Androgen Receptor Signaling Inhibitors Research Articles

Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC).

Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC). Several rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo. While screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR+ CRPC cells but not AR- CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR+ and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues. These results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC.

Urolithin A analog inhibits castration-resistant prostate cancer by targeting the androgen receptor and its variant, androgen receptor-variant 7.

We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR- CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.

Abstract P1-13-14: Increased androgen receptor expression as a mechanism of acquired anti-androgen resistance in androgen receptor-positive triple negative breast cancer

Abstract Background: Triple negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, and despite recent treatment advances, clinical outcomes remain poor, particularly in the metastatic setting. TNBC is a biologically heterogeneous entity, and up to 50% of TNBC express the androgen receptor (AR). Gene expression subtyping has identified a subset of AR-TNBC with a luminal AR-driven (LAR) phenotype. Consequently, there has been great interest in translating androgen receptor signaling inhibitors (ARSIs) approved for use in prostate cancer such as enzalutamide and bicalutamide into the management of LAR-TNBC. However, early phase clinical trials of anti-androgens in metastatic AR-TNBC have had modest results. While multiple mechanisms of anti-androgen resistance have been identified in prostate cancer, including AR amplification and over-expression, emergence of AR splice variants (AR-Vs), and transition to AR independent growth, molecular determinants of anti-androgen resistance in TNBC remain poorly understood, and pre-clinical models to study acquired ARSI resistance in LAR-TNBC have been limited. Methods: A novel pre-clincial model of acquired ARSI resistance was derived from the LAR subtype MDA-MB-453 cell line through serial passaging with increasing concentrations of enzalutamide. Celltiter Blue viability assays were used to determine enzalutamide IC50 of parental and enzalutamide-resistant (EnzR) cell lines. RNA was extracted from the parental and resistant cells, reverse transcribed and expression of AR, splice-variants and canonical AR target genes were evaluated using RT-qPCR. Immunofluorescence was used to investigate the amount and nuclear localization of the AR protein within the parental and enzalutamide resistant cells. Results: EnzR MDA-MB-453 cells were derived through culture in increasing concentrations of enzalutamide for >6 months, and found to have a significant increase in enzalutamide IC50 compared to the parental cell line. EnzR MDA-MB-453 cells had a 4.5 fold increase in full-length AR expression at the transcriptional level compared to the parental cell line. AR protein expression and nuclear localization were also increased in EnzR cells compared to the parental cell line. Canonical AR targets including NKX3.1 were downregulated in response to enzalutamide in parental but not EnzR cells. While pathogenic AR splice variants (AR-Vs) implicated in ARSI resistance in prostate cancer were detected at low levels in MDA-MB-453 cells, no increase in AR-V expression was observed in the EnzR cell line. Conclusions: We have developed a novel pre-clinical model of anti-androgen/ARSI resistance in LAR-TNBC, and identified AR overexpression and persistent AR signaling associated with acquired enzalutamide resistance in LAR-TNBC. While pathogenic AR splice variants have been implicated in ARSI resistance in metastatic prostate cancer and are detected in the MDA-MB-453 cell line model, enzalutamide resistance was not associated with increased AR splice variant expression in this model. Future work will investigate mechanisms leading to AR overexpression as well as combination therapeutic strategies to overcome acquired ARSI resistance. Citation Format: Hannah Krause, Marina N. Sharifi, Serena K. Wolfe, Jamie M. Sperger, Kari B. Wisinski, Ruth O’Regan, Joshua Lang. Increased androgen receptor expression as a mechanism of acquired anti-androgen resistance in androgen receptor-positive triple negative breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-14.

Cardiovascular and thromboembolic events associated with intense neoadjuvant androgen deprivation therapy followed by prostatectomy in patients with localized prostate cancer: A meta-analysis of clinical trials.

341 Background: Several phase II trials have investigated neoadjuvant novel androgen receptor signaling inhibitors (ARSIs) in combination with androgen deprivation therapy (ADT) followed by radical prostatectomy (RP) in prostate cancer (PC) patients (pts). However, data regarding complications of the intense hormone therapy and surgical complications are scarce. The phase III trial PROTEUS testing ARSIs plus ADT added an amendment for thrombotic prophylaxis in the perioperative setting. We conducted a systematic review and meta-analysis to evaluate cardiovascular (CV) and thromboembolic (TE) adverse events (AEs) during neoadjuvant and perioperative intervals. Methods: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered with PROSPERO (CRD42022344104). A comprehensive search of PubMed, Embase, and Scopus databases and conference abstracts was performed from January 2010 to June 2022. Eligible studies include randomized and single-arm trials testing ARSIs prior to prostatectomy which adequately reported safety data regarding TE and CV AEs, peri-operative complications, and mortality during therapy. DerSimon and Laird method for random effects model was performed to estimate the pooled incidence (PI) of events with 95% confidence interval (95% CI). Heterogeneity was tested with I2 value. Results: 8 RCTs and 3 single-arm phase II trials comprising 674 pts were included (674 pts for CV and TE AEs and 499 for perioperative complications). Neoadjuvant regimen was classified as monotherapy with ADT (21 pts), ARSIs (100 pts), combination therapy with ADT + ARSI (338 pts), or ADT + ARSI + ARSI (215 pts). PI of all grade TE was 3.2% (95% CI, 1.6% – 4.8%, I2 = 0.0%, p = 0.92); TE incidence during perioperative period was 3.9% (95% CI, 1.6 – 6.1%, I2 = 0.0%, p = 0.67). 7 deaths were reported, with a PI of 3.0% (95% CI, 0.7–5.3%, I2 = 0.0%, p = 0.98). 2 of the mortality AE were considered treatment-related within perioperative interval. Incidence of hypertension grade 3-5 was 8.9% (95% CI, 5.2–12.7%, I2= 51.6%, p = 0.02). Incidence measures per regimen are described. Conclusions: CV and TE events associated with intense neoadjuvant hormone therapy in patients with localized PC can occur in up to 3.9% of cases. Our data warns for further assessment of thrombotic risk and prophylactic anticoagulation in this setting. [Table: see text]

Characteristics of long-term responder (LTR) patients (pts) treated with androgen-receptor signaling inhibitors (ARSI) as a first-line treatment for metastatic castration-resistant prostate cancer (mCRPC): Real-world evidence from four high-volume institutions.

164 Background: ARSI [enzalutamide (ENZA) and abiraterone (ABI)] demonstrated to be efficacious as a first-line therapy for mCRPC, showing a median progression-free survival of 16 and 20 months (mos) in pivotal trials, respectively. Nevertheless, some pts of daily clinical practice show exceptionally prolonged disease control with very long duration of treatment. The present study aimed at identifying the characteristics of LTR pts who received one ARSI as a first-line for mCRPC. Methods: We retrospectively reviewed the clinical records of a consecutive series of 647 pts treated in the daily clinical practice with one ARSI as first-line mCRPC in four Italian high-volume Institutions. Pts who had previously received docetaxel in castration-sensitive setting were excluded. Pts received standard AA or ENZA doses (1,000 mg po daily plus prednisone 10 mg po daily or 160 mg po daily, respectively). ARSI were administered until progression and were followed according to each Institution policy. For each pt we recorded pre and post-ARSI clinical history, baseline characteristics, treatment details and clinical outcomes. Pts were considered as LTR in presence of an ARSI exposure ≥ 36 mos. LTR were compared to the progressed pts with an ARSI exposure < 36 mos. On-treatment pts with an ARSI exposure < 36 mos were not considered. Results: We identified 81 LTR pts (53 treated with ENZA and 28 treated with ABI). The median age was 76 yrs (range 56-89). The median treatment duration was 46.1 mos (range 36.4-88.6) and 52 pts were still on treatment. LTR were compared to no-LTR 415 pts (233 treated with ENZA and 182 treated with ABI). Compared to no-LTR, LTR pts showed longer PSA doubling time (PSADT) (PSADT) (p = 0.001) and time to mCRPC (p < 0.0001), lower levels of basal PSA (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01), better ECOG PS (p = 0.01), lower Gleason score (p = 0.01), and less pain level (p = 0.04). ECOG PS, ALP, time to mCRPC and PSADT were all identified as independent predictors of time to treatment interruption in multivariate analysis. LTR showed an 89% decreased risk of death compared to no-LTR (HR = 0.11 IC95% 0.06-0.18). Conclusions: In our experience, several variables, which are usually considered as having a prognostic value, demonstrated to be able to predict the probability of prolonged disease control in mCRPC pts treated with first-line ARSI.

Outcomes of post-progression therapies in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) progressing after docetaxel (DOC): Real-world data from an Italian multicenter observational study (ECHOS trial).

171 Background: The introduction of DOC in mCSPC raises the issue concerning the best therapeutic strategy after pts’ progression. Different options are available: a switch strategy with an androgen receptor signaling inhibitor (ARSI), an alternative chemotherapy-based strategy based on cabazitaxel (CABA), or a re-challenge strategy by using DOC again. In this view, it could be of interest to describe the outcomes of post-progression strategies adopted in the real-world. From 2014, ECHOS multicenter study is collecting real world data from mCSPC pts in Italy. Here, we present post-progression preliminary findings of 568 pts treated with DOC and enrolled in the study within 31 December 2021. Methods: We reviewed the clinical records of the mCSPC pts treated with DOC in 34 Italian Institutions. For each pt we recorded pre- and post-DOC clinical history, baseline characteristics, treatment details and clinical outcomes. Results: Among the 568 pts, after a median follow-up of 22 mos, 389 pts experienced disease progression and 227 died. The progression occurred after a median of 10.4 mos (range 0.3-62.1). Among the progressed pts, 47 did not received further active treatment, while 342 received at least one systemic treatment after progression. The most frequent post-progression treatment was ARSI (73.1%), followed by CABA (19%), combination of ARSI and PARP inhibitors within clinical trials (2.6%), DOC re-challenge (2.1%), platinum-based chemotherapy (1.8%), and radium 223 (0.9%). The outcomes of the first-line agents and the number of subsequent administered life-prolonging agents (LPA) are described. The length of disease control obtained with DOC influenced the duration of first post-progression therapy: in pts who progressed after DOC within 10.4 mos, the duration was significantly shorter than in pts with later disease progression (5.9 mos vs 9.8 mos, p < 0.0001). Noteworthy, pts with more aggressive disease leading to a faster progression received more frequently CABA than ARSI: disease progression after DOC in CABA group and in ARSI group occurred with a median of 9.1 mos and 13.2 mos, respectively (p = 0.002). Conclusions: This is one of the largest real-world report on the outcomes of first post-progression therapies after DOC in mCSPC pts. We showed that ARSI-based therapy is the most common strategy adopted after DOC progression. Our findings suggested a different first post-progression strategy according to the time of post-DOC progression onset. [Table: see text]

Oncologists’ perspectives on metastatic hormone sensitive prostate cancer management.

84 Background: The treatment of metastatic hormone sensitive prostate cancer (mHSPC) has evolved over the past 7 years. Combination therapies with either [Androgen deprivation therapy (ADT) + Docetaxel] or [ADT + androgen receptor signaling inhibitors (ARSi) such as abiraterone acetate/enzalutamide/apalutamide] have demonstrated overall survival (OS) benefit compared to ADT + placebo in mHSPC. Recently two trials (ARASENS and PEACE-1) also demonstrate an OS benefit from the addition of docetaxel to ADT + ARSi (abiraterone acetate or darolutamide) compared to ADT + docetaxel. Given these recent advances there is not a clear consensus on how to best manage patients with mHSPC as there are no head-to-head trials. In this study, we assess oncologists’ treatment preferences as it pertains to this subset of patients. Methods: An 8-item online survey was sent on September 6th, 2022 to medical oncologists in the United States. We described five different case scenarios and three demographic questionnaires. Cases consisted of patients with mHSPC both de novo and primary progressive with low and high volumes. Treatment options included ADT monotherapy, ADT + ARSi (doublet), or ADT + ARSi + docetaxel (triplet therapy). Respondents reported their practice setting, location, and years of clinical experience. Data was collected and analyzed via REDCap. Results: Surveys were completed by (n=83) medical oncologists across the US. 14.5% of respondents were from Kentucky; 51.8% have been in practice < 10 years, 20.5% 10-20 years, and 27.7%> 20 years. For patients with de novo high volume disease, 85.5% (71) preferred treatment with triplet therapy. For the same patient population, 94.4% (51) of university-based providers preferred triplet therapy vs 68.9% (20) of those in a non-academic setting. Preferences differed regarding patients with primary progressive high-volume disease in which 59.8% (49) preferred a triplet regimen while 37.8% (31) preferred a doublet regimen. Of those choosing triplet therapy, 53.7% (29) were from an academic institution while 71.4% (20) practiced in a nonacademic setting. Of those choosing doublet therapy, 42.6% (23) were from an academic institution versus 28.6% (8) in a nonacademic setting. For patients with de novo or primary progressive low volume disease, 81.5% of respondents preferred doublet therapy without a notable difference between academic and non-academic responders. Conclusions: We find a consensus in management of patients with de novo high volume mHSPC (prefer triplet) and de novo or primary progressive low volume disease (prefer doublet) regardless of practice setting, location, or practice duration. However, for patients with primary progressive high-volume disease, a higher percentage of non-academic providers prefer triplet therapy compared to their university counterparts.

First look at the baseline characteristics of participants in IRONMAN, the international registry for men with advanced prostate cancer.

85 Background: Patients with advanced prostate cancer (APC) experience high mortality and increasingly deteriorating quality of life due to the disease itself and the therapies they are treated with. Despite recent advances in the treatment landscape, disparities in outcomes have only worsened. There is an urgent need to identify disparities in treatment patterns and outcomes in advanced disease in diverse populations. The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is uniquely equipped to address these needs. Methods: IRONMAN is a prospective registry initiated in 2017 with a planned accrual of 5000 patients with newly diagnosed metastatic hormone-sensitive (mHSPC) and castration-resistant (CRPC) prostate cancer. As of 10/11/2022, 2890 patients have enrolled from 14 countries at 113 sites, with 2 more countries pending activation. Sites were selected to create a diverse cohort across race/ethnicity, geography and socioeconomic factors. Patients are followed for survival, clinically significant adverse events, changes in cancer treatments, biomarkers, and Patient-Reported Outcome Measures (PROMs). This analysis includes patients with treatment data reported from Baseline through Month 3 as of October 2021 (n=1931, 9 countries). Results: Patients were recruited across the USA (N=799), Australia (146), Canada (282), Spain (238), England (205), and all other countries (261). 61% had mHSPC, and 39% had CRPC at enrollment with little variation in these proportions across countries. Based on self-report, 87% of patients were White, 9% Black, 4% reported other races/ethnicities, and 353 did not report race. In the US, 18% of patients were Black. Globally, 22% of respondents reported current or former military service. The most common first systemic therapy on study was androgen receptor signaling inhibitors (ARSI) +/- ADT in 1039 (54%), ranging between 12% and 66% of patients by country. 19% received chemotherapy +/- ADT and 18% received ADT alone. ARSI use varied by age, race, and metastatic disease site. Conclusions: Our preliminary results highlight our ability to successfully enroll and follow APC patients from 113 sites across 14 countries, with 2890 of 5000 planned patients enrolled. Accrual is greater in de novo mHSPC patients than anticipated. Differences in treatment patterns are already emerging, with more ARSI use in the mHSPC setting in North America than other regions. Our data demonstrates that IRONMAN participating sites are rapidly adopting new treatment recommendations into clinical practice of real-world patients.

Androgen receptor (AR) mutations in men with metastatic castration-resistant prostate cancer (mCRPC): Incidence and natural history.

221 Background: AR ligand binding domain (LBD) activating somatic point mutation is a known mechanism of resistance to androgen-receptor signaling inhibitor (ARSI) treatment in mCRPC, leading to a persistent addiction to steroid hormones. Two early phase trials investigating CYP11A1 inhibitors - CYPIDES (ODM208, NCT03436485) and STESIDES (ODM209, NCT03878823) - recruited mCRPC patients with and without pre-specified AR LBD mutation. In CYPIDES Part 1, AR LBD mutations (ARm) strongly predicted for PSA decline with ODM-208 (Fizazi, ASCO GU 2021). Here, we evaluated clinical and genomic data associated with ARm in patients with mCRPC. Methods: We reviewed clinical and molecular data from patients with mCRPC who progressed after ≥1 ARSI and ≥1 line of taxane-based chemotherapy or were ineligible to chemotherapy, pre-screened in CYPIDES and STESIDES trials at our center. Circulating tumor DNA (ctDNA) was tested for AR LBD mutation (Guardant360 CDx and Sysmex OncoBEAM) and for genomic analysis (FoundationOne Liquid CDx, STING trial, NCT04932525) to screen for actionable targets. Results: From March 2020 to January 2022, 272 men were screened. Median age was 62y. Overall, 212 (78%), 202 (74%), and 240 (88%) patients had received previous abiraterone, enzalutamide, and docetaxel respectively. Median PSA at screening was 59 ng/mL (IQR 11; 246). ARm was found in 69 patients (25%). The most frequent mutations were L702H (15%), T878A (12%), H875Y (7%), V716M (2%), F877L (2%), W742C (1%), globally consistent with previous reports. Associations of ARm with relevant baseline characteristics of patients are summarized. Duration of enzalutamide exposure was correlated with the number of AR mutations per patient (p = 0.006) whereas no correlation was found for abiraterone exposure duration (p=0.71). In 173 (64%) patients with available genomic testing, no alterations were found to be mutually exclusive with ARm, including in DNA repair alteration. Conclusions: AR LBD mutations were detected in ctDNA in 25% of men with advanced mCRPC treated with at least one ARSI. Their incidence was associated with a longer duration of treatment with enzalutamide and a longer time from CRPC and prostate cancer diagnosis. [Table: see text]

Effect of Janus kinase (JAK) signaling inhibition on lineage plasticity and drug sensitivity in castrate resistant prostate cancer.

227 Background: Despite the remarkable successes of targeted cancer therapies, certain cancers, including lung, breast, and prostate cancer and melanoma, invariably become resistant to therapy. One mechanism of secondary resistance—lineage plasticity—arises when cells alter their identity and transition into aggressive states. In the case of prostate cancer, cells can acquire a neuroendocrine histology. This is often associated with a loss of tumor suppressor genes, such as TP53, RB1, and PTEN. However, while these genomic events initiate plasticity, tumor progression is not always associated with successive genomic alterations. This, in essence, not only poses a clinical challenge, but also confronts us with a wide-open biological question—what are the molecular underpinnings of lineage plasticity, and importantly, can the process be reversed? Methods: To study the temporal evolution of lineage plasticity and its relationship to androgen receptor signaling inhibitor (ARSI) resistance, we utilized genetically engineered mouse models (GEMMs) and murine organoids that were deleted for Tp53, Rb1, and/or Pten. Single cell RNA analyses were utilized to dissect which genes and pathways were up-regulated and most associated with the progression of plasticity. Plasticity-associated genes and pathways were perturbed using FDA-approved inhibitors or genetic editing tools. The presence of these pathways was confirmed in a subset of metastatic index lesions obtained by radiologically guided biopsies and as visualized by metabolic imaging. Furthermore, relevant findings were functionally validated in human tumor derived organoids (“tumoroids”). Results: Using GEMMs and organoid models, we found the lineage plasticity depended on increased Janus Kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Pharmacologic inhibition using FDA–approved inhibitors of JAK/STAT (ruxolitinib) and FGFR (erdafinitib), or through genetic knockdown, demonstrated increased androgen receptor (AR) signaling and restored ARSI sensitivity. These findings were further validated in a subset of ARSI-insensitive human tumoroids. By performing single cell RNA sequencing on mCRPC tumors biopsies, the presence of highly plastic JAK/STAT- and FGFR-high cells were confirmed, with implications for stratifying patients for clinical trials. Conclusions: JAK/STAT and FGFR signaling pathways promote lineage plasticity and result in complete insensitivity to androgen receptor signaling inhibitors (ARSIs). FDA-approved inhibitors of JAK/STAT (ruxolitinib) and FGFR (erdafitinib) synergize to reverse lineage plasticity and restore ARSI sensitivity.

Efficacy and safety of docetaxel (D) vs androgen-receptor signaling inhibitors (ARSi) as second-line therapy (Rx) after progression on alternative ARSi as first-line Rx for patients who are elderly (≥75 years old) with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter international database: A SPARTACUSS–Meet-URO 26 study.

166 Background: About 2/3 of all prostate cancer (PCa) deaths occur in patients aged ≥75, who are frequently diagnosed with advanced PCa. ARSi abiraterone acetate (AA) and enzalutamide (E) are the most common 1st line Rx for patients with mCRPC. Yet, the optimal treatment sequence for the elderly ≥75 after ARSi failure is still unclear. Methods: Using available medical records, patients aged ≥75 who started ARSi as 1st line Rx for mCRPC within January 2015 - April 2019 and, upon progression, 2nd line alternative ARSi or D were identified from the IRB approved hospital registries of 10 centers in Europe, North and South America. Patients were categorized by type of 2nd line Rx for mCRPC into cohorts AA/E and D. Primary endpoints were overall survival (OS) from 1st line AA/E start, OS and radiographic progression-free survival (rPFS) from 2nd line Rx start, and safety. The Kaplan Meier method was used to calculate endpoint distributions and medians (95% CI). Results: Of the 122 patients identified, 57 (46.7%) had AA/E and 65 (53.3%) D, as 2nd line Rx for mCRPC. Median follow-up was 26.3 months (95% CI, 23.1-27.9 months). Cohort AA/E tended to be older (81 vs 78 years; p=0.001) and with high-volume disease (45.5% vs 25.0%; p=0.022) compared to cohort D. No significant difference in OS from 1st line ARSi onset and OS or rPFS from 2nd line Rx start was found between the 2 cohorts. Cohort AA/E had longer rPFS than cohort D, albeit not significant (18.5 vs 12.0 months; p=0.13). Rates of adverse events (AEs) of any grade (42.1 vs 53.8; p=0.21) and AEs of grade ≥3 (19.3% vs 18.5%; p=1.0) did not show significant differences between the 2 cohorts. Conclusions: Within the limitations of small cohorts and retrospective design, treatment sequences with 2nd line AA/E or D after failure of 1st line alternative ARSi for mCRPC showed similar efficacy and safety in the elderly ≥75 years old.

Phase III study of local or systemic therapy intensification directed by PET in prostate cancer patients with post-prostatectomy biochemical recurrence (INDICATE): ECOG-ACRIN EA8191.

TPS402 Background: Salvage radiation therapy (sRT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). PET imaging with recently FDA-approved agents in this setting (18F-Fluciclovine, 18F-DCFPyL and 68Ga-PSMA-11), have shown improved accuracy for detection of metastases not identified with conventional imaging (CIM). Given the greater sensitivity and specificity of PET, its findings are being increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for different treatment intensification approaches. In metastatic prostate cancer, metastasis-directed RT (MDT) has been used to avoid or delay systemic therapy in men with oligometastatic disease. Apalutamide (Apa) is an androgen receptor signaling inhibitor that has been shown to improve outcomes when added to ADT in mCSPC. This study will evaluate whether patients with PET-detected lesions outside the pelvis will benefit from addition of MDT to treatment intensification with STAD/Apa, and whether patients with no PET-detected lesions outside the pelvis will benefit from addition of Apa to standard sRT/STAD. Methods: PC pts with post-RP BCR (PSA>0.5ng/mL; >0.2ng/mL if first detectable within 12 mos of RP) and no extrapelvic metastases on CIM who are candidates for SOC ST (sRT to prostate bed and pelvic nodes with STAD) are eligible. Pts will undergo SOC baseline PET using a FDA-approved tracer. Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic metastases). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- MDT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death, whichever occurs first. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of MDT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish a 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified logrank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish a 5-year PFS rate of 76.5% in the experimental arm from 61.5% in the control arm. Secondary endpoints include overall and event-free survival, toxicity, PET progression and quality of life. Clinical trial information: NCT04423211 .

A study to determine enzalutamide long term safety and efficacy for men with castration-resistant prostate cancer: A multicenter, prospective DELC study.

66 Background: In the PREVAIL study, enzalutamide was demonstrated to be effective in men with chemo-naïve metastatic castration-resistant prostate cancer (CRPC). In Japan, enzalutamide was introduced in 2014. Real-world evidence is needed for the long-term safety and efficacy of enzalutamide. The aim of this study was to evaluate the efficacy, safety and prognostic factors in CRPC treated with enzalutamide. Methods: This multicenter, prospective, observational study enrolled 163 Japanese CRPC patients between January 2016 and March 2019. Eligibility criteria were men with chemo-naïve CRPC, no prior treatment with novel androgen receptor signaling inhibitors, and an ECOG- Performance Status ≤ 2. The switching of bicalutamide and flutamide was eligible. Written consent for participation has been obtained from the patient. Enzalutamide 160 mg/day was administered once daily according to usual practice. Data were collected from medical records at baseline and every 3 months until march 2021. The primary endpoint was overall survival (OS), and factors associated with OS were examined. Cox proportional hazards model was used for statistics. The secondary endpoints were PSA response and safety. Results: At a median follow-up of 26.0 months, the median OS was 42.1 months and 24-month OS rate was 69%. Univariate analysis showed that time to CRPC, pretreatment serum PSA, baseline NSE, and baseline interleukin-6 (IL-6) levels were associated with OS. Multivariate analysis revealed that pretreatment serum PSA (hazard ratio [HR] 2.30, 95% confidence interval [CI] 1.30-4.10), baseline NSE (HR 2.97, 95%CI 1.24-7.11), and baseline IL-6 (HR 2.32 95%CI 1.32-4.09) were independent risk factors for OS. PSA decline more than 50% was 74% (n=120). Fatigue (30%, n=49), constipation (20%, n=32) and appetite loss (18%, n=29) were the most common adverse events (AEs). Dose reduction/drug discontinuation rates were 20% (n=33) due to AEs and 18% (n=29) due to patient request. Conclusions: The efficacy and safety of enzalutamide in Japanese real clinical practice were comparable to those reported in PREVAIL study. The present analysis also suggests that serum PSA, NSE and IL-6 levels are independent prognostic factors in CRPC patients. Clinical trial information: UMIN000019855 . [Table: see text]

An oral androgen receptor RIPTAC for prostate cancer.

184 Background: Resistance to Androgen Receptor Signaling Inhibitors (ARSIs) in prostate cancer occurs in almost all patients and is driven primarily by genomic alterations in AR and increases in AR expression. In the metastatic castration-resistant setting, more than 80% of these patients harbor amplifications of the AR gene or the upstream enhancer region of DNA. Our RIPTAC technology leverages the high level of AR expression to selectively kill prostate cancer cells while sparing normal tissues. Methods: We describe here a novel orally bioavailable heterobifunctional small molecule AR RIPTAC that recruits an essential cellular protein (EP) into a stable ternary complex with AR, thereby inhibiting EP function and leading to cell death selectively in AR-positive cells. Molecules were designed to achieve cooperative binding between AR and EP, oral bioavailability and AR-selective cell killing. Results: AR RIPTACs form a ternary complex between AR and EP across PCa cell lines with an EC50 ~1nM, leading to concomitant inhibition of the EP and antiproliferative activity across PCa cell lines. The cell killing activity of AR RIPTACs is dependent on the presence of AR in the cell. AR RIPTACs induce apoptosis at low nM concentrations in cells overexpressing AR but not in control cells. In castrated mice bearing VCaP xenografts, AR RIPTACs accumulate in the tumor and induce AR:RIPTAC:EP ternary complex formation at a low oral dose, resulting in tumor specific inhibition of the EP and tumor growth inhibition. Leading AR RIPTACs possess pharmacokinetic properties suitable for a drug candidate, and readily achieve efficacious exposures following oral dosing in mouse, rat and dog. Conclusions: In summary, we report preclinical data on orally bioavailable heterobifunctional AR RIPTACs that are active in multiple prostate cancer models. The lead molecules are being evaluated in toxicology studies, with IND filing slated for 2024.

Prognostic value of genomic mutations in metastatic prostate cancer

Metastatic prostate cancer (mPC) has a poor prognosis, and new treatment strategies are currently being offered for patients in clinical practice, but mPC is still incurable. A considerable proportion of patients with mPC harbor homologous recombination repair (HRR) mutations, which may be more sensitive to poly (ADP-ribose) polymerase inhibitors (PARPis). We retrospectively included genomic and clinical data from 147 patients with mPC from a single clinical center, with a total of 102 circulating tumor DNA (ctDNA) samples and 60 tissue samples. The frequency of genomic mutations was analyzed and compared with that in Western cohorts. Cox analysis was used to assess progression-free survival (PFS) and prognostic factors related to prostate-specific antigen (PSA) after standard systemic therapy for mPC. The most frequently mutated gene in the HRR pathway was CDK12 (18.3%), followed by ATM (13.7%) and BRCA2 (13.0%). The remaining common ones were TP53 (31.3%), PTEN (12.2%), and PIK3CA (11.5%). The frequency of BRCA2 mutation was close to that of the SU2C-PCF cohort (13.3%), but the frequency of CDK12, ATM, and PIK3CA mutations was significantly higher than that in the SU2C-PCF cohort: 4.7%, 7.3%, and 5.3%, respectively. CDK12 mutation were less responsive to androgen receptor signaling inhibitors (ARSIs), docetaxel, and PARPi. BRCA2 mutation helps predict PARPi efficacy. Additionally, androgen receptor (AR)–amplified patients do not respond well to ARSIs, and PTEN mutation are associated with poorer docetaxel response. These findings support the genetic profiling of patients with mPC after diagnosis to guide treatment stratification to customize personalized treatment.

Prognostic Value of Low-Pass Whole Genome Sequencing of Circulating Tumor DNA in Metastatic Castration-Resistant Prostate Cancer.

Multiple treatments are available for metastatic castration-resistant prostate cancer (mCRPC), including androgen receptor signaling inhibitors (ARSI) enzalutamide and abiraterone, but therapy resistance remains a major clinical obstacle. We examined the clinical utility of low-pass whole-genome sequencing (LPWGS) of circulating tumor DNA (ctDNA) for prognostication in mCRPC. A total of 200 plasma samples from 143 mCRPC patients collected at the start of first-line ARSI treatment (baseline) and at treatment termination (n = 57, matched) were analyzed by LPWGS (median: 0.50X) to access ctDNA% and copy number alteration (CNA) patterns. The best confirmed prostate specific antigen (PSA) response (≥50% decline [PSA50]), PSA progression-free survival (PFS), and overall survival (OS) were used as endpoints. For external validation, we used plasma LPWGS data from an independent cohort of 70 mCRPC patients receiving first-line ARSI. Baseline ctDNA% ranged from ≤3.0% to 73% (median: 6.6%) and CNA burden from 0% to 82% (median: 13.1%) in the discovery cohort. High ctDNA% and high CNA burden at baseline was associated with poor PSA50 response (P = 0.0123/0.0081), poor PFS (P < 0.0001), and poor OS (P < 0.0001). ctDNA% and CNA burden was higher at PSA progression than at baseline in 32.7% and 42.3% of the patients. High ctDNA% and high CNA burden at baseline was also associated with poor PFS and OS (P ≤ 0.0272) in the validation cohort. LPWGS of ctDNA provides clinically relevant information about the tumor genome in mCRPC patients. Using LPWGS data, we show that high ctDNA% and CNA burden at baseline is associated with short PFS and OS in 2 independent cohorts.

Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models

Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology and U-box-containing protein 1 (HSP70/STUB1) machinery are involved in androgen receptor (AR) and AR variant protein stabilization. Targeting HSP70 could be a viable strategy to overcome resistance to androgen receptor signaling inhibitor (ARSI) in advanced prostate cancer. Here, we showed that a novel HSP70 allosteric inhibitor, JG98, significantly suppressed drug-resistant C4–2B MDVR and CWR22Rv1 cell growth, and enhanced enzalutamide treatment. JG98 also suppressed cell growth in conditional reprogramed cell cultures (CRCs) and organoids derived from advanced prostate cancer patient samples. Mechanistically, JG98 degraded AR/AR-V7 expression in resistant cells and promoted STUB1 nuclear translocation to bind AR-V7. Knockdown of the E3 ligase STUB1 significantly diminished the anticancer effects and partially restored AR-V7 inhibitory effects of JG98. JG231, a more potent analog developed from JG98, effectively suppressed the growth of the drug-resistant prostate cancer cells, CRCs, and organoids. Notably, the combination of JG231 and enzalutamide synergistically inhibited AR/AR-V7 expression and suppressed CWR22Rv1 xenograft tumor growth. Inhibition of HSP70 using novel small-molecule inhibitors coordinates with STUB1 to regulate AR/AR-V7 protein stabilization and ARSI resistance.

Clinical impact of volume of disease and time of metastatic disease presentation on patients receiving enzalutamide or abiraterone acetate plus prednisone as first-line therapy for metastatic castration-resistant prostate cancer

BackgroundMetastatic castration-resistant prostate cancer remains a challenging condition to treat. Among the available therapeutic options, the androgen receptor signaling inhibitors abiraterone acetate plus prednisone (AA) and enzalutamide (Enza), are currently the most used first-line therapies in clinical practice. However, validated clinical indicators of prognosis in this setting are still lacking. In this study, we aimed to evaluate a prognostic model based on the time of metastatic disease presentation (after prior local therapy [PLT] or de-novo [DN]) and disease burden (low volume [LV] or high-volume [HV]) at AA/Enza onset for mCRPC patients receiving either AA or Enza as first-line.MethodsA cohort of consecutive patients who started AA or Enza as first-line treatment for mCRPC between January 1st, 2015, and April 1st, 2019 was identified from the clinical and electronic registries of the 9 American and European participating centers. Patients were classified into 4 cohorts by the time of metastatic disease presentation (PLT or DN) and volume of disease (LV or HV; per the E3805 trial, HV was defined as the presence of visceral metastases and/or at least 4 bone metastases of which at least 1 out the axial/pelvic skeleton) at AA/Enza onset. The endpoint was overall survival defined as the time from AA or Enza initiation, respectively, to death from any cause or censored at the last follow-up visit, whichever occurred first.ResultsOf the 417 eligible patients identified, 157 (37.6%) had LV/PLT, 87 (20.9%) LV/DN, 64 (15.3%) HV/PLT, and 109 (26.1%) HV/DN. LV cohorts showed improved median overall survival (59.0 months; 95% CI, 51.0–66.9 months) vs. HV cohorts (27.5 months; 95% CI, 22.8–32.2 months; P = 0.0001), regardless of the time of metastatic presentation. In multivariate analysis, HV cohorts were confirmed associated with worse prognosis compared to those with LV (HV/PLT, HR = 1.87; p = 0.029; HV/DN, HR = 2.19; P = 0.002).ConclusionOur analysis suggests that the volume of disease could be a prognostic factor for patients starting AA or Enza as first-line treatment for metastatic castration-resistant prostate cancer, pending prospective clinical trial validation.

Suppression of androgen receptor signaling induces prostate cancer metastasis via activation of the CCL20–CCR6 axis

Suppression of androgen receptor signaling induces prostate cancer metastasis via activation of the CCL20–CCR6 axis

Fracture and fall risk in men with advanced or metastatic prostate cancer treated with novel androgen receptor signalling inhibitors: A systematic review and meta-analysis of randomised controlled trials

Fracture and fall risk in men with advanced or metastatic prostate cancer treated with novel androgen receptor signalling inhibitors: A systematic review and meta-analysis of randomised controlled trials