Androgen Receptor Pathway Inhibitors Research Articles

Lutetium (¹⁷⁷Lu) Vipivotide Tetraxetan (Pluvicto)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses 177Lu vipivotide tetraxetan (Pluvicto), solution for injection, 1 GBq/mL (27 mCi/mL) at calibration.
 Indication: The treatment of adults with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer who have received at least 1 androgen receptor pathway inhibitor and taxane-based chemotherapy.

Steroidogenesis in castration-resistant prostate cancer.

Castration resistance is in part attributable to aberrant activation of androgen receptor (AR) signaling by the intracrine activation of androgen precursors derived from adrenal glands. To overcome this, novel AR pathway inhibitors (ARPIs) that suppress androgen synthesis by CYP17 inhibition or AR activation by antiandrogen effects have been developed. However, primary or acquired resistance to these ARPIs occurs; in turn attributable, at least in part, to the maintained androgen milieu despite intensive suppression of AR signaling similar to castration resistance. In addition to the classical pathway to produce potent androgens such as testosterone and dihydrotestosterone, the alternative pathway and the backdoor pathway which bypasses testosterone to produce dihydrotestosterone have been shown to play a role in intratumor steroidogenesis. Furthermore, the 11β-hydroxyandrostenedione pathway to produce the potent oxygenated androgens 11-ketotestosterone and 11-ketodihydrotestosterone has been suggested to be functional in prostate cancer. These steroidogenesis pathways produce potent androgens that promote tumor resistance to endocrine therapy including novel ARPIs. Here, we overview the current evidence on the pathological androgen milieu by altered metabolism and transport in prostate cancer, leading to resistance to endocrine therapy.

Emergence of triplet therapy for metastatic castration-sensitive prostate cancer: An updated systematic review and network meta-analysis.

There have been a growing number of treatment options available for men with metastatic castration-sensitive prostate cancer. Not only have newer agents entered the clinical landscape, there is a trend toward treatment intensification by combining multiple agents simultaneously. We aim to assess the best contemporary treatment option for men with mCSPC. We perform an updated systematic review and network meta-analysis of randomized control trials that evaluated systemic therapies in men with castration-sensitive prostate cancer. We searched multiple databases up to April 2022. We included all randomized trials assessing the effect of systemic agents. We performed subgroup analyses based on disease volume and timing of presentation. Statistical analysis was performed with Bayesian methods. We found 10 eligible trials with 10,065 patients who were included in this analysis. Triplet therapy with darolutamide or abiraterone with docetaxel and ADT improved overall survival. In the sensitivity analysis, the respective hazard ratios for triplet therapy was HR 0.70 (95%CI 0.61-0.80) compared to docetaxel+ADT and 0.77 (95%CI 0.65-0.91) compared to androgen receptor pathway inhibitors+ADT combinations. It was estimated that there was 96% chance that one of the triplet therapy combinations were the best treatment option from an OS perspective. Triplet therapy also improved progression-free survival. These benefits were pronounced in men with high-volume disease burden and those with de novo metastatic disease. The finding suggest that triplet therapy is likely the most efficacious available option in men with metastatic, castration-sensitive prostate cancer, especially in those with high-volume disease burden.

Triplet Therapy in Metastatic Castrate Sensitive Prostate Cancer (mCSPC)-A Potential New Standard of Care.

The treatment paradigm for metastatic castrate-sensitive prostate cancer (mCSPC) has evolved rapidly in the past decade with the approval of several life-prolonging therapies including docetaxel chemotherapy and multiple androgen receptor pathway inhibitors (ARPI) in combination with androgen deprivation therapy (ADT). Recently reported phase-three trials have demonstrated a survival benefit of upfront triplet therapy with ADT, docetaxel plus either abiraterone acetate or darolutamide when compared to ADT plus docetaxel alone. However, multiple questions including the incremental benefit of docetaxel to a combination of ADT and ARPI, the timing of ARPI, optimal patient selection for triplet therapy and clinical and genomic biomarkers still remain to be answered. Moreover, real-world data suggest suboptimal treatment intensification with many patients treated with ADT alone highlighting challenges in implementation. In this article, we review the phase-three data associated with triplet therapy in mCSPC. We also discuss the knowledge gaps that exist despite the completion of these studies and how ongoing studies are likely to change the paradigm in the near future. Finally, we provide a simple algorithm based on current data that clinicians can use in daily practice to select patients for appropriate treatment strategies.

Abstract 2303: Adverse clinical outcomes and distinct genomic phenotype of BRCA-deficient metastatic castration-resistant prostate cancer (mCRPC)

Abstract Defects in the homologous recombination (HR) pathway, particularly in BRCA2, are of particular therapeutic relevance in mCRPC as they confer sensitivity to PARP inhibitors (PARPi). Nevertheless, durable responses to PARPi remain elusive and primary resistance is an additional major challenge. As a result, dissecting therapeutic vulnerabilities in HR-aberrant patients is crucial and may reveal novel PARPi-based combinations for evaluation in future clinical trials.In this multi-institutional study, we used the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay that assesses 152 genes to profile plasma from 375 mCRPC patients from Australia and the USA. Reportable alterations included pathogenic single-nucleotide (somatic and germline) and copy number variants. Association between alterations and clinical outcomes were assessed using log rank, cox proportional, and chi-squared analyses.Overall, 65 patients (17%) had evidence of a pathogenic BRCA2 aberration, which were commonly hemizygous (78% vs 22% homozygous deletions), monoallelic (70% vs 30% bi-allelic), somatic (87% vs 13% germline), and clonal (83% vs 17% subclonal) in nature. There was no significant difference in plasma tumour fraction in patients with single vs two-copy loss of BRCA2, and BRCA2 zygosity did not have differing effects on outcomes, with both being similarly associated with shorter overall survival (HR 0.48, p<0.002, and HR 0.45, p=0.003, respectively). Pathogenic BRCA1 aberrations were present in 10 patients (3%). PSA response rates to androgen-receptor pathway inhibitors (ARPI) were significantly lower in patients with a BRCA1 and/or a BRCA2 aberration (32% vs 60%, p=0.02), and we observed this BRCA-defective subgroup to be enriched for AR aberrations (71% had >1 AR aberration vs 38% in BRCA-intact patients, p=0.001). BRCA-defective cancers were also significantly enriched for aberrations in key neuroendocrine markers TP53 (62% vs 28%), RB1 (60% vs 17%), and MYC (27% vs 9%), as well as for PI3K pathway aberrations (PTEN 63% vs 25% and PIK3CA 37% vs 14%). In summary, we show that BRCA alterations are associated with worse prognosis in mCRPC and reduced benefit from ARPI, and that the prognostic and predictive utility of cfDNA-detected BRCA2 may be independent of zygosity state, potentially due to constraints with copy number loss identification in samples with low tumour DNA. Additionally, on top of a high proportion of AR alterations, BRCA-defective cancers were also enriched in a number of potentially actionable targets and neuroendocrine markers. Clinical trials that leverage rational co-targeting strategies will provide an opportunity to enhance the efficacy of PARPi in mCRPC. Citation Format: Heidi Fettke, Chao Dai, Edmond M. Kwan, Tiantian Zheng, Winston Tan, P Du, Nicole Ng, Patricia Bukszynska, Maria Docanto, L K. Graham, Kate Mahon, Lisa G. Horvath, Shidong Jia, Manish Kohli, Arun A. Azad. Adverse clinical outcomes and distinct genomic phenotype of BRCA-deficient metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2303.

Abstract 3064: Exosome-based therapeutic strategy for neuroendocrine prostate cancer

Abstract Background: Therapy-induced neuroendocrine prostate cancer (NEPC) is an aggressive variant of castration-resistant prostate cancer (CRPC) that is increasing in incidence with the widespread use of second generation of androgen receptor (AR)-pathway inhibitors (APIs) such as Enzalutamide (ENZ). NEPC arises from CRPC-Adenocarcinomas (CRPC-Adeno) via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED) wherein prostate cancer cells (PCa) undergo a lineage switch. As a result of this lineage switching, PCa cells exhibit neuroendocrine (NE) features, characterized by expression of neuronal markers such as enolase 2 (ENO2), chromogranin A (CHGA) and synaptophysin (SYP). Due to lack of AR signaling, these PCa variants are impervious to anti-androgen therapy and constitute an aggressive variant of advanced CRPC with survival times < 1 year. Clinically, NEPC manifests as the presence of visceral metastatic disease including metastasis to liver, lung, central nervous system or bone despite low serum PSA levels. Current therapeutic options for NEPC are limited to highly toxic platinum drugs. The primary objective of our study is to evaluate novel, exosome-based therapies for NEPC. Methods: Exosomes were isolated from HEK-293T cells by ultracentrifugation. Isolated exosomes were characterized by Nanoparticle Tracking Analyses and electron microscopy. These exosomes were engineered to express biotinylated CEACAM-5 antibody on their cell surface. Exosomes were packaged with a combination of drugs (EZH2 inhibitor and AR inhibitor) by sonication. Engineered exosomes were tested in vitro using NEPC cell line NCI-H660 and in vivo using LuCaP 145.1 patient-derived xenograft model. Results: Engineered exosomes reduced the viability of NEPC cells. CEACAM5-labelled exosomes trafficked to tumor cells as CECAM5 is a surface protein expressed by NEPC cells. Conclusions: Engineered-exosome based therapy may provide a new avenue as a targeted therapy for NEPC. Citation Format: Amritha Sreekumar, Sharanjot Saini. Exosome-based therapeutic strategy for neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3064.

Abstract 3441: A multivalent peptoid conjugate that inhibits therapy-resistant prostate cancer cell proliferation by modulating androgen receptor transcriptional activity

Abstract Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance despite the continued expression and function of the AR. We developed a new approach to antagonize the proliferative activity of AR and inhibit castration-resistant prostate cancer (CRPC) growth using multivalent peptoid conjugates (MPCs). Our strategy is to display multiple copies of the AR antagonist, ethisterone, on a peptoid scaffold. Such a multivalent display increases the ligand’s effective local concentration, thus targeting AR with high affinity and affecting AR interactions with coregulators. Here, we report a new potent MPC called MPC309, which displays three ethisterone groups and binds to AR with nanomolar affinity. MPC309 reduces the proliferation of enzalutamide-resistant prostate cancer cells, including those harboring AR splice variants, AR ligand binding mutations, and non-canonical AR gene expression programs. We provide evidence that MPC309 enters cells via macropinocytosis, which facilitates the fluid-phase uptake of extracellular macromolecules. Macropinocytotic uptake of MPC309 enhances cancer cell-specific delivery, thus limiting systemic toxicities. MPC309 displays favorable pharmacological properties and produced significantly greater tumor suppression in xenograft studies than enzalutamide, the standard of care anti-androgen in clinical use. Mechanistically, MPC309 inhibits prostate cancer growth by eliciting a unique gene expression program through alterations in AR chromatin occupancy compared to dihydrotestosterone (DHT) or enzalutamide. Thus, MPC309 represents a novel AR antagonist that activates an AR anti-proliferative program to repress the growth of CRPC and supports further investigation of the MPC compound class for treating CRPC. Citation Format: Justine Habault, Jeffrey A. Schneider, Susan Ha, Rachel Ruoff, Joseph Puccini, Dafna Bar-Sagi, Kwok-Kin Wong, Amina Zoubeidi, Frank Claessens, David R. Wise, Susan K. Logan, Kent Kirshenbaum, Michael J. Garabedian. A multivalent peptoid conjugate that inhibits therapy-resistant prostate cancer cell proliferation by modulating androgen receptor transcriptional activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3441.

Abstract 3783: Role of microRNA 28-3p in prostate cancer progression

Abstract Prostate cancer (PCa) is a leading cause of cancer incidence and mortality among men. Prostate cancer is driven by androgens acting via androgen receptor (AR). Therefore, this cancer is treated with androgen deprivation therapy (ADT) initially. However, the cancer rapidly evolves to be resistant to ADT and progresses to a more invasive stage referred to as ‘Castration Resistant prostate cancer’ (CRPC). CRPC is treated with second generation of AR pathway inhibitors such as Enzalutamide and Abiraterone. These treatments are effective initially. However, drug resistance develops in a significant fraction of patients and the cancer undergoes ‘neuroendocrine trans-differentiation (NED) to a lethal variant called ‘neuroendocrine prostate cancer’ (NEPC). As a result of NED, PCa cells express neuronal markers such as synaptophysin, chromogranin A and enolase. The molecular basis of NED is not yet fully defined. With a focus on identifying the role of microRNAs (miRNAs) in NEPC, we performed small RNA sequencing in CRPC tumors with and without NED. This sequencing identified miR-28-3p to be significantly downregulated in CRPC-NE samples as compared to CRPC-adenocarcinomas (CRPC-Adeno). In view of this, we examined the role of this miRNA in NEPC. Analyses of TCGA data of prostate adenocarcinomas suggest that miR 28-3p has an oncogenic role in primary prostate tumors. However, its expression declines in tumors with increasing Gleason score. We profiled the expression of miR-28-3p in patient-derived xenograft models and clinical CRPC-NE and CRPC-Adeno tissues by real time PCR. Our profiling showed a trend towards downregulation with increased NED. Basal expression of miR 28-3p in various prostate cancer cell lines showed an elevated level in androgen dependent cell lines whereas significantly less expression in NEPC cell lines, LASCPC-01 and NCI-H660. In this study, we generated PC3 cell line that stably expresses miR-28 for understanding its functional role in regulating PCa. Preliminary functional assays including cell viability assay, cell cycle studies and invasion and migration assay suggest a tumor suppressor role of miR-28-3p in advanced prostate cancer. In conclusion, our data shows that miR 28-3p potentially has a biphasic role in PCa, where it is oncogenic in early stages and acts as a tumor suppressor in late stage PCa. Citation Format: Amritha Sreekumar, Sharanjot Saini. Role of microRNA 28-3p in prostate cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3783.

MP20-20 CHAPERONE-MEDIATED AUTOPHAGY PROMOTES PCA SURVIVAL DURING ARPI THROUGH SELECTIVE PROTEOME AND PATHWAY REMODELING

You have accessJournal of UrologyCME1 Apr 2023MP20-20 CHAPERONE-MEDIATED AUTOPHAGY PROMOTES PCA SURVIVAL DURING ARPI THROUGH SELECTIVE PROTEOME AND PATHWAY REMODELING Nicholas Nikesitch, Eliana Beraldi, Fan Zhang, Hans Adomat, Robert Bell, Kotaro Suzuki, Ladan Fazli, Sonia Kung, Christopher Wells, Nicholas Pinette, Neetu Saxena, Yuzhuo Wang, and Martin Gleave Nicholas NikesitchNicholas Nikesitch More articles by this author , Eliana BeraldiEliana Beraldi More articles by this author , Fan ZhangFan Zhang More articles by this author , Hans AdomatHans Adomat More articles by this author , Robert BellRobert Bell More articles by this author , Kotaro SuzukiKotaro Suzuki More articles by this author , Ladan FazliLadan Fazli More articles by this author , Sonia KungSonia Kung More articles by this author , Christopher WellsChristopher Wells More articles by this author , Nicholas PinetteNicholas Pinette More articles by this author , Neetu SaxenaNeetu Saxena More articles by this author , Yuzhuo WangYuzhuo Wang More articles by this author , and Martin GleaveMartin Gleave More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The androgen receptor (AR) plays an important role in PCa metabolism, with androgen receptor pathway inhibition (ARPI) subjecting PCa cells to acute metabolic stress caused by reduced biosynthesis and energy production. Defining acute stress response mechanisms that alleviate ARPI stress and therefore mediate prostate cancer (PCa) treatment resistance will help improve therapeutic outcomes of patients treated with ARPI. METHODS: CMA induction and activity was studied within several in-vitro, in-vivo and ex-vivo PCa models using QPCR, Western Blot and CMA-reporter assays. CMA upregulation/downregulation on PCa growth was measured in-vitro and in-vivo via cell confluence or tumour volume/PSA levels. Proteome profiling of PCa cells was perfromed by TMT mass spec, with metabolic assays performed using western blot, colormetric and flow cytometry. RESULTS: We identified the up-regulation of chaperone-mediated autophagy (CMA) in response to acute ARPI stress, which persisted in castration-resistant PCa (CRPC); previously undefined in PCa. CMA is a selective protein degradation pathway and a key stress response mechanism up-regulated under several stress stimuli, including metabolic stress. Through selective protein degradation, CMA orchestrates the cellular stress response by regulating cellular pathways through selective proteome remodeling. Through broad-spectrum proteomic analysis, CMA coordinates metabolic reprogramming of PCa cells to sustain PCa growth and survival during ARPI; through the upregulation of mTORC1 signaling and pathways associated with PCa biosynthesis and energetics. This not only promoted PCa growth during ARPI, but also promoted the emergence of CRPC in-vivo. During CMA inhibition, PCa metabolism is compromised, leading to ATP depletion, resulting in a profound anti-proliferative effect on PCa cells, and is enhanced when combined with ARPI. Furthermore, CMA inhibition prevented in-vivo tumour formation, and also re-sensitized enzalutamide-resistant cell lines in-vitro. The profound anti-proliferative effect of CMA inhibition was attributed to cell cycle arrest mediated through p53 transcriptional repression of E2F target genes. CONCLUSIONS: In summary, CMA is an acute ARPI stress response mechanism, essential in alleviating ARPI induced metabolic stress, essential for ensuring PCa growth and survival. CMA plays a critical role in the development of ARPI resistance in PCa. Source of Funding: Terry Fox New Frontiers Program Project (1062) and PCFBC Grant-In-Aid Program © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e283 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nicholas Nikesitch More articles by this author Eliana Beraldi More articles by this author Fan Zhang More articles by this author Hans Adomat More articles by this author Robert Bell More articles by this author Kotaro Suzuki More articles by this author Ladan Fazli More articles by this author Sonia Kung More articles by this author Christopher Wells More articles by this author Nicholas Pinette More articles by this author Neetu Saxena More articles by this author Yuzhuo Wang More articles by this author Martin Gleave More articles by this author Expand All Advertisement PDF downloadLoading ...

MP29-07 APC MUTATION CONTRIBUTES TO NEUROENDOCRINE DIFFERENTIATION AND POOR OVERALL SURVIVAL IN METASTATIC PROSTATE CANCER PATIENTS

You have accessJournal of UrologyCME1 Apr 2023MP29-07 APC MUTATION CONTRIBUTES TO NEUROENDOCRINE DIFFERENTIATION AND POOR OVERALL SURVIVAL IN METASTATIC PROSTATE CANCER PATIENTS Yuto Baba, Takeo Kosaka, Kohei Nakamura, Yota Yasumizu, Nobuyuki Tanaka, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Ryuichi Mizuno, Hiroshi Nishihara, and Mototsugu Oya Yuto BabaYuto Baba More articles by this author , Takeo KosakaTakeo Kosaka More articles by this author , Kohei NakamuraKohei Nakamura More articles by this author , Yota YasumizuYota Yasumizu More articles by this author , Nobuyuki TanakaNobuyuki Tanaka More articles by this author , Toshikazu TakedaToshikazu Takeda More articles by this author , Kazuhiro MatsumotoKazuhiro Matsumoto More articles by this author , Shinya MoritaShinya Morita More articles by this author , Ryuichi MizunoRyuichi Mizuno More articles by this author , Hiroshi NishiharaHiroshi Nishihara More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although therapeutic strategies for metastatic prostate cancer (PCa) have expanded, some patients still suffer rapid progression. We investigated if their genomic characteristics correlated with treatment resistance and their clinical outcomes. METHODS: We identified 70 metastatic prostate cancer patients who underwent gene-panel tests since 2018. The correlation between the profiles of genomic mutation and the oncological outcomes including overall survival, time to treatment-related neuroendocrine prostate cancer (tNEPC), and the efficacy of each sequential treatment such as androgen receptor pathway inhibitors (ARPI), docetaxel (DTX), cabazitaxel (CBZ), and platinum-based chemotherapies were evaluated. RESULTS: Among the 70 patients, 27 (38.6%) patients developed metastases after definitive therapies while 43 (61.4%) already had metastases at the initial diagnosis. The most common genomic mutations were TP53 (35.7%), BRCA2 (22.9%), PTEN (21.4%), RB1 (18.6%), MYC (14.3%), APC (11.4%), and CDK12 (10.0%). As for treatment profiles, all the patients received androgen-deprivation therapy (ADT), 53 (75.7%) patients received ARPI, 48 (68.6%) patients received DTX, 32 (45.7%) patients received CBZ, and 37 (52.9%) patients received platinum-based therapy. Second biopsy of prostate or metastatic lesion revealed the pathological transformation from adenocarcinoma to tNEPC in 25 (35.7%) patients. Univariate and Multivariate analysis also indicated that that patients with APC and MYC mutations had shorter overall survival (HR=17.9, p=0.006 and HR=3.98, p=0.018, respectively). Focusing on the 8 APC-mutated patients, while their 30% PSA response rare after ARAT or DTX were not statistically low (p=0.74 and p=0.23), five out of them (62.5%) showed NEPC in the second biopsy samples and shorter time to NEPC development compared with those without APC mutations (p=0.05). In our cohort, APC mutation did not exist alone but coincided with either RB1 (5 patients, 62.5%) or TP53 (4 patients, 50%), major tumor suppressor genes. CONCLUSIONS: APC mutation, associated with other genomic alteration of tumor suppressor and NED, can be an important prognostic indicator in PCa patients. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e383 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yuto Baba More articles by this author Takeo Kosaka More articles by this author Kohei Nakamura More articles by this author Yota Yasumizu More articles by this author Nobuyuki Tanaka More articles by this author Toshikazu Takeda More articles by this author Kazuhiro Matsumoto More articles by this author Shinya Morita More articles by this author Ryuichi Mizuno More articles by this author Hiroshi Nishihara More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement PDF downloadLoading ...

Rezvilutamide: yet another androgen receptor pathway inhibitor for metastatic hormone-sensitive prostate cancer?

Rezvilutamide: yet another androgen receptor pathway inhibitor for metastatic hormone-sensitive prostate cancer?

MP29-02 EFFICACY AND SAFETY OF DAROLUTAMIDE IN COMBINATION WITH ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN THE NORTH AMERICAN POPULATION FROM ARASENS

You have accessJournal of UrologyCME1 Apr 2023MP29-02 EFFICACY AND SAFETY OF DAROLUTAMIDE IN COMBINATION WITH ANDROGEN-DEPRIVATION THERAPY AND DOCETAXEL IN THE NORTH AMERICAN POPULATION FROM ARASENS Neal D. Shore, Bertrand Tombal, Maha Hussain, Fred Saad, Karim Fizazi, Cora N. Sternberg, E. David Crawford, Luke Nordquist, Ronald Tutrone, Laurence Belkoff, Shivani Kapur, Jay Jhaveri, Shankar Srinivasan, Heikki Joensuu, and Matthew R. Smith Neal D. ShoreNeal D. Shore More articles by this author , Bertrand TombalBertrand Tombal More articles by this author , Maha HussainMaha Hussain More articles by this author , Fred SaadFred Saad More articles by this author , Karim FizaziKarim Fizazi More articles by this author , Cora N. SternbergCora N. Sternberg More articles by this author , E. David CrawfordE. David Crawford More articles by this author , Luke NordquistLuke Nordquist More articles by this author , Ronald TutroneRonald Tutrone More articles by this author , Laurence BelkoffLaurence Belkoff More articles by this author , Shivani KapurShivani Kapur More articles by this author , Jay JhaveriJay Jhaveri More articles by this author , Shankar SrinivasanShankar Srinivasan More articles by this author , Heikki JoensuuHeikki Joensuu More articles by this author , and Matthew R. SmithMatthew R. Smith More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003257.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In ARASENS (NCT02799602), darolutamide (DARO) + androgen-deprivation therapy (ADT) + docetaxel significantly reduced the risk of death by 32.5% (HR 0.68, 95% CI 0.57–0.80; P<0.0001) vs placebo (PBO) + ADT + docetaxel in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC). DARO maintained quality of life, with similar control of disease-related physical symptoms and pain vs placebo, and had a favorable safety profile. We report clinical outcomes in North American (NA) pts in ARASENS. METHODS: This international, double-blind, phase 3 trial randomized pts 1:1 to DARO 600 mg twice daily or PBO in addition to ADT + docetaxel. The primary endpoint was overall survival (OS). Key secondary endpoints included time to castration-resistant prostate cancer (CRPC) and safety. RESULTS: Of 1305 pts analyzed, 244 (18.7%) were enrolled in North America (US/Canada 218/26; DARO/PBO 125/119) and of these, 36 (14.8%) were Black/African American (AA) pts. Baseline characteristics of the NA population were generally similar to those of the overall population, except for the proportion of pts with de novo metastatic disease (75.8% NA vs 86.1% overall). In NA pts, DARO + ADT + docetaxel was associated with OS benefit vs PBO + ADT + docetaxel (HR 0.59, 95% CI 0.39–0.89), with 4-year survival rates of 66% vs 50%, respectively. The DARO vs PBO group had longer time to CRPC (HR 0.32, 95% CI 0.21–0.48). The safety profile of DARO in NA pts was consistent with that of the overall population (grade 3/4 treatment-emergent adverse events [TEAEs] 61% NA vs 66% overall; serious TEAEs 44% NA vs 45% overall). The incidences of TEAEs associated with androgen receptor pathway inhibition for DARO vs PBO were generally consistent, particularly when adjusted for treatment exposure. The OS benefit and safety profile of DARO vs PBO was also seen in Black/AA pts, consistent with the overall population. CONCLUSIONS: In NA pts with mHSPC, addition of DARO to ADT + docetaxel led to a clinically meaningful reduction in risk of death by 41% and improved the key patient-relevant secondary endpoint of time to CRPC. Incidences of TEAEs were generally similar between treatment groups in NA pts and consistent with the overall population. Source of Funding: Bayer AG and Orion Pharma. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e380 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal D. Shore More articles by this author Bertrand Tombal More articles by this author Maha Hussain More articles by this author Fred Saad More articles by this author Karim Fizazi More articles by this author Cora N. Sternberg More articles by this author E. David Crawford More articles by this author Luke Nordquist More articles by this author Ronald Tutrone More articles by this author Laurence Belkoff More articles by this author Shivani Kapur More articles by this author Jay Jhaveri More articles by this author Shankar Srinivasan More articles by this author Heikki Joensuu More articles by this author Matthew R. Smith More articles by this author Expand All Advertisement PDF downloadLoading ...

Lutetium (¹⁷⁷Lu) Vipivotide Tetraxetan (Pluvicto)

&#x0D; CADTH recommends that Pluvicto should be reimbursed by public drug plans for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) if certain conditions are met.&#x0D; Pluvicto should only be covered to treat patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who have received previous treatment with at least 1 androgen receptor pathway inhibitor (ARPI) and at least 1 taxane-containing regimen (i.e., chemotherapy), and who are in relatively good health (i.e., have good performance status).&#x0D; Pluvicto should not be reimbursed in combination with anticancer therapies other than androgen-deprivation therapy (ADT), usage should be limited to 6 cycles, and the cost of Pluvicto should be reduced.&#x0D;

A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer.

Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.

Based on ARASENS trial: efficacy and safety of darolutamide as an emerging option of endocrinotherapy for metastatic hormone-sensitive prostate cancer-an updated systematic review and network meta-analysis.

The newly published ARASENS trial has demonstrated the clinical efficacy of darolutamide for metastatic hormone-sensitive prostate cancer (mHSPC). However, the use of darolutamide as the latest first-line androgen receptor pathway inhibitor for mHSPC has not been compared with other androgen receptor targeted agents (ARTAs). Given the lack of head-to-head randomized trials, we performed this updated meta-analysis to conduct indirect comparison for the efficacy and safety of darolutamide with other new-generation ARTAs. By searching the databases of PubMed, Scopus, Cochrane Library, and Embase, 9 large randomized controlled trials evaluating ARTAs for mHSPC patients were eventually screened according to PRISMA. We extracted data from overall survival, castration-resistant progression, and adverse events for network meta-analysis using the Bayesian and standard frequentist models. Darolutamide combination emerged with superiority (HR = 0.68, 95%CrI = 0.57-0.81) among four androgen receptor inhibitors for patients with high Gleason score (HR = 0.71, 95%CrI = 0.59-0.86). Darolutamide was best tolerated in several androgen suppression-related adverse events (AEs). Darolutamide appears to be an optional androgen receptor inhibitor for mHSPC patients, especially for patients with Gleason score ≥ 8. Its well-tolerated characteristic may provide a preferred drug option for patients with poor cardiovascular function and bone health.

Real-world treatment patterns and progression-free survival among patients with metastatic castration-resistant prostate cancer: Examining the benefits of sequential androgen receptor pathway inhibitor use.

64 Background: Numerous treatments with different mechanisms of action are approved for metastatic castration-resistant prostate cancer (mCRPC), but real-world studies increasingly indicate that androgen receptor pathway inhibitors (ARPIs) are the most common treatment choice at both first- (1L) and second-line (2L). Nonetheless, robust evidence on the clinical effectiveness of ARPIs when used sequentially is lacking. The aim of this study was to examine the real-world treatment patterns and associated progression-free survival (PFS) among patients with mCRPC in the United States (US). Methods: This retrospective cohort study used Flatiron Health electronic health record data from 01/01/2013 to 06/30/2020. Included patients were male, aged ≥18 years, had a confirmed diagnosis of mCRPC within the study period, and received ≥1 systemic therapy post-mCRPC diagnosis. Three treatment subgroups were examined, with ARPI defined as abiraterone or enzalutamide: all 1L ARPI users; all 2L ARPI users irrespective of 1L therapy; and 1L ARPI users who received another ARPI at 2L. Treatment patterns were evaluated descriptively; time to next therapy (TTNT) was measured from the start of the ARPI of interest to the start of the subsequent line of therapy. The Kaplan-Meier method was used to evaluate PFS from the start of the ARPI therapy of interest until progression or death from any cause. Results: The study included 2,588 patients (mean age 72 years). ARPIs were the most prescribed systemic therapy in both the 1L and 2L settings: 63% (1,634/2,588) and 46% (808/1,760), respectively. Among 1L ARPI patients, 28.9% received 2L ARPI, 14.0% 2L taxane, 14.3% 2L combo therapies, and 32% received no further therapy. The median TTNT was 7.6, 6.2, and 5.1 months for 1L ARPIs, 2L ARPIs among all users, and 2L ARPIs among patients who received 1L ARPIs, respectively. The corresponding median PFS was 6.5 months, 4.5 months, and 3.9 months, respectively. Conclusions: Among real-world mCRPC patients in the US, ARPIs remain the most common therapy at both 1L and 2L. However, sequential ARPI use appeared to provide diminishing returns, with a PFS of &lt;4 months seen at 2L in those who had received 1L ARPIs. [Table: see text]

A phase I trial of androgen deprivation, darolutamide, and ipatasertib in a safety cohort with castration-resistant prostate cancer (ADDITION).

174 Background: Alterations activating the PI3K-AKT pathway are found in 40-50% of patients with aggressive prostate cancer. This leads to an abrogated response to therapy with androgen-receptor (AR) pathway inhibitors (ARPIs) and is associated with poor outcomes. Preclinical in vivo models suggest there is synergy between ARPIs and AKT inhibitors. Methods: This is a single-arm study of the AR inhibitor darolutamide, the AKT inhibitor ipatasertib, and androgen deprivation therapy (ADT). The phase I safety cohort included patients with castration-resistant prostate cancer (CRPC). ADT was administered per institutional standards. Patients started with a lead-in of ipatasertib for 7 days, followed by ipatasertib combined with darolutamide 600 mg BID. The starting dose of ipatasertib was 400 mg daily with plans to de-escalate if ≥ 2 dose-limiting toxicities (DLTs) were identified in the first six patients. The DLT period was the first 4 weeks of combination therapy. The primary endpoint was to identify the recommended phase II dose (RP2D) of ipatasertib. A phase II biomarker-selected cohort was planned to receive the combination neoadjuvantly. That portion of the study was terminated prior to patient enrollment due to the withdrawal of industry support. Results: Six patients with metastatic CRPC were enrolled in the phase I cohort. They had received a median of 3 prior systemic therapies in addition to ADT (range 1-6). All patients completed the DLT period, and no DLTs were observed. The RP2D of ipatasertib, when given with darolutamide, is 400mg daily. Two patients (33%) had serious adverse events (SAEs) (diarrhea; grade 3) related to ipatasertib outside the DLT period. Two patients (33%) had SAEs unrelated to study drugs; pyelonephritis (one patient; grade 3) secondary to obstruction, and respiratory failure (one patient; grade 5) attributed to disease progression. Two (33%) patients had at least a 50% decline in PSA as the best PSA response, including 2 of 3 patients with known PI3K pathway alterations. Median PSA progression free survival (PFS) was 3.35 months (95% CI 3.06-NA). Median radiographic PFS was 2.91 months (95% CI 2.79-NA). Conclusions: Combination therapy with darolutamide and ipatasertib in CRPC is safe and a RP2D of ipatasertib was established. Toxicity was similar to the therapies given alone, and the most common treatment-related SAE was diarrhea. Partial response to combination therapy was seen in men with CRPC and known PI3K alterations. Clinical trial information: NCT04737109 .

Activity of lutetium-177 PSMA (Lu-PSMA) and determinants of outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with cabazitaxel: The PACAP study.

180 Background: Cabazitaxel and Lu-PSMA both improved survival in patients with mCRPC after docetaxel and an androgen receptor pathway inhibitor (ARPI), but there is limited data regarding Lu-PSMA activity after cabazitaxel. We aimed at assessing activity of Lu-PSMA and determinants of outcomes in this setting. Methods: Consecutive mCRPC patients from 6 European centers treated with Lu-PSMA after cabazitaxel were included in this retrospective study. Endpoints included radiographic progression-free survival (rPFS), time to PSA progression (PSA-TTP), PSA decline, objective response, overall survival, and safety. Results: Of 101 patients included (median age 67y), 64% had ISUP grade 4-5 disease; 71% had bone +/- nodal (LN) metastases, 22% visceral metastases, 7% LN only. All patients and 92% had received previous docetaxel and a prior ARPI (≥ 2 in 47%) before cabazitaxel respectively. Patients had received a median number of 6 cabazitaxel cycles (range 1-26). DNA damage repair alterations (DDR) were found in 11/48 (23%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (range 1-14). With a median follow-up of 5.7 months, the median rPFS from Lu-PSMA initiation was 4.3 months (m, 95%CI 3.2-5.7) and median PSA-TTP was 3.5 m (95%CI 3.0-4.5). Overall, 44 patients (44%) experienced a PSA decline ≥ 50% (PSA50), 54 (53%) ≥ 30% (PSA30), and 67 (66%) any PSA decline. Objective response rate was 34%. Baseline characteristics associated with shorter rPFS on Lu-PSMA included ISUP grade 4-5 disease (median rPFS of 3.5 vs. 7.2m, p=0.02) and a time to castration resistance &lt; 12 months (3.1m vs. 4.5m, p=0.04). Patients with LN only had longer rPFS compared to those with bone and visceral metastases (median NR vs. 3.6 and 3.7m, respectively, p=0.02). There was no association between activity of Lu-PSMA and DNA damage repair alterations, duration of previous cabazitaxel therapy, and number of previous ARPI. During Lu-PSMA, a profound PSA decline was associated with longer rPFS: patients achieving PSA50, PSA30 or any PSA decline had respective median rPFS rates of 9.0, 8.3 and 6.2 months, while those who did not experience any PSA decline had a median rPFS of only 2.6 months. Conclusions: Lu-PSMA demonstrated substantial PSA decline but limited duration of response after cabazitaxel in a real-life setting. Adverse baseline characteristics and absence of PSA decline may help early identification of poor responders.

Early outcomes from lutetium Lu-177 vipivotide tetraxetan treatment in patients selected for therapy with piflufolastat F-18 PET imaging.

191 Background: The Vision trial utilized Ga 68 PSMA 11 imaging to select patients for treatment with Lutetium Lu 177 Vipivotide Tetraxetan. Current guidelines allow not only Ga 68 PSMA 11 PET but also Piflufolastat F 18 PET when selecting patients for Lutetium Lu 177 Vipivotide Tetraxetan but little is published on outcomes to this approach. Methods: Patients were enrolled on an IRB approved managed access protocol and were treated by a single investigator at a single institution. Eligible patients had mCRPC and had received previous treatment with at least one androgen receptor pathway inhibitor and at least one round of taxane based chemotherapy. Baseline imaging, demographics, treatment history, and tumor characteristics were collected. Patients were treated with 7.4 GBq of Lutetium Lu 177 Vipivotide Tetraxetan every 6 weeks for up to six cycles. Adverse events and PSA response were collected. Results: Fourteen patients were enrolled between August 2021 and August 2022. All patients had advanced mCRPC, were heavily pre-treated, and had failed both hormonal as well as chemotherapeutic options. The average number of androgen receptor pathway inhibitor courses for the cohort is 2.4 (range 1-4) and the average number of taxane courses for the cohort is 1.5 (Range 1-3). 11 patients underwent Piflufolastat F 18 PET and 3 patients had Ga 68 PSMA 11 PET. Baseline PSA varied significantly from 2.51 - 961.71 ng/mL. Declines of 50% in PSA were observed in 8/14 patients. 2 patients had greater than 80% PSA reductions. Conclusions: PSA treatment responses were similar to those reported in the Vision trial in this cohort of patients selected with either Piflufolastat F 18 PET or Ga 68 PSMA 11 PET supporting the guideline recommendations. Clinical trial information: NCT04825652 .

Heterogeneity of canonical prostate cancer markers across lesions in metastatic castration-resistant prostate cancer.

219 Background: Metastatic castration-resistant prostate cancers (mCRPC) show a diversity of clinical responses and phenotypes, suggesting molecular heterogeneity. Understanding molecular phenotypes is critical for patient stratification and selection of therapeutic targets. Treatment with androgen receptor (AR) pathway inhibitors are thought to drive AR-negative disease and the emergence of neuroendocrine lineages. There are several emerging biomarkers for mCRPC, including novel targets, such as PSMA and STEAP1, and markers of neuroendocrine and aggressive disease, such as INSM1, DLL3, and loss of p53, RB1 and PTEN. Our understanding of the co-expression of such biomarkers across multiple metastatic sites is currently limited. This study aimed to determine biomarker expression in multiple anatomical sites within individual mCRPC patients. Methods: Through the rapid-autopsy CASCADE program at the Peter MacCallum Cancer Centre, tissue was obtained from 5-14 tumor sites from 12 individual mCRPC patients yielding samples from a total of 110 tumor sites (8 primary and 102 metastatic). Ten patients were diagnosed with prostate adenocarcinoma (89 sites), and 2 patients with neuroendocrine histopathology in all sites (21 sites). Tissue was stained for AR, PSMA, STEAP1, INSM1, DLL3 p53, RB1 and PTEN by immunohistochemistry (IHC). Serial sections were reviewed and scored by a pathologist. IHC results were corroborated with genetic information derived from DNA sequencing. Results: In the adenocarcinoma cohort, on average 77% of sites of individual patients had AR expression, suggesting intra-patient heterogeneity. Co-expression of AR and PSMA was common (55/89 sites), but 6/10 adenocarcinoma patients had 1 to 6 PSMA+AR- lesions. Co-expression of PSMA and STEAP1 was also common in adenocarcinoma patients (60/89 sites), although 8/10 patients had 1 to 2 PSMA-STEAP1+ lesions, and 7 patients had 1 to 3 PSMA+STEAP1- lesions. Expression of INSM1 and DLL3 was mostly seen in the 2 patients (20/21 sites) with neuroendocrine prostate cancer. In contrast, only 2 INSM1+DLL3+ tumor sites in liver and 1 INSM1-DLL3+ prostate cancer sample were detected in the adenocarcinoma cohort. Of the 110 sites, p53 loss was observed in 9, RB1 loss in 30 and PTEN loss in 25 sites. Of these, 8/9, 14/30 and 8/25 occurred in INSM1+DLL3+ sites, suggesting that loss of these markers does not always correlate with INSM1 and DLL3 expression. Conclusions: While AR, PSMA and STEAP1 expression are frequently detected in a single site of disease, this co-expression is not consistent across all sites. In this dataset, INSM1 and DLL3 expression was almost exclusively confined to neuroendocrine prostate cancer. Loss of RB1 and PTEN often occurs without INSM1 and DLL3 expression. Understanding differential biomarker expression in mCRPC may guide future targeted treatments and warrants further research.