Androgen Receptor Pathway Inhibitors Research Articles

Potential and real drug interactions in patients treated with abiraterone or enzalutamide in clinical practice

ABSTRACT Background Abiraterone and enzalutamide, androgen receptor pathway inhibitors (ARPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC), are at high risk of potential drug interactions (PDIs). We aimed to describe PDIs and their management, and triggered adverse events (AEs) in clinical practice. Methods We conducted a cross-sectional study in mCRPC patients who started treatment with abiraterone or enzalutamide in a university hospital between August 1st, 2016 and July 31st, 2020. Lexicomp® was used to identify and analyze PDIs, and the clinical records to assess their management and the occurrence of AEs. Results We included 173 patients: 36.8% and 93.0% treated with abiraterone and enzalutamide, respectively, had at least 1 PDI. Globally, 6.3% of PDIs had X-risk (contraindication due to high probability of AE). Treatment was modified in 9.2% of patients and 9.8% suffered AEs due to PDIs. Factors associated with a higher risk of PDIs were polypharmacy (OR= 41.0, p 0.003) and treatment with enzalutamide (OR= 128.26, p < 0.001). Conclusions At least two-thirds of patients treated with ARPI suffered a PDI. Overall, abiraterone would have a more favorable PDI profile. Knowing these interaction profiles may be helpful to develop a more efficient therapeutic follow-up and to select the safest treatment.

Abstract P202: Initial findings from an ongoing first-in-human phase 1 study of the CBP/p300 inhibitor FT-7051 in men with metastatic castration-resistant prostate cancer

Abstract Background: Prostate cancer is the 2nd leading cause of cancer-related deaths among men in the US. CREB binding protein (CBP) and paralog p300 are co-activators of androgen receptor (AR) relevant to metastatic castration-resistant prostate cancer (mCRPC) progression and AR therapy resistance. FT-7051 is an oral, potent and selective inhibitor of CBP/p300 bromodomain with activity in preclinical prostate cancer models, including those resistant to enzalutamide. Methods: The Courage Study (NCT04575766) is a first-in-human, multicenter, phase 1, open-label study to examine the safety, PK/PD, and preliminary anti-tumor activity of FT-7051 in mCRPC patients (pts) who have progressed despite prior therapy, including at least one AR pathway inhibitor. The study uses a Bayesian optimal interval (BOIN) design with an accelerated titration phase. FT-7051 is dosed on a 28-d cycle (21-d on/7-d off). Following accelerated titration, dose escalation/de-escalation decisions are made by comparing the observed dose-limiting toxicity (DLT) rate at the current dose with pre-specified dose escalation/de-escalation boundaries. The primary objectives are to evaluate safety and tolerability of FT-7051 and determine the recommended phase 2 dose. Key secondary endpoints include PSA at 12 wks, time to PSA progression, time to radiographic progression, overall response rate, and PK parameters. Biomarker analyses include PD assessments of CBP/p300 inhibition in surrogate tissues and genetic analyses in circulating tumor cells (AR, AR-v7) and peripheral blood. Results: As of 18-June-2021, a total of 5 pts were enrolled with exposure data entered into the database, with 2 pts ongoing and 3 pts discontinued (disease progression, n=1; no longer clinically benefitting, n=1; subject withdrawal, n=1). Pts had a median age of 71 yrs (range: 66-82) with a median time since first mCRPC diagnosis of 2.3 yrs (0.4-4.7) and a median of 3 (1-5) prior lines of mCRPC therapy. Mutations reported by the investigator for 3 pts included MYC, p53, RB1, AR, and PTEN loss. Preliminary PK analyses indicated that FT-7051 exposure increased with dose in a greater than dose-proportional manner. Importantly, observed FT-7051 exposures were consistent with the predicted efficacious exposure threshold derived from PK/efficacy modeling in preclinical studies. TEAEs were reported in 4 (80%) pts. Most TEAEs were mild (Gr1) or moderate (Gr2), ≥Gr3 TEAEs included one event of possibly related Gr3 hyperglycemia and one event of unrelated Gr5 disease progression. Conclusions: Preliminary safety and PK data from the accelerated titration phase of this BOIN study support the continued investigation of FT-7051 in men with mCRPC. Initial PK data confirm that FT-7051 exposure is consistent with the predicted efficacious exposure threshold determined by PK/efficacy modeling. Additional analyses of PSA, PD assessments, and genetic analyses, including AR-v7 status, will be reported. Citation Format: Andrew J. Armstrong, Michael S. Gordon, Melissa A. Reimers, Arif Hussain, Vaibhav G. Patel, Elaine T. Lam, Alex Sedkov, Von Potter, Neal Shore. Initial findings from an ongoing first-in-human phase 1 study of the CBP/p300 inhibitor FT-7051 in men with metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P202.

A phase 1 study to assess the safety, pharmacokinetics, and anti-tumor activity of the androgen receptor n-terminal domain inhibitor epi-506 in patients with metastatic castration-resistant prostate cancer

EPI-506 is the first of a new class of drugs targeting the N-terminal domain (NTD) of the androgen receptor (AR), potentially overcoming known resistance mechanisms to androgen receptor pathway inhibitors (ARPIs) among men with metastatic castration resistant prostate cancer (mCRPC). Patients with mCRPC who had progressed on prior ARPI were enrolled in this phase 1 open-label, adaptive 3 + 3 dose escalation study. The primary outcome was safety and tolerability of oral EPI-506. Secondary objectives included determination of the maximal tolerated dose (MTD), pharmacokinetic profile, and antitumor efficacy. 28 mCRPC patients were enrolled into 7 dose cohorts of EPI-506 ranging from 80-3600mg given once daily and 1800mg given twice daily. Six DLTs occurred in 4 patients; Grade 4 elevated amylase; Grade 3 abdominal pain; Grade 3 elevated ALT and Grade 3 elevated AST; Grade 2 nausea and Grade 1 vomiting which resulted in study drug intake of < 75% of the expected dose during the DLT assessment period. The most common drug-related adverse events included diarrhea, nausea and fatigue. Six patients had a PSA decline not meeting PSA response criteria. The study was terminated prior to reaching the MTD due to poor oral bioavailability. This phase 1 trial established the safety of EPI-506 and provides proof of concept for targeting the AR NTD. Next generation compounds with improved bioavailability and potency are in clinical development.

Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 Inhibitors.

Following treatment with androgen receptor (AR) pathway inhibitors, ≈20% of prostate cancer patients progress by shedding their AR-dependence. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). No targeted therapies are available for CRPC-NEPCs, and there are minimal organoid models to discover new therapeutic targets against these aggressive tumors. Here, using a combination of patient tumor proteomics, RNA sequencing, spatial-omics, and a synthetic hydrogel-based organoid, putative extracellular matrix (ECM) cues that regulate the phenotypic, transcriptomic, and epigenetic underpinnings of CRPC-NEPCs are defined. Short-term culture in tumor-expressed ECM differentially regulated DNA methylation and mobilized genes in CRPC-NEPCs. The ECM type distinctly regulates the response to small-molecule inhibitors of epigenetic targets and Dopamine Receptor D2 (DRD2), the latter being an understudied target in neuroendocrine tumors. In vivo patient-derived xenograft in immunocompromised mice showed strong anti-tumor response when treated with a DRD2 inhibitor. Finally, wedemonstrate that therapeutic response in CRPC-NEPCs under drug-resistant ECM conditions can be overcome by first cellular reprogramming with epigenetic inhibitors, followed by DRD2 treatment. The synthetic organoids suggest the regulatory role of ECM in therapeutic response to targeted therapies in CRPC-NEPCs and enable the discovery of therapies to overcome resistance.

Poly(ADP-ribose) polymerase inhibitors in prostate cancer: a cornerstone in precision oncology.

Poly-(ADP-ribose) polymerase (PARP) inhibitors act in cells with defects in homologous recombination DNA repair (HRR) caused by genomic aberrations such as BRCA mutations. This phenomenon called synthetic lethality is known now to be more common in prostate cancer than previously thought. Olaparib and rucaparib, two PARP inhibitors, were successfully tested in clinical trials for HRR-deficient metastatic castration-resistant prostate cancer. They received a breakthrough USFDA approval in HRR altered metastatic castration-resistant prostate cancer in May 2020. Consequently, the combination of PARP inhibitors with other agents such as androgen receptor pathway inhibitors, immune checkpoint inhibitors or DNA damage inducing chemotherapy are being currently largely studied. In our review, we aim to summarize the key PARP inhibitors published and ongoing trials in prostate cancer.

Prognostic impact of dose reduction in androgen receptor pathway inhibitors for castration-resistant prostate cancer.

BackgroundAndrogen receptor pathway inhibitors (ARPIs) such as abiraterone and enzalutamide have been shown to prolong survival in patients with advanced prostate cancer. However, there is limited evidence on the anticancer effect of a reduced dose of ARPIs. This study compared the prognosis in patients with chemotherapy-naïve castration-resistant prostate cancer (CRPC) between ARPI treatment with standard dose and treatment with reduced dose.MethodsJapanese patients who were treated with ARPI as first-line treatment for CRPC between 2014 and 2018 were included. The associations between dose reduction and clinicopathological factors, progression-free survival, and overall survival were investigated.ResultsOf the 162 patients included, 33 (20.4%) patients had their dose reduced during ARPI treatment. In the multivariate analysis, higher PSA, abiraterone treatment, and dose reduction were significant prognostic factors for progression-free survival (PFS); however, dose reduction was not associated with overall survival. In the enzalutamide-treated group, the median PFS was 12.1 months (95% CI, 8.5–21.4 months) in the standard-dose group and 7.2 months (95% CI, 5.0–11.5 months) in the reduced-dose group (P = 0.038).ConclusionThis study suggests inferior oncological outcome when treated with reduced-dose ARPI for CRPC. Full-dose administration of ARPI for CRPC may be appropriate if feasible.

Current treatment options for newly diagnosed metastatic hormone-sensitive prostate cancer-a narrative review.

Prostate cancer continues to be one of the most commonly diagnosed cancers in men globally and a leading cause of male cancer deaths. The landscape of metastatic hormone-sensitive prostate cancer has significantly changed over the past decade. For many years, androgen deprivation therapy alone through surgical or chemical castration was the mainstay of treatment yielding limited 5-year survival rates. New treatment approaches using Docetaxel chemotherapy or androgen receptor pathway inhibitors to intensify upfront systemic therapy have resulted in significantly improved survival rates compared to androgen deprivation therapy alone. Clinicians are now equipped with an arsenal of drugs capable of prolonging life for metastatic hormone-sensitive prostate cancer patients. Furthermore, new treatment modalities are being tested in clinical trials making treatment of metastatic hormone-sensitive prostate cancer an extremely dynamic space. In this narrative review, we provide an overview of the key systemic treatments for metastatic hormone-sensitive prostate cancer, namely androgen deprivation therapy, novel androgen receptor pathway inhibitors and Docetaxel. We summarise a series of landmark trials that have led to the integration of novel androgen receptor pathway inhibitors and docetaxel into the treatment paradigm for metastatic hormone-sensitive prostate cancer. Lastly, we discuss nursing, financial and side-effect considerations pertaining to the use of these drugs. This article aims to give its readers an understanding of the evidence and clinical aspects of novel therapies in metastatic hormone-sensitive prostate cancer as they become increasingly available for use around the world.

Finding the optimal treatment sequence in metastatic castration-resistant prostate cancer-a narrative review.

Over the last two decades, there has been significant progress in the treatment of metastatic prostate cancer. Multiple treatments with diverse mechanisms of action have improved clinical outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC) including taxane chemotherapy, immunotherapy, potent androgen receptor pathway inhibitors (ARPI), and radiopharmaceuticals (radium-223). As these treatments have entered standard clinical practise, clinicians have been challenged on how to optimally select and sequence them as the landmark studies establishing their efficacy had control arms with placebo or minimally effective therapy and there is a paucity of prospective trials examining treatment sequencing. More recently, the situation has been further complicated as the earlier up-front use of docetaxel and ARPI with standard gonadal testosterone inhibition has been shown to impart substantial improvements in disease control and survival for patients with castration sensitive prostate cancer. As new therapies enter into clinical practise such as the inhibitors of Poly (ADP-Ribose) Polymerase and Prostate Specific Membrane Antigen (PSMA)-targeted therapy, how to optimally select and sequence available treatments will be a continued dilemma in the absence of validated predictive biomarkers. This review will summarize the literature supporting the use of each active agent in mCRPC. We will propose a framework which will guide the selection of appropriate agents based on prior therapies, disease characteristics and biomarkers.

Predictive factors of survival outcomes in first-line therapy for metastatic castration-resistant prostate cancer.

To investigate predictive factors of survival of metastatic castration-resistant prostate cancer patients undergoing first-line treatment with androgen receptor pathway inhibitors or docetaxel. Japanese patients with metastatic castration-resistant prostate cancer treated with androgen receptor pathway inhibitor or docetaxel between 2008 and 2018 were included. The differential impact of various clinicopathological factors on the outcome, including progression-free survival and overall survival, was compared between treatment with androgen receptor pathway inhibitor and docetaxel. Of 254 patients with metastatic castration-resistant prostate cancer, 119 (46.9%) and 135 (53.2%) were treated with androgen receptor pathway inhibitor and docetaxel, respectively. The multivariate analysis showed that androgen receptor pathway inhibitor was an independent prognostic factor for better progression-free survival (hazard ratio 0.62, 95% confidence interval 0.42-0.92, P = 0.016) and overall survival (hazard ratio 0.61, 95% confidence interval 0.41-0.93, P = 0.021), compared with docetaxel. Pretreatment prostate-specific antigen levels and time to castration-resistant prostate cancer were differentially associated with progression-free survival and overall survival between androgen receptor pathway inhibitor or docetaxel. In patients who presented <6 months to castration-resistant prostate cancer, progression-free survival was shorter in those treated with androgen receptor pathway inhibitor (median 1.1 months, 95% confidence interval 0.2-2.8 months) compared with those who received docetaxel (median 5.0 months, 95% confidence interval 1.8-6.7 months; P = 0.014). First-line therapy with androgen receptor pathway inhibitor is associated with a better prognosis when compared with docetaxel, even after adjustment for prognostic factors. However, a shorter time to castration-resistant prostate cancer is associated with better progression-free survival for patients receiving docetaxel, suggesting that docetaxel is the preferred option for patients with a shorter time to castration-resistant prostate cancer.

Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer

BackgroundMetastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (177Lu)–PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.MethodsWe conducted an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor–pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)–labeled PSMA-11 positron-emission tomographic–computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment.ResultsFrom June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. 177Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001). All the key secondary end points significantly favored 177Lu-PSMA-617. The incidence of adverse events of grade 3 or above was higher with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected.ConclusionsRadioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer. (Funded by Endocyte, a Novartis company; VISION ClinicalTrials.gov number, NCT03511664.)

648TiP PSMAfore: A phase III study to compare 177Lu-PSMA-617 treatment with a change in androgen receptor pathway inhibitor in taxane-naïve patients with mCRPC

[177Lu]Lu-PSMA-617 (177Lu-PSMA-617) is a high-affinity prostate-specific membrane antigen (PSMA)-targeted radioligand therapy that delivers β-particle radiation to PSMA-expressing cells and their surrounding microenvironment. In the phase III VISION trial, 177Lu-PSMA-617 significantly prolonged radiographic progression-free survival (rPFS) and overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with ≥ 1 androgen receptor pathway inhibitor (ARPI) and 1–2 taxanes.

604P Predictive genomic biomarkers in non-metastatic castration resistant prostate cancer (nmCRPC) treated with androgen receptor pathway inhibitors (ARPi)

Although recent trials have demonstrated overall survival (OS) and metastasis free survival (MFS) benefit with the use of ARPi in high-risk nmCRPC, individual treatment outcomes may vary. This retrospective multicentre analysis explores the association between genomic mutations with ARPi treatment outcomes in nmCRPC patients to identify predictive biomarkers.

647TiP PSMAddition: A phase III trial to compare treatment with 177Lu-PSMA-617 plus standard of care (SOC) versus SOC alone in patients with metastatic hormone-sensitive prostate cancer

[177Lu]Lu-PSMA-617 (177Lu-PSMA-617) is a high-affinity prostate-specific membrane antigen (PSMA)-targeted radioligand therapy that delivers β-particle radiation to PSMA-expressing cells and the surrounding microenvironment. Androgen receptor pathway inhibitors (ARPI) may alter PSMA expression and radiosensitivity. PSMAddition will assess the efficacy and safety of 177Lu-PSMA-617 plus standard of care (SOC) versus SOC alone in adults with metastatic hormone-sensitive prostate cancer (mHSPC).

Differential prognostic impact of complete blood count-related parameters by prior use of novel androgen receptor pathway inhibitors in docetaxel-treated castration-resistant prostate cancer patients.

There are multiple reports on the value of complete blood count (CBC)-related parameters on prognosis in docetaxel-treated castration-resistant prostate cancer (CRPC) patients before the emergence of androgen receptor pathway inhibitors (ARPIs). We investigated the prognostic significance of CBC-related parameters in docetaxel-treated CRPC patients. Patients treated with docetaxel chemotherapy for CRPC between 2008 and 2018 were included. We analyzed the relevance of CBC-related parameters to oncological prognosis in docetaxel chemotherapy, associated with prior use of novel ARPIs. Among 144 Japanese men treated with docetaxel, 49 men (34.0%) had already received ARPI therapy. A high neutrophil-lymphocyte ratio (NLR) was a prognostic factor for poor progression-free survival and overall survival (OS) in both univariate and multivariate analyses. In addition, a low hemoglobin (Hb) level and a high systemic immune-inflammation index (SII) were prognostic factors of poor OS in univariate analysis. Hb level was a prognostic factor of OS in both ARPI-naive and ARPI-treated patients. However, a high NLR and SII were only associated with a poor prognosis in ARPI-naive but not in ARPI-treated patients. Hb, NLR, and SII have been suggested to be prognosticators in docetaxel-treated CRPC patients. The differential prognostic value of NLR and SII between ARPI-naive and ARPI-treated patients may require caution when using these markers in docetaxel-treated CRPC patients.

Going beyond Polycomb: EZH2 functions in prostate cancer.

The Polycomb group (PcG) protein Enhancer of Zeste Homolog 2 (EZH2) is one of the three core subunits of the Polycomb Repressive Complex 2 (PRC2). It harbors histone methyltransferase activity (MTase) that specifically catalyze histone 3 lysine 27 (H3K27) methylation on target gene promoters. As such, PRC2 are epigenetic silencers that play important roles in cellular identity and embryonic stem cell maintenance. In the past two decades, mounting evidence supports EZH2 mutations and/or over-expression in a wide array of hematological cancers and solid tumors, including prostate cancer. Further, EZH2 is among the most up-regulated genes in neuroendocrine prostate cancers, which become abundant due to the clinical use of high-affinity androgen receptor pathway inhibitors. While numerous studies have reported epigenetic functions of EZH2 that inhibit tumor suppressor genes and promote tumorigenesis, discordance between EZH2 and H3K27 methylation has been reported. Further, enzymatic EZH2 inhibitors have shown limited efficacy in prostate cancer, warranting a more comprehensive understanding of EZH2 functions. Here we first review how canonical functions of EZH2 as a histone MTase are regulated and describe the various mechanisms of PRC2 recruitment to the chromatin. We further outline non-histone substrates of EZH2 and discuss post-translational modifications to EZH2 itself that may affect substrate preference. Lastly, we summarize non-canonical functions of EZH2, beyond its MTase activity and/or PRC2, as a transcriptional cofactor and discuss prospects of its therapeutic targeting in prostate cancer.

Independent prognostic impact of plasma NCOA2 alterations in metastatic castration-resistant prostate cancer.

The androgen receptor (AR) pathway-associated gene nuclear receptor coactivator 2(NCOA2) has an established oncogenic role in early prostate cancer and likewise is a driver of metastatic disease and castration-resistant prostate cancer. However, its significance as a biomarker in metastatic castration-resistant prostate cancer (mCRPC), both alone and in conjunction with co-occurring AR alterations using a liquid biopsy approach has not been investigated. Ninety-one patients were included in this study, (n = 68 receiving an androgen receptor pathway inhibitorand n = 23 receiving taxane chemotherapy). Up to 30 ml of peripheral blood was collected before commencing treatment from each patient. Plasma cell-free DNA, along with a matched germline sample, underwent targeted next-generation sequencing using a validated, highly sensitive in-house prostate cancer panel. Variants in AR and NCOA2 were identified and correlated with clinical outcomes. Plasma AR and NCOA2 aberrations were identified in 35% and 13% of the cohort, respectively, whilst 8% had concurrent AR and NCOA2 alterations. NCOA2 copy number gain and any NCOA2 aberration predicted for lower prostate-specific antigen (PSA) response rates. Likewise, median overall survival was shorter for NCOA2 gain (10.1vs. 18.3 months; p = .004), remaining significant after adjusting for covariates including circulating tumor DNA fraction and tumor suppressor gene alterations. Importantly, dual AR and NCOA2 aberrations were also associated with inferior outcomes, including no PSA responses in patients treated with AR pathway inhibitors (0% vs. 64%; p = .02). These data highlight the importance of identifying multiple markers of AR pathway modulation in mCRPC and represent the first instance of the assessment of plasma NCOA2 status as a prognostic biomarker for standard-of-care therapies. Further assessment is warranted to determine if NCOA2 aberrations are a marker of primary resistance to AR pathway inhibitors.

Overview of Olaparib as a treatment option for metastatic castration-resistant prostate cancer

ABSTRACT Introduction: Men with prostate cancer undergoing castration will eventually progress. In addition to androgen receptor pathway inhibitors (like abiraterone and enzalutamide) or chemotherapy (like docetaxel), exists olaparib, a relatively new drug that interferes with the base excision repair (BER) pathway mainly due to selective inhibition of Poly ADP-ribose polymerase (PARP) 1 and 2. Areas covered: Herein, the authors evaluate the basic characteristics of olaparib, including its pharmacokinetics, mechanism of action, efficacy, and safety profile. The authors also provide their expert opinion and future perspectives for the place of this drug in the current treatment armamentarium. Expert opinion: Olaparib is the first drug to prove that genetic sequencing and precise medicine is a viable and important option for prostate cancer patients. In patients with deletions in preselected genes, its efficacy renders it as a viable option for second- or third-line management of metastatic castrate resistance prostate cancer (mCRPC). This fact, along with its acceptable toxicity profile, provide physicians with a new weapon in their armamentarium against this extremely difficult to treat disease.

Abstract 1152: Targeted inhibition of SIRT6 by engineered exosomes suppressed tumorigenesis and metastasis in prostate cancer

Abstract The great majority of prostate cancer occurrence and development are driven by androgen receptor signaling, which has led to androgen dependent therapy (ADT) as the backbone of systemic therapy for advanced prostate cancer patients until now. Although ADT has improved clinical outcome in patients with castration-sensitive disease and the next-generation androgen receptor pathway inhibitors (ARPIs) like enzalutamide are commonly used in advanced prostate cancer patients, the cross-resistance between AR-targeted drugs significantly limits the therapeutic effect. Besides, early use and potentially long exposure to ARPIs preferentially lead to the evolvement of the alternative downstream signaling instead of AR pathway. Hence, targeting the AR fails to develop inescapable drug resistance, and no effective approach is available for targeting metastatic and castration-resistant prostate cancer (mCRPC), which is a major clinical challenge in prostate cancer treatment. Undoubtedly, new targets and therapeutic strategies are needed to improve the clinical outcomes. Sirt6 belongs to the Sirtuin family proteins, and as a nuclear protein, regulates diverse physiological functions like aging and metabolism. Silencing SIRT6 could inhibit prostate cancer proliferation, and in this study, we further exploited this phenomenon. We found that expression of SIRT6 was positively related with the Gleason score of the patients' prostate tissue sample and knockdown the expression of SIRT6 in prostate cancer cell lines significantly reduced migration and invasion both in vitro and in vivo. Furthermore, SIRT6 deficiency upregulated the expression of E-cadherin and downregulated the expression of N-cadherin and Vimentin, suggesting its role in regulation of epithelial-mesenchymal transition (EMT). Silencing SIRT6 inhibited both the proliferation and metastasis in prostate cancer, indicating the therapeutic value of targeting SIRT6 in the treatment of metastatic PCa. We then tested the therapeutic value of SIRT6 in prostate cancer in vivo by using aptamer-modified exosomes carrying SIRT6 siRNA. To achieve this goal, the cholesterol-covalent E3 aptamer was inserted into the membrane of 293T-derived exosomes to target specifically the prostate cancer cells, followed by SIRT6-siRNA loading into the modified exosomes with an electroporation apparatus. The engineered exosomes suppressed the proliferation and metastasis in subcutaneously and orthotopically xenograft mice tumor models, and confirmed that SIRT6 could be considered as a selective and novel target in high-grade prostate cancer. Citation Format: Qing Han, Qian Reuben Xie, Fan Li, Yirui Cheng, Tingyu Wu, Jianjun Sha, Weiliang Xia. Targeted inhibition of SIRT6 by engineered exosomes suppressed tumorigenesis and metastasis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1152.

Evaluation of Darolutamide (ODM201) Efficiency on Androgen Receptor Mutants Reported to Date in Prostate Cancer Patients.

Simple SummaryProstate cancer (PCa) is the most commonly diagnosed non-skin cancer in men and one of the leading causes of cancer-related death. The driver of PCa proliferation and growth is the androgen receptor (AR) and inhibiting this receptor is the standard of care for patients, following surgery or radiotherapy. Unfortunately, the effectiveness of current therapeutics is temporary, with the cancer eventually developing drug resistance. Among the mechanisms of resistance are the arising mutations in the AR that make the receptor promiscuously activated by drugs or non-specific ligands, thus promoting cancer progression. The aim of this study is to characterize the responses of 44 AR mutants, derived from PCa patients, to available steroids that activate the receptor as well as to various treatments currently used in the clinic. This work will help create a tool to guide the medical team in selecting the best personalized treatment option for each patient.Resistance to drug treatments is common in prostate cancer (PCa), and the gain-of-function mutations in human androgen receptor (AR) represent one of the most dominant drivers of progression to resistance to AR pathway inhibitors (ARPI). Previously, we evaluated the in vitro response of 24 AR mutations, identified in men with castration-resistant PCa, to five AR antagonists. In the current work, we evaluated 44 additional PCa-associated AR mutants, reported in the literature, and thus expanded the study of the effect of darolutamide to a total of 68 AR mutants. Unlike other AR antagonists, we demonstrate that darolutamide exhibits consistent efficiency against all characterized gain-of-function mutations in a full-length AR. Additionally, the response of the AR mutants to clinically used bicalutamide and enzalutamide, as well as to major endogenous steroids (DHT, estradiol, progesterone and hydrocortisone), was also investigated. As genomic profiling of PCa patients becomes increasingly feasible, the developed “AR functional encyclopedia” could provide decision-makers with a tool to guide the treatment choice for PCa patients based on their AR mutation status.

Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition.

Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance. We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA). Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements. Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.