 0.002, and HR 1.82, 95% CI 1.15-2.88, p 0.01, respectively]. In multivariable analyses including ctDNA variation, changing bone mets pattern, age, performance status, and presence of concomitant visceral mets, ctDNA change at 3 month ARSI resulted the only independent predictor of both rPFS/OS (HR 2.27, 95% CI 1.04-4.94, p 0.027 and HR 2.98, 95% CI 1.31-6.81, p 0.033, respectively). Visceral mets were associated with only OS (HR 3.87, 95% CI 1.76-8.51, p 0.0008). Conclusions: Early ctDNA variation may reflect changes in bone mets pattern on ARSI allowing to track pattern of bone progression and predict outcome. Further studies to validate these findings are warranted.

A randomized phase 2 trial to evaluate the antitumor activity of enzalutamide (EZ) and talazoparib (TALA) for the treatment of metastatic hormone-naïve prostate cancer (mHNPC): ZZFIRST.

TPS209 Background: Multiple lines of evidence suggest a crosstalk between androgen receptor (AR) signaling and DNA damage repair (DDR) in prostate cancer. Co-targeting both pathways in mHNPC can result in a clinically relevant synergistic effect. ZZFIRST trial is evaluating the combination of TALA –a poly(ADP-ribose) polymerase inhibitor– and EZ –an AR signaling inhibitor– in mHNPC patients. Methods: This is a multicenter, open-label, randomized, investigator-initiated phase 2 clinical trial. Men aged ≥18 years with histologically confirmed mHNPC, an ECOG performance status of 0-1, and a prostate-specific antigen (PSA) ≥4 ng/mL at enrolment are eligible. Patients must have not received previous systemic treatment for locally advanced or mHNPC. A total of 54 patients will start treatment with EZ 160 mg/day for 2 28-day cycles in addition to standard androgen-deprivation therapy (ADT). Patients are then randomized and stratified based on homologous recombination gene alterations on a 1:2 ratio to either continue EZ 160 mg/day, or to receive EZ 160 mg/day plus TALA 0.5 mg/day. In both arms, patients will continue ADT throughout the trial. Treatment will continue until progressive disease (PD) or unacceptable toxicity. PSA will be determined every 4 weeks and radiological tumor extend will be assessed at screening and every 8 weeks for the 6 initial months of treatment and every 12 weeks thereafter until PD. Primary endpoint is PSA-complete response defined as the percentage of patients with PSA &lt; 0.2 ng/mL at 12 months of therapy. Secondary endpoints include PSA-complete response at any time point and at month 7, PSA response ( &lt; 4 ng/ml) at 7 and 12 months, PSA-progression-free survival (PSA-PFS), radiologic PFS, time to castration resistance based on PSA-PFS and rPFS, and overall survival. Safety will be assessed as per NCI-CTCAE 5.0. Exploratory endpoints include analysis of transcriptional changes in AR and DDR pathways and assessment of genomic signatures on tumor and liquid biopsies collected at baseline, 4 weeks, and PD. An imaging sub-study of whole-body diffusion weighted MRI will help to further study antitumor activity and drug resistance mechanisms. This trial was opened to accrual in July 2020. Currently 44 patients have been enrolled (with 37 randomized by cycle 3 day 1) out of 54 expected. Analysis will be assessed with the exact binomial test. At least 11 patients must maintain PSA &lt; 0.2 ng/mL by 12 months of therapy among 32 evaluable patients in the combination arm to justify further investigation of this strategy. A drop-out rate of 10% has been considered. Clinical trial information: NCT04332744.

Modulation of the plasma lipidomic profile with simvastatin in metastatic castration-resistant prostate cancer (mCRPC).

154 Background: Elevated circulating sphingolipids are associated with poorer outcomes across the natural history of prostate cancer (PC), including metastatic relapse in localised PC, earlier androgen deprivation failure in metastatic hormone-sensitive PC, and shorter overall survival (OS) in mCRPC. We have derived and validated a poor prognostic 3-lipid signature (3LS) [consisting of ceramide Cer(d18:1/24:1), sphingomyelin SM(d18:2/16:0) and phosphatidylcholine PC(16:0/16:0)], which was independently associated with shorter radiographic progression-free survival (rPFS) and OS in men with mCRPC commencing taxanes or androgen receptor signaling inhibitors (ARSI). Statins significantly reduce plasma levels of ceramides, sphingomyelin and cholesterol in cardiovascular disease. We hypothesised that this therapy could change the poor prognostic lipid profile of patients with mCRPC. This study assessed whether the addition of simvastatin to standard treatment for mCRPC modulates the circulating lipidomic profile. Methods: This investigator-initiated, multi-centre, single arm, pilot study enrolled men with mCRPC commencing taxanes or ARSI for disease progression, who were not on a lipid-lowering agent. Men were treated with simvastatin 40mg orally once daily for 12 weeks, commencing on day 1 of treatment for mCRPC. Plasma was taken at baseline and after 12 weeks of simvastatin, and underwent lipidomic profiling of ̃800 lipids. Differences in lipid levels between baseline and post-simvastatin samples and between those with and without the 3LS were assessed using t-tests. Results: 27 men (74% on taxanes, 26% on ARSI) were recruited between May 2018 to March 2021. 46% of the men had the poor prognostic 3LS at baseline, of whom 45% lost the 3LS after simvastatin. Comparison between all paired baseline and post-simvastatin samples showed significant reduction (p &lt; 0.05) in free cholesterol, cholesteryl esters and some sphingolipids (sphingomyelins, hexosylceramides) with simvastatin treatment. Baseline profiles with the 3LS displayed significantly higher levels (p &lt; 0.05) of ceramides, hexosylceramides and sphingomyelins, relative to baseline profiles without the 3LS. Men who lost the 3LS after treatment (n = 5) demonstrated significant reductions in ceramides (23-45%, p≤0.046), hexosylceramides (27-52%, p≤0.049) and sphingomyelins (28-44%, p≤0.047). These changes were not seen in men with persistent 3LS after treatment (n = 6). Conclusions: Simvastatin in addition to standard treatment for mCRPC can modulate the circulating lipidomic profile and eliminate the presence of a poor prognostic 3LS in 45% of participants with the 3LS. Further prospective randomised control studies are required to determine if modulation of the 3LS by simvastatin can improve clinical outcomes. Clinical trial information: ACTRN12617000965303.

Lipidomic profiling in patients with heavily pretreated castration-resistant prostate cancer.

174 Background: Despite the advent of chemotherapy and androgen-receptor signaling inhibitors (ARSi), patients with metastatic castration-resistant prostate cancer (mCRPC) still show poor prognosis and reduced survival. The selective pressure induced by treatments favors the activation of alternative metabolic pathways that allow the persistence of cancer cells in unfavorable conditions. This study aimed at assessing the lipidomic profiles of patients with mCRPC, in order to identify lipid species potentially useful to predict for prognosis and response to therapies. Methods: Plasma samples were collected from patients with mCRPC who were starting a first-line treatment for mCRPC (1L) (n = 30) and from those who had already received at least two lines of treatment for mCRPC ( &gt; 2L) (n = 19), including at least one ARSi and a taxane. Lipids were extracted from plasma samples using a modified Matyash method employing a mix of cold MeOH and MTBE and containing a mix of deuterated standards (Splash Lipidomix). Lipids were then analyzed with an untargeted lipidomic approach using an UHPLC Vanquish system coupled with a Q-Exactive Plus instrument. T-test was then applied to identify lipid species and classes that were differentially expressed in 1L vs &lt; 2L patients. Results: We identified and quantified a total of 907 plasma lipids. Overall, 68 lipid species were significantly dysregulated in &gt; 2L compared to 1L plasma samples. 56 species were found to be upregulated, whereas 12 were downregulated, with a fold change (FC) &gt; 1.3 or &lt; 0.75 and a p-value &lt; 0.05. At the level of lipid classes, &gt; 2L patients showed higher levels of acylcarnitine (CAR), diacylglycerols (DG), phosphatidylethanolamine (PE) and triacylglycerols (TG). The following lipids showed the highest FC: DG28:2 = 4.2; CAR14:0 = 3.7; CAR20:1 = 2.6; CAR18:0 = 2.3; PE40:6 = 2.3. Conversely, significantly lower levels of specific phosphatidylcholines (PC) and sterols (ST) were found in &gt; 2L compared to 1L patients. The following species showed the lowest FC: PCO-39:3 = 0.52; ST29:1;O;S = 0.55; PC36:5 = 0.55; PC36.4 = 0.60. These results suggest that patients with strongly pretreated mCRPC show higher levels of lipid species involved in the switch between the glucose and fatty acid metabolism. We also found a dysregulation of ceramides and sphingomyelins which are well-known lipid species involved in apoptosis and cancer progression. Specific lipids warrant further investigation to be used as potential prognostic and predictive biomarkers in patients with mCRPC. Conclusions: Using a quantitative mass spectrometry approach, we investigated the dysregulation of lipids and lipid metabolism in mCRPC patients at different disease stages. We found that specific lipid species show differential levels in patients pretreated with ARSi and chemotherapy, compared to those who are naïve to these treatments, paving the way for further investigations in this field.

The effect of prior docetaxel (DOC) treatment on efficacy and safety of apalutamide (APA) plus androgen deprivation therapy (ADT) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) from TITAN.

89 Background: Addition of androgen receptor signaling inhibitors to ADT + DOC has been shown to improve clinical outcomes in pts with mCSPC. TITAN, a placebo-controlled phase 3 study, showed that APA + ADT improved overall survival (OS) and other clinical outcomes in mCSPC (Chi, J Clin Oncol 2021). This post hoc analysis of TITAN evaluated outcomes in pts who had received DOC prior to treatment with APA + ADT versus those who did not. Methods: In TITAN, 1052 pts were randomized 1:1 to APA (240 mg QD) or placebo added to ongoing ADT. We assessed radiographic progression-free survival (rPFS), OS, and time to prostate-specific antigen (PSA) progression in pts receiving DOC and ADT prior to adding APA vs those receiving only ADT plus APA. Outcomes by prior DOC were also assessed in pts with high- or low-volume disease at randomization (baseline [BL]) per adapted CHAARTED criteria, or those with matched BL characteristics. A Cox proportional hazards model was used to derive hazard ratios (HRs) and p values. rPFS was assessed using the first interim analysis cutoff (23 mo median follow-up); OS and time to PSA progression were assessed using the final analysis cutoff (44 mo median follow-up). Results: A total of 58/525 (11%) pts from the APA + ADT group had received DOC prior to randomization: 76% (n = 44) had high-volume disease, 62% (n = 36) had bone-only metastases, 16% (n = 9) had visceral metastases, and 59% (n = 34) had &gt; 10 bone lesions. In the overall APA-treated population and in the subset of pts with high-volume disease, OS, rPFS, and time to PSA progression were similar in those who received prior DOC and those who did not (Table). Pts with low-volume disease also had similar results, although the number of pts was small. Clinical outcomes in pts with matched BL characteristics (including PSA and time from initial diagnosis to randomization, among others) were similar regardless of prior use of DOC (Table). The safety profile of APA was not substantially different between pts with or without prior DOC. Limitations of this analysis include lack of data on tumor volume and other disease characteristics at the initiation of prior DOC treatment; interpretation was based on small number of pts with prior DOC (only 11% of TITAN pts), most notably in the rPFS analysis. Conclusions: Prior use of DOC in pts with mCSPC did not further improve clinical benefits of APA + ADT in TITAN. Clinical trial information: NCT02489318. [Table: see text]

Phase 1 results of the ODM-208 first-in-human phase 1-2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES).

18 Background: ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). We report the first results of the first-in-man phase I CYPIDES trial. Methods: ODM-208 was examined in a dose finding phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. ODM-208 was administered up to 150 mg/day with glucocorticoid (GC) and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT). The phase 1 endpoints included dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling. Results: By Jan 22 2021, 41 patients (median age 70 yrs.) had received ODM-208. The dose finding was completed and included doses ranging from 10 to 150 mg/day. 22 (54%) patients had previously received both abiraterone and enzalutamide, and 23 (56%) patients both docetaxel and cabazitaxel. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 15/41 (37%) patients experienced Grade 3 AI requiring short-term high-dose GC treatment. ODM-208 plasma exposure was dose proportional. Serum testosterone was undetectable after 4 weeks of start of ODM-208 in almost all patients, as were serum DHEA sulphate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone and pregnenolone. Overall 12/36 (33%) evaluable patients achieved a PSA decline of ≥50%. In evaluable patients with AR LBD mutation 10/15 (67%) achieved a PSA decline of ≥50%. Clinical improvement in symptoms such as pain was also observed in some men. Conclusions: Administration of ODM-208 to mCRPC men pretreated with abiraterone/enzalutamide and taxanes was highly effective in blocking the production of steroid hormones and showed promising antitumor activity, especially in men with AR mutation-positive cancers. The phase 2 dose expansion part of CYPIDES is ongoing. Clinical trial information: NCT03436485.

A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer.

Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) is effective in the initial treatment of prostate cancer, resistance to ADT or to next-generation androgen pathway inhibitors invariably arises, most commonly through the re-activation of the AR axis. Thus, orthogonal approaches to inhibit AR signaling in advanced prostate cancer are essential. Here, via genome-scale CRISPR-Cas9 screening, we identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling. PRMT1 regulates the recruitment of AR to genomic target sites and the inhibition of PRMT1 impairs AR binding at lineage-specific enhancers, leading to decreased expression of key oncogenes, including AR itself. In addition, AR-driven prostate cancer cells are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a key regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 in advanced prostate cancer.

Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKC\u03b21

The androgen receptor (AR) is a central driver of aggressive prostate cancer. After initial treatment with androgen receptor signaling inhibitors (ARSi), reactivation of AR signaling leads to resistance. Alternative splicing of AR mRNA yields the AR-V7 splice variant, which is currently an undruggable mechanism of ARSi resistance: AR-V7 lacks a ligand binding domain, where hormones and anti-androgen antagonists act, but still activates AR signaling. We reveal PKCβ as a druggable regulator of transcription and splicing at the AR genomic locus. We identify a clinical PKCβ inhibitor in combination with an FDA-approved anti-androgen as an approach for repressing AR genomic locus expression, including expression of AR-V7, while antagonizing full-length AR. PKCβ inhibition reduces total AR gene expression, thus reducing AR-V7 protein levels and sensitizing prostate cancer cells to current anti-androgen therapies. We demonstrate that this combination may be a viable therapeutic strategy for AR-V7-positive prostate cancer.

Expression of Fibroblast Activation Protein Is Enriched in Neuroendocrine Prostate Cancer and Predicts Worse Survival.

Background: Advanced prostate cancer (PC) may accumulate genomic alterations that hallmark lineage plasticity and transdifferentiation to a neuroendocrine (NE) phenotype. Fibroblast activation protein (FAP) is a key player in epithelial-to-mesenchymal transition (EMT). However, its clinical value and role in NE differentiation in advanced PC has not been fully investigated. Methods: Two hundred and eight patients from a multicenter, prospective cohort of patients with metastatic castration-resistant prostate cancer (CRPC) with available RNA sequencing data were analyzed for tumor FAP mRNA expression, and its association with overall survival (OS) and NE tumor features was investigated. Results: Twenty-one patients (10%) were found to have high FAP mRNA expression. Compared to the rest, this subset had a proportionally higher exposure to taxanes and AR signaling inhibitors (abiraterone or enzalutamide) and was characterized by active NE signaling, evidenced by high NEPC- and low AR-gene expression scores. These patients with high tumor mRNA FAP expression had a more aggressive clinical course and significantly shorter survival (12 months) compared to those without altered FAP expression (28 months, log-rank p = 0.016). Conclusions: FAP expression may serve as a valuable NE marker indicating a worse prognosis in patients with metastatic CRPC.

RB1 loss in castration-resistant prostate cancer confers vulnerability to LSD1 inhibition.

Genomic loss of RB1 is a common alteration in castration-resistant prostate cancer (CRPC) and is associated with poor patient outcomes. RB1 loss is also a critical event that promotes the neuroendocrine transdifferentiation of prostate cancer (PCa) induced by the androgen receptor (AR) signaling inhibition (ARSi). The loss of Rb protein disrupts the Rb-E2F repressor complex and thus hyperactivates E2F transcription activators. While the impact of Rb inactivation on PCa progression and linage plasticity has been previously studied, there is a pressing need to fully understand underlying mechanisms and identify vulnerabilities that can be therapeutically targeted in Rb-deficient CRPC. Using an integrated cistromic and transcriptomic analysis, we have characterized Rb activities in multiple CRPC models by identifying Rb directly regulated genes and revealed that Rb has distinct binding sites and targets in CRPC with different genomic backgrounds. Significantly, we show that E2F1 chromatin binding and transcription activity in Rb-deficient CRPC are highly dependent on LSD1/KDM1A, and that Rb inactivation sensitizes CRPC tumor to the LSD1 inhibitor treatment. These results provide new molecular insights into Rb activity in PCa progression and suggest that targeting LSD1 activity with small molecule inhibitors may be a potential treatment strategy to treat Rb-deficient CRPC.

Inhibition of Androgen Receptor Signaling Reduces Inflammation in the Lung with SARS-CoV-2 Infection Through Dampening IL6 Signaling

Inhibition of Androgen Receptor Signaling Reduces Inflammation in the Lung with SARS-CoV-2 Infection Through Dampening IL6 Signaling

Inhibition of androgen receptor signaling exacerbates pathological changes in a mouse model of porcine pancreatic elastase-induced pulmonary emphysema.

Inhibition of androgen receptor signaling exacerbates pathological changes in a mouse model of porcine pancreatic elastase-induced pulmonary emphysema.

Inhibitory effects of Centella asiatica (L.) Urban on enlarged prostate through androgen receptor and PI3K/Akt signaling pathways.

Centella asiatica (L.) Urban (C. asiatica) is a traditional herbal medicine that has been used for wound healing and anti-inflammation since ancient times. Various biological effects of C. asiatica ethanolic extract (CAE) were previously reported. However, in our previous study, C. asiatica aqueous extract (CAA) exhibited higher inhibitory activity on benign prostatic hyperplasia (BPH) than CAE. Therefore, the aim of this study was to investigate the effect of CAA on BPH, and elucidate the inhibitory mechanism through in vitro and in vivo experiments as well as metabolite analysis of CAA. A BPH rat model was induced by daily subcutaneous injection of testosterone propionate (TP, 3 mg kg-1) dissolved in corn oil for 4 weeks after castration. The experimental group, the CAA treatment group, was orally administered CAA (100 mg kg-1) for 4 weeks while inducing prostatic hyperplasia. Saw palmetto extract (Saw, 100 mg kg-1) and Finasteride (Fi, 1 mg kg-1) were used as positive controls and were administered orally for 4 weeks. CAA significantly inhibited androgen receptor signaling related factors overexpressed by dihydrotestosterone (DHT) treatment in prostate cell lines. Afterwards, the testosterone-induced BPH model was used to verify the alleviation efficacy of CAA in prostatic hyperplasia. Prostate size and the thickness of the prostate tissue epithelium were significantly decreased in the group treated with CAA compared to those in the BPH group. The results of protein expression in the prostate tissue confirmed that CAA inhibited androgen receptor signaling in BPH and decreased the expression of growth factors. Moreover, CAA suppressed the expression of the PI3K/Akt pathway and cell proliferation-related factors compared to the BPH group. Taken together, these results indicate that CAA improves the inhibitory efficacy of BPH by inhibiting the androgen receptor and PI3K/Akt pathways, suggesting that CAA may be a promising candidate for biopharmaceutical formulations of BPH.

Assessment of androgen receptor signaling inhibitors therapy in metastatic hormone-sensitive prostate cancer

Assessment of androgen receptor signaling inhibitors therapy in metastatic hormone-sensitive prostate cancer