Androgen Receptor Pathway Inhibitors Research Articles

Treatment Landscape for Patients with Castration-Resistant Prostate Cancer: Patient Selection and Unmet Clinical Needs.

Metastatic castration resistant prostate cancer (CRPC) is an inevitably fatal disease. However, in recent years, several treatments have been shown to improve the outcome of CRPC patients both in the non-metastatic (nmCRPC) as well as the metastatic setting (mCRPC). In nmCRPC patients with a PSA doubling time <10 months, the addition of enzalutamide, apalutamide and darolutamide to androgen deprivation therapy (ADT) compared to ADT alone resulted in improved metastases free (MFS) and overall survival (OS). For mCRPC patients, several treatment options have been shown to be effective: two taxane based chemotherapies (docetaxel and cabazitaxel), two androgen-receptor pathway inhibitors (ARPI) (abiraterone and enzalutamide), two radiopharmaceutical agents (radium 223 and 177Lutetium-PSMA-617), one immunotherapy treatment (sipuleucel-T) and two poly ADP-ribose polymerase (PARP) inhibitors (olaparib and rucaparib). Pembrolizumab is US Food and Drug Administration (FDA) approved in all MSI high solid tumors, although a very small proportion of prostate cancer patients harboring this characteristic will benefit. Despite having a broad variety of treatments available, there are still several unmet clinical needs for CRPC. The objective of this review was to describe the therapeutic landscape in CRPC patients, to identify criteria for selecting patients for specific treatments currently available, and to address the current challenges in this setting.

Positive epigenetic regulation loop between AR and NSUN2 promotes prostate cancer progression.

BackgroundProstate cancer (PCa) is a major type of cancer in man worldwide. Androgen deprivation therapy (ADT) and the next‐generation androgen receptor (AR) pathway inhibitors have acquired great success in treating PCa. However, patients treated with ADT or AR targeted therapy are inevitably developing into castration‐resistant prostate cancer (CRPC) or becoming drug resistance. The role of mRNA 5‐methylcytosine (m5C) modification in cancers is largely unknown. This study aimed to explore the role of the m5C methyltransferase NSUN2 in Prostate cancer (PCa).MethodsThe expression of NSUN2 and its clinicopathological impact were evaluated in PCa cohorts. The effect of NSUN2 on the biological characteristics of PCa cells was investigated on the basis of gain‐offunction and loss‐of‐function analyses. Subcutaneous models further uncovered the role of NSUN2 in tumor growth. Epi‐transcriptome assays with RNA bisulfite sequencing (RNA‐BisSeq) analysis and in vitro enzyme reaction assays were performed to validate the targeted effect of NSUN2 on AR. AR‐binding sites in the NSUN2 promoter were investigated by ChIP and luciferase assays to uncover the interplay between NSUN2 and AR signaling. RIP‐qPCR and EMSA methods were performed to confirm that YBX1 binds to AR m5C sites.ResultsNSUN2 is highly expressed in PCa and predicts poor outcome. NSUN2 plays roles as a PCa oncogene both in vitro and in vivo. Depletion of NSUN2 results in decreased expression and activities of AR, including AR‐V7. Mechanistically, NSUN2 posttranscriptionally stabilized AR by cluster m5C modification in a m5CYBX1‐dependent manner. Strikingly, treatment with enzalutamide, an effective AR inhibitor, reduces NSUN2 expression and decreases the m5C modification level in prostate cancer cells. Finally, we found that AR transcriptionally regulates NSUN2.ConclusionNSUN2 stabilizes AR mRNA through cluster 5‐methylcytosine modification and activates a positive feedback loop to promote prostate cancer.

1364MO Preliminary phase II results of the CYPIDES study of ODM-208 in metastatic castration-resistant prostate (mCRPC) cancer patients

ODM-208 is a first in class, oral, non-steroidal, and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in mCRPC. We report the first results of the phase 2 expansion of the CYPIDES trial. ODM-208 5mg BID (with dexamethasone and fludrocortisone) was evaluated in an open-label expansion cohort in patients with progressing mCRPC who had previously received ≥1 line of 2nd generation AR pathway inhibitor and ≥1 line of taxane-based chemotherapy. All patients had a pre-specified activating AR LBD mutation by pre-screening of cell-free DNA (Guardant 360). Study objectives were safety and preliminary efficacy assessed by PSA and RECIST response and standard safety measures. ODM-208 treatment was continued until subsequent disease progression. The study was conducted at 18 sites in France, Finland, UK and USA. 81 of 390 (20.8%) pre-screened patients had a pre-specified AR LBD mutation, of which 45 patients (median age 68 yrs) were enrolled and initiated ODM-208 treatment (43 at data cut-off 17 March 2022). 51% patients had previously received both abiraterone and enzalutamide, and 65% patients both docetaxel and cabazitaxel. Based on the emerging data ODM-208 profoundly suppressed androgen synthesis resulting in >50% best PSA reduction in more than 50% patients and at least 4 RECIST partial responses in 17 evaluable patients (data immature). ODM-208 has been well-tolerated with a much lower rate of hospitalisation for adrenal insufficiency than in phase 1 with typically higher doses (2.3% vs. 33% to date). Efficacy and safety data will be presented for the complete cohort with at least 5 months follow-up for all patients. Administration of ODM-208 to heavily pre-treated mCRPC patients with AR LBD mutation was highly effective in blocking the production of steroid hormones and showed promising antitumor activity. NCT03436485.

Advancing Patient Care in the Evolving Prostate Cancer Treatment Landscape

Most prostate cancer cases present as localised disease at initial diagnosis but can progress in about a fifth of patients to castration-resistant prostate cancer (CRPC) within 5 years. A major concern for patients and physicians is the development of metastases, affecting quality of life (QoL), and reducing overall survival (OS). Treatment guidelines for the different stages of prostate cancer continue to be modified with the publication of clinical trial results. Currently, androgen receptor inhibitors (ARi) are used in the management of non-metastatic CRPC. Among these, explained Martin Bögemann, Department of Urology, University of Münster, Germany, darolutamide’s unique structure means it causes minimal side effects, likely due to reduced blood-brain barrier penetration, while also reducing the potential for drug-drug interactions, which is especially important for patients treated for comorbidities. Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) depends on a variety of factors, including when metastases developed in the course of disease and their volume. Bertrand Tombal, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Belgium, described the evolution of mHSPC therapy from androgen deprivation therapy (ADT) and surgical castration as the only available options, to the emergence of the chemotherapeutic docetaxel and androgen receptor pathway inhibition (ARPI). He explained the results of Phase III clinical trials of various combination approaches, with a combination treatment of docetaxel, ADT, and darolutamide showing promise for overall survival. Discussions are ongoing about which patients with mHSPC should receive this triple therapy approach. Christian Gratzke, Department of Urology, University Hospital Freiburg, Germany followed by describing how treatment decisions are made, including the role of imaging, with a case study of a patient with non-metastatic castration-resistant prostate cancer (nmCRPC), and another with mHSPC. A further panel discussion considered treatment options for various presentations of prostate cancer, and why one would be chosen over another. The panel concluded with a question and answer sessions that focused on when and why patients with prostate cancer are sent for genetic testing.

Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer

Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4-O-sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4-O-sulfated chondroitin levels. Inhibition of the tumor cell CS glycocalyx delays CRPC progression, and impairs growth and motility of prostate cancer after ARPI. Thus, a reactive CS glycocalyx supports adaptive survival and treatment resistance after ARPI, representing a therapeutic opportunity in patients with advanced prostate cancer.

Interferon signalling contributes to therapy‐resistant prostate cancer progression

Interferon signalling contributes to therapy‐resistant prostate cancer progression

New Drug for Metastatic Castration-Resistant Prostate Cancer.

Pluvicto (lutetium Lu 177 vipivotide tetraxetan) has been approved for the treatment of adult patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer who have received androgen receptor pathway inhibition and taxane-based chemotherapy.

The Androgen Receptor and Its Crosstalk With the Src Kinase During Castrate-Resistant Prostate Cancer Progression.

While the androgen receptor (AR) signalling is the mainstay therapeutic target for metastatic prostate cancers, these tumours will inevitably develop therapy resistance to AR pathway inhibitors suggesting that prostate tumour cells possess the capability to develop mechanisms to bypass their dependency on androgens and/or AR to survive and progress. In many studies, protein kinases such as Src are reported to promote prostate tumour progression. Specifically, the pro-oncogene tyrosine Src kinase regulates prostate cancer cell proliferation, adhesion, invasion, and metastasis. Not only can Src be activated under androgen depletion, low androgen, and supraphysiological androgen conditions, but also through crosstalk with other oncogenic pathways. Reciprocal activations between Src and AR proteins had also been reported. These findings rationalize Src inhibitors to be used to treat castrate-resistant prostate tumours. Although several Src inhibitors had advanced to clinical trials, the failure to observe patient benefits from these studies suggests that further evaluation of the roles of Src in prostate tumours is required. Here, we summarize the interplay between Src and AR signalling during castrate-resistant prostate cancer progression to provide insights on possible approaches to treat prostate cancer patients.

Abstract 395: Characterizing the role of chaperone-mediated autophagy in prostate cancer treatment resistance

Abstract Androgen deprivation therapy (ADT) and androgen receptor pathway inhibition (ARPI) remains the standard of care for advanced prostate cancer (PCa). As part of its canonical activities, the androgen receptor (AR) plays an important role in PCa metabolism. AR inhibition with ARPI subjects PCa cells to acute metabolic stress caused by reduced biosynthesis and energy production. The upregulation of ARPI-induced stress response mechanisms is essential adaptive mechanism for cell proliferation and survival. This process requires PCa cells undergoing rapid phenotypic changes to adapt to their environment and circumvent lethal outcomes. By profiling the proteomic pathway alterations associated with the ARPI stress response in LNCaP cells, we noted a significant upregulation of chaperone mediated autophagy (CMA), a stress response mechanism yet to be defined in PCa. CMA, a selective protein degradation pathway, specifically targets protein substrates via a CMA recognition motif and is an essential survival mechanism in cancer cells during energy depleted metabolic stress. Within in-vitro and in-vivo PCa models, ARPI induced CMA is reflected through the increased activity of CMA lysosomes and specifically by the increased expression of the CMA marker, lysosomal associated membrane protein 2a (L2A). L2A knockdown using shRNA not only elicited a strong anti-proliferative effect in PCa cells, but also compromised PCa metabolism with decreases in ATP levels and mTORC1 signaling. Proteomic analysis by mass spectrometry further identified that CMA promotes chromatin silencing, and the suppression of pathways associated with transcription. Conversely, L2A overexpression not only promoted PCa cell proliferation during Enza treatment, but upregulated of hallmark target genes of AR-indifferent PCa growth. The upregulation of CMA facilitated proteome remodeling during ARPI, leading to increased mTORC1 signaling and biosynthesis. In summary, our data illustrates the importance of CMA in mediating the ARPI stress response in PCa, providing novel insights into the mechanisms of ARPI treatment resistance. Citation Format: Nicholas Nikesitch, Eliana Beraldi, Fan Zhang, Hans Adomat, Robert Bell, Ladan Fazli, Christopher Wells, Nicholas Pinette, Yuzhuo Wang, Martin Gleave. Characterizing the role of chaperone-mediated autophagy in prostate cancer treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 395.

Abstract 532: Circulating tumor DNA and outcomes with lutetium-PSMA in advanced prostate cancer: Preliminary results from an Australian study

Abstract Recent clinical trials have revealed that Lutetium PSMA-617 (Lu-PSMA, a small molecular inhibitor of prostate-specific membrane antigen radiolabelled with the beta emitter 177-Lutetium) significantly improves clinical outcomes including overall survival for patients with metastatic castration resistant prostate cancer (mCRPC). Nevertheless, owing to the highly heterogeneous nature of mCRPC, responses to Lu-PSMA therapy can be variable, with resistance inevitable. Currently, there are no existing data on the genomic landscape of mCRPC in the context of this therapy, with the identification of biomarkers linked to outcomes with Lu-PSMA being a critical unmet need in order to select patients most likely to benefit from treatment and to dissect mechanisms of resistance. mCRPC patients with high PSMA expression on positron emission tomography scans and prior treatment with docetaxel chemotherapy and an androgen receptor pathway inhibitor were enrolled on a compassionate access prospective registry at Peter MacCallum Cancer Centre. Patients received Lu-PSMA every 6 weeks for 4-6 cycles and entered into follow-up. Peripheral blood samples were collected for plasma circulating tumour DNA (ctDNA) analysis at baseline and prior to cycle 2 of therapy. A highly-sensitive targeted next-generation sequencing assay was applied to patient plasma and matched leukocytes. Somatic mutations (single nucleotide variants/indels) and copy number alterations from 43 genes were reported, along with the estimated ctDNA fraction. Current patient numbers preclude formal statistical analysis of genomic aberrations, however dynamic changes in ctDNA were assessed in relation to prostate-specific antigen (PSA) response and clinical and/or radiographic progression. In total, 19 plasma samples were analysed from 13 mCRPC patients with a median age of 71. Patients had between one and four prior lines of therapy for mCRPC and had a median time on Lu-PSMA therapy of 3.7 months. ctDNA was detected in 17/19 plasma samples with a median fraction of 26% (range 0-89%). Overall, a PSA response rate of 54% was observed. Interestingly, patients with higher baseline ctDNA fractions were more likely to experience a PSA response to Lu-PSMA therapy (median ctDNA fraction of responders 49% vs 10% in non-responders, p=0.1). Additionally, no PSA responses were seen in patients who did not attain a reduction in plasma ctDNA from baseline to cycle 2. This is the first targeted assessment of serial plasma samples from patients receiving Lu-PSMA therapy. Using a highly sensitive liquid biopsy assay, ctDNA was detectable in almost all samples. In this preliminary analysis, both baseline ctDNA fraction and early dynamic changes in ctDNA fraction appear to have clinical importance in Lu-PSMA therapy. Recruitment to this registry is proceeding rapidly, with further data available by April 2022. Citation Format: Heidi Fettke, Nicole Ng, Christine Hauser, Patricia Bukczynska, Elizabeth Medhurst, Louise Kostos, James Buteau, Jason Steen, Tu Nguyen-Dumont, Michael Hofman, Arun A. Azad. Circulating tumor DNA and outcomes with lutetium-PSMA in advanced prostate cancer: Preliminary results from an Australian study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 532.

Abstract 3625: Clonal architecture and evolution of treatment-resistant prostate cancer via deep whole-genome ctDNA sequencing

Abstract Background: Circulating tumor DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring. However, integration of ctDNA tests into clinical management is critically impeded by the poor understanding of the distinct somatic populations comprising bulk ctDNA—including their relationship to synchronous metastatic tissue, and their temporal dynamics during standard-of-care treatment. Prior approaches relying on targeted and/or low-resolution techniques (e.g. targeted exon sequencing, low-pass (shallow) whole-genome sequencing; WGS) do not permit comprehensive dissection of clonal architecture and unbiased analysis of putative resistance mechanisms. Methods: We performed deep WGS on serial plasma ctDNA (median depth: 185×) and synchronous metastatic tissue biopsies with high tumor purity from 35 patients with metastatic castration-resistant prostate cancer. We developed a subclonal reconstruction algorithm optimized for our data enabling resolution of per-patient evolutionary histories and ctDNA clonal composition. ctDNA nucleosome footprinting was used to infer mRNA abundance in synchronously biopsied metastases and androgen receptor (AR) transcription factor activity at 3224 AR binding sites (ARBS). Results: We comprehensively assess all classes of genomic alterations and demonstrate that ctDNA harbors greater populational heterogeneity than metastatic tissue (p&amp;lt;0.001). The evolutionary histories of ctDNA populations indicate frequent whole-genome doubling and attenuation of C&amp;gt;T aging-associated mutation signature during subclonal differentiation. Although driver alterations were largely concordant between tissue and ctDNA, each individual metastasis contributed only a minor share of total ctDNA (average ctDNA contribution: 17%). By comparing serial ctDNA before and after clinical progression on potent AR pathway inhibitors, we reveal population restructuring converging solely on AR copy augmentation as the dominant genomic driver of acquired treatment-resistance. Nucleosome depletion at transcription start-sites is highly correlated with same-patient metastatic tissue mRNA abundance, indicating that ctDNA fragmentomics can recapitulate transcriptomic patterns in metastatic lesions. Most ctDNA samples exhibited strong ARBS nucleosome depletion which correlated with AR gene copy number (R=0.36, p=0.003). Finally, serial ctDNA nucleosome profiling at ARBS revealed adaptive transcriptomic resistance to AR pathway inhibitors, including lineage switch to a neuroendocrine-like (AR-low) state. Conclusions: We show that the populations comprising ctDNA are typically complex and more heterogeneous than those found in bulk WGS of a synchronous metastasis. Our work advocates for liquid biopsy as a comprehensive multi-omic discovery tool for cancers with high ctDNA fractions. Citation Format: Cameron Herberts, Matti Annala, Joonatan Sipola, Sarah W. Ng, Xinyi E. Chen, Anssi Nurminen, Olga Korhonen, Aslı D. Munzur, Kevin Beja, Elena Schönlau, Cecily Q. Bernales, Elie Ritch, Jack V. Bacon, Nathan A. Lack, Matti Nykter, Rahul Aggarwal, Eric J. Small, Martin E. Gleave, David A. Quigley, Felix Y. Feng, Kim N. Chi, Alexander W. Wyatt. Clonal architecture and evolution of treatment-resistant prostate cancer via deep whole-genome ctDNA sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3625.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Abstract 1481: A microRNA classifier for predicting neuroendocrine differentiation in castration-resistant prostate cancer patients

Abstract Therapy-induced neuroendocrine prostate cancer (NEPC) is an extremely 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) and Abiraterone. This aggressive variant arises from CRPC-Adenocarcinomas (CRPC-Adeno) via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED) wherein cells undergo a lineage switch and exhibit neuroendocrine (NE) features, characterized by expression of neuronal markers such as enolase 2 (ENO2), chromogranin A (CHGA) and synaptophysin (SYP). Currently, histopathological assessment combined with immunohistochemical detection in PCa tissues/serum levels of neuronal markers including SYP, NSE, CHGA and CD56 is used to monitor NED in CRPC patients. However, these markers are not sufficiently specific, highlighting the urgent need of novel molecular markers to assess emergence of NED in CRPC patients. We demonstrated that progression of CRPC-Adeno to CRPC-NE states is associated with a characteristic set of miRNA alterations. Here we validate a ‘novel miRNA classifier’ to robustly stratify CRPC-NE tumors from CRPC-Adenocarcinomas in independent clinical cohorts and deduce the optimal miRNA genes required for NEPC diagnosis. Methods: Human FFPE sections from CRPC-Adeno and CRPC-NE patients were microdissected, RNA were extracted and small RNA sequencing was performed using an Illumina NextSeq 500 platform. Sequencing data were analyzed and machine learning algorithms were applied (random forest machine learning technique with leave-pair-out cross validation (LPOCV)). The performance of classifier was measured using receiver operating characteristic (ROC) analysis with area under the curve (AUC) as the primary evaluation metric. Results: Unsupervised analysis of sequencing data by principal component analyses (PCA) revealed distinct clustering of the CRPC-NE tumors from CRPC-Adenocarcinomas based on miRNA profiles suggesting that miRNA profiles can be used to stratify these tumor types. We applied the ‘43-miRNA classifier data’ we deduced earlier to these validation cohorts. Our analyses showed that a set of 5 miRNAs of the classifier are important in distinguishing between CRPC-Adeno vs CRPC-NE with an AUC=0.8318. Conclusions: A ‘5- miRNA’ classifier was validated to be of significance in two independent validation cohorts employing clinical samples from two independent sites. We propose this miRNA classifier as an important tool for diagnosing NED in CRPC patients. Citation Format: Sharanjot Saini, Amritha Sreekumar, Jin Tae Lee, Nikhil Patel, Ashok Sharma. A microRNA classifier for predicting neuroendocrine differentiation in castration-resistant prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1481.

Abstract 1543: Regulatory role of miR-410 in prostate cancer

Abstract Prostate cancer (PCa), a leading cause of male cancer related mortality, is dependent upon androgens acting via androgen receptor (AR) signaling. Androgen targeted therapies are often used as the first line of treatment for prostate cancer that are effective initially. However, PCa eventually progresses to castration-resistant stage that has limited treatment options. Castration-resistant prostate cancer (CRPC) is treated by second generation of AR pathway inhibitors such as Enzalutamide and Abiraterone. Resistance to these agents develop owing to various mechanisms such as evolution to androgen-independent neuroendocrine prostate cancer (NEPC). In this study, we examined the potential role of miR-410 in different stages of prostate cancer. Analyses of miR-410 in PCa clinical samples and patient-derived xenograft (PDX) models showed that miR-410 is frequently upregulated in PCa. Its expression was further increased in CRPC cases with neuroendocrine differentiation (NED). We examined the functional role of miR-410 by stably expressing miR-410 in androgen dependent and androgen independent cell lines. Our data suggests a context dependent role of miR-410 in prostate cancer cell lines. In androgen independent cell line, miR-410 plays an oncogenic role by impacting epithelial to mesenchymal transition (EMT) via directly targeting SNAIL. Also, it was found to increase the expression of neuronal genes such as Synaptophysin and neural transcription factor BRN2. However, in androgen dependent cell line, miR-410 was found to target PTEN. In conclusion, our data suggests that miR-410 play an important regulatory role in prostate cancer with effects on EMT and neuronal differentiation programs. Citation Format: Amritha Sreekumar, Nikhil Patel, Sharanjot Saini. Regulatory role of miR-410 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1543.

Multitarget Molecular Imaging in Metastatic Castration Resistant Adenocarcinoma Prostate Cancer with Therapy Induced Neuroendocrine Differentiation.

Neuroendocrine differentiation of prostate cancer (NEDPC) includes de novo presentation and secondary to epigenetic changes, referred as therapy-induced neuroendocrine prostate cancer (t-NEPC). Molecular imaging with prostate-specific membrane antigen (PSMA) and somatostatin analogues positron emission tomography (PET/CT) in NEDPC have not been validated. 18F-FDG (fluorodeoxyglucose) PET/CT has numerous limitations in prostate cancer (PCa) and the utility in NEDPC has only been reported in a few series of cases. The objective of this study is to compare the lesions detection rate of the three radiotracers in metastatic t-NEPC patients. (1) Material and Methods: Retrospective evaluation of patients with prostate adenocarcinoma treated with androgen deprivation therapy, chemotherapy, a novel androgen receptor pathway inhibitor or a combination of them and a second tumour biopsy confirming t-NEPC was made. All patients underwent 18F PSMA-1007, 18F AlF-NOTA-Octreotide, and 18F-FDG PET/CT. Evaluation of positive lesions was determined and SUVmax of each radiotracer was estimated and correlated with computer tomography (CT) findings. (2) Results: A total of eight patients were included. The mean time from diagnosis of prostate adenocarcinoma to t-NEPC was 28.2 months, with a mean serum specific prostate antigen (PSA) of 16.6 ng/dl at the time of NEPC diagnosis. All patients were treated with antiandrogen therapy and 87.5% with chemotherapy. A total of 273 lesions were identified by CT from which 182 were detected by 18F-FDG PET/CT, 174 lesions by 18F PSMA-1007, and 59 by 18F AlF-NOTA-Octreotide. An interpatient analysis of the lesions was performed and dual tracer 18F-FDG PET/CT and 18F PSMA-1007 PET/CT detected a total of 270/273 lesions (98.9%). (3) Conclusions: NEDPC patients demonstrated wide inter and intrapatient molecular imaging heterogeneity within the three radiotracers. 18F-FDG detected most lesions in t-NEPC among all radiotracers, especially in visceral sites; 18F PSMA-1007 detected more bone lesions. 18F AlF-NOTA-Octreotide showed no significant utility.

Androgen receptor genomic alterations and treatment resistance in metastatic prostate cancer

Genomic alterations to the androgen receptor (AR) are common in metastatic castration-resistant prostate cancer (mCRPC). AR copy number amplifications, ligand-binding domain missense mutations, and intronic structural rearrangements can all drive resistance to approved AR pathway inhibitors and their detection via tissue or liquid biopsy is linked to clinical outcomes. With an increasingly crowded treatment landscape, there is hope that AR genomic alterations can act as prognostic and/or predictive biomarkers to guide patient management. In this review, we evaluate the current evidence for AR genomic alterations as clinical biomarkers in mCRPC, focusing on correlative studies that have used plasma circulating tumor DNAto characterize AR genotype. We highlight data that demonstrates the complexity of AR genotype within individual patients, and suggest that future studies should account for cancer clonal heterogeneity and variable tumor content in liquid biopsy samples. Given the potential for cooccurrence of multiple AR genomic alterations in the same or competing subclones of a patient, it is distinctly challenging to attribute blanket clinical significance to any individual alteration. This challenge is further complicated by the varied treatment exposures in contemporary patients, and the fact that AR genotype continues to evolve in the mCRPC setting across sequential lines of systemic therapy. As treatment access and liquid biopsy technology continues to improve, we posit that real-time measures of AR biology are likely to play a key role in emerging precision oncology strategies for metastatic prostate cancer.

Real-world treatment patterns in the U.S. and trends pre-post CARD trial among patients with metastatic castration-resistant prostate cancer.

e17024 Background: Numerous treatments with different mechanisms of action are approved for metastatic castration-resistant prostate cancer (mCRPC). The sequencing for management of these patients has been evolving post availability of trials such as the CARD trial, looking at clinical outcomes post androgen receptor pathway inhibitor (ARPI) and docetaxel. This study examined real-world treatment patterns and sequencing among United States patients with mCRPC. Methods: This retrospective cohort study used Flatiron Health electronic health record data from Jan 1, 2013 to June 30, 2020 (study period). 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. Index date was the date of first-line (1L) therapy initiation post-mCRPC diagnosis. Patient characteristics and treatment patterns were evaluated descriptively. Across analyses, treatments were grouped as follows: ARPI (abiraterone, enzalutamide), taxane (docetaxel, cabazitaxel), sipuleucel-T, radium-223, targeted therapy (TT; olaparib, rucaparib), mitoxantrone, combo therapy (any combination regimen containing ≥1 of the preceding therapies), and other (any other therapy or combination of therapies). Results: 2,588 patients were included in the study; mean±SD age was 72±8 years and 66% were White. The most common 1L therapy was ARPI (63%), followed by taxane (11%), combo therapy (11%), radium-223 (6%), sipuleucel-T (6%), and other therapy (2%). No patient received TT or mitoxantrone alone in 1L. Median time to next treatment post-1L was longest for combo therapy (8.1 months) and ARPI (7.6 months) and shortest for sipuleucel-T (3.4 months). The most common sequence of treatment for mCRPC patients was 1L ARPI to another ARPI at second-line (2L) (29%); taxane and combo therapy (both 14%) were the next most common (Table). Treatment patterns were similar pre- and post- read-out of the CARD trial. Conclusions: The majority of mCRPC patients who receive 1L ARPI will receive another at 2L rather than switching to an alternative type of treatment.[Table: see text]

177Lu]Lu-PSMA-617 in PSMA-positive metastatic castration-resistant prostate cancer: Prior and concomitant treatment subgroup analyses of the VISION trial.

5001 Background: In the phase 3 VISION trial, targeted radioligand therapy with lutetium (177Lu) vipivotide tetraxetan ([177Lu]Lu-PSMA-617; 177Lu-PSMA-617) significantly prolonged radiographic progression-free survival (rPFS) and overall survival (OS) when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA) PET-positive metastatic castration-resistant prostate cancer. Benefits were consistent across most pre-specified subgroups. In this post hoc exploratory analysis, we examined rPFS and OS in the context of prior and concomitant cancer-directed treatments. Methods: In VISION, adult patients previously treated with at least 1 androgen receptor pathway inhibitor (ARPI) and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, up to 6 cycles) + SoC or SoC alone. Protocol-permitted SoC excluded cytotoxic chemotherapy, systemic radioisotopes, immunotherapy, or other investigational drugs. Exploratory subgroup analyses of rPFS and OS were performed by: number of prior ARPIs; taxane regimens; non-taxane regimens and immunotherapies; prior treatment with bone-sparing agents; 223Ra and PARP inhibitors; and concomitant treatment with ARPIs, radiation therapy, and bone-sparing agents. Results: Prior and concomitant treatments were generally well balanced between study groups (Table). rPFS and OS benefits with 177Lu-PSMA-617 were consistent across all prior treatment subgroups. Notably, there were benefits in patients who had not received a second prior taxane. There were also consistent benefits regardless of concomitant systemic and radiation therapy as part of SoC. Conclusions: The clinical efficacy of 177Lu-PSMA-617 was observed regardless of prior treatment or SoC chosen, suggesting that disease biology rather than prior and concomitant treatment context drives outcomes. Small differences in outcomes between subgroups may warrant further study to understand better the predictors of improved clinical benefit. Clinical trial information: NCT03511664. [Table: see text]

On-treatment plasma ctDNA fraction and treatment outcomes in metastatic castration-resistant prostate cancer.

5051 Background: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naive metastatic castration-resistant prostate cancer (mCRPC), but primary or rapidly acquired resistance is common. Early identification of resistant disease is critical for improving management strategies. We investigated whether on-treatment changes in plasma ctDNA fraction (ctDNA%; the proportion of cell-free DNA that is tumor-derived) associate with ARPI treatment outcomes. Methods: We collected serial plasma cell-free DNA from 81 patients with mCRPC: at baseline and following 4 weeks of treatment during two prospective multi-center observational studies (NCT02426333; NCT02471469). CtDNA% was calculated by integrating deep targeted and shallow whole-genome sequencing. Samples were dichotomized at above and below 1%, and designated as high or low ctDNA%, respectively. Outcome measurements were radiographic and/or clinical progression-free survival (rcPFS) and overall survival (OS). Non-durable responses were defined as rcPFS &lt; 6 months, excluding patients with PSA progression alone (n = 3) or treatment cessation for toxicity (n = 4). Results: Median follow-up was 27.4 months (IQR 17.7-34.9). CtDNA% was high in 47/81 (58%) patients at baseline and 29/81 (36%) patients at 4 weeks. The median ctDNA% for patients with high ctDNA was 15.0% (IQR 4.9-43.8%) at baseline and 5.0% (IQR 2.0-20.6%) at 4 weeks. High baseline ctDNA% was prognostic for rcPFS and OS (Table). RcPFS and OS was shortest for patients that retained high ctDNA% at 4 weeks. However, patients converting from high to low ctDNA% at 4 weeks did not experience different outcomes to patients with low ctDNA at both timepoints. ctDNA% associations with rcPFS and OS were independent of established clinical prognostic factors. 23/27 (85%) patients experiencing non-durable responses had high ctDNA% at baseline and 4 weeks. Only 3/47 patients (6%) experiencing durable responses had high ctDNA% at both timepoints. Sensitivity and specificity for predicting non-durable response was 85% and 94%, respectively. Conclusions: Early changes in ctDNA% are strongly linked to duration of first-line ARPI treatment benefit in mCRPC and may have utility for informing clinical trials testing early therapy switches in patients unlikely to experience durable disease responses. Clinical trial information: NCT02426333; NCT02471469. [Table: see text]

Biallelic loss of TP53, PTEN, and RB1 in association to aggressive clinical features and poor outcomes in metastatic castration-resistant prostate cancer (mCRPC).

5055 Background: Deleterious alterations in tumor suppressor genes (TSGs) TP53, RB1, and PTEN are potential markers of small cell neuroendocrine prostate cancer (SCNP), and androgen receptor pathway inhibitor (ARPI) resistance. We examined the outcomes and clinical features of mCRPC patients (pts) harboring biallelic loss in 0, 1, 2 or all 3 TSGs. Methods: We identified 210 consecutive mCRPC pts providing ≥1 plasma cell-free DNA sample with ≥20% circulating tumor DNA fraction (ctDNA%) during their mCRPC disease course. ctDNA% ≥20% enabled sensitive characterization of biallelic TSG loss (including by homozygous deletions and mutation plus somatic loss-of-heterozygosity; LOH). Patient records were reviewed for baseline characteristics, SCNP histology, and presence of liver metastases. We investigated associations between TSG loss and the following clinical outcomes: PSA response (PSA decline ≥50% (PSA50 RR)), progression free survival (PFS) on 1L therapy, and overall survival (OS) from 1L therapy. Results: Median follow-up was 16.5 months (range: 0.4-112.4) and OS event rate was 95%. Median age at 1L mCRPC was 71 years (range: 48-98). Most pts were ECOG PS 0-1 (79%) and 13% had liver metastases. 91% received ARPI for 1L mCRPC and 7% received ARPI for castration-sensitive disease. TP53 was primarily inactivated by somatic mutation plus LOH (90%), whereas RB1 (71%) and PTEN (86%) were more commonly inactivated by homozygous deletions. Compared to pts without evidence of biallelic TSG loss, pts with loss of 3 TSGs were significantly enriched for de-novo M1 disease (86 vs. 60%, p=0.05) and liver metastases (28.5 vs. 6.8%, p&lt;0.05). Ten pts (4.7%) had histologically confirmed SCNP and provided ctDNA at time of SCNP diagnosis. Of these, 7 (70%) had biallelic loss of ≥2 TSGs. For all pts receiving 1L therapy, loss of ≥1 TSG(s) was associated with decreased OS (HR: 1.86, 95% CI: 1.40-2.48, p&lt;0.01) and PFS (HR:1.74, 95% CI 1.29-2.34, p&lt;0.01) compared to pts with no biallelic TSG loss. Furthermore, a cumulative increase in the number of TSGs lost was associated with an incremental reduction in OS and PFS (Table). Conclusions: In a cohort enriched for poor prognosis (i.e. high ctDNA%), cumulative loss of TSGs is associated with aggressive disease features and poor clinical outcomes. These patients may benefit from alternative treatment intensification strategies. [Table: see text]