Advanced Metastatic Prostate Cancer Research Articles

Real-world treatment landscape in advanced metastatic castration resistant prostate cancer.

e17032 Background: Despite a rapidly evolving treatment landscape in advanced prostate cancer (aPC) marked by recent emergence of therapies such as radioconjugates and PARP inhibitors, outcomes remain poor for many patients. Future care improvements will require innovative treatments and simplifying treatment planning. The goal of this study is to understand how the evolving treatment landscape has impacted care and outcomes in patients with aPC using real world (rw) data. This study evaluates outcomes of mCRPC patients who have advanced to a 3rd line of therapy (L3) with prior exposure to both an androgen receptor signaling inhibitor (ARSI) therapy and a taxane or platinum-based chemotherapy, in any aPC disease setting. Methods: mCRPC patients in the Flatiron Database who progressed to L3 with pre-L3 exposure to both an ARSI (abiraterone, enzalutamide, apalutamide, and darolutamide) and chemotherapy (cabazitaxel and docetaxel) were eligible for inclusion. Patients whose mCRPC diagnosis occurred between Dec 2010 and Nov 2023 were included. As the objective was to study the aPC treatment landscape, patients with prior exposure to therapies approved in the mCRPC disease setting such as radioconjugates, PARP inhibitors, radiation, investigational and palliative drugs were excluded. Outcomes were reported as median real-world overall survival (rwOS) indexed to start of L3 treatment, and median rw time to next treatment (rwTTNT) from the start of L3 to the beginning of L4 treatment. Results: 660 patients met all inclusion criteria and had at least one year of treatment history in the aPC disease setting. Median follow up time (indexed to L3 start) for all patients was 7.55 months. Median rwOS for all patients was 10.8 months (95% CI 9.9 - 12.2), while median rwTTNT was 5 months (95% CI 4.6 - 5.4). The most common L3 therapy class was chemotherapy, followed by ARSIs (Table). To aid in treatment planning strategies, drug sequence patterns were also analyzed. Frontline ARSIs were followed by second line chemotherapy for most of the patients (n = 349; 53%). Conclusions: Relatively short survival times and short durations on L3 therapies for aPC demonstrate a high unmet need, with therapeutic options dominated by ARSIs and chemotherapy. Recently approved radioconjugate therapies, like Pluvicto â, have reported median OS 15.3 months (Fallah, 2023) in prostate-specific membrane antigen (PSMA)-positive patients, which is greater than the 10.8 months observed in general mCRPC population analyzed in this study. These findings underscore the need to develop effective therapies and treatment strategies that are tailored for advanced prostate cancer. [Table: see text]

Real-world treatment landscape in advanced metastatic castration resistant prostate cancer.

e17032 Background: Despite a rapidly evolving treatment landscape in advanced prostate cancer (aPC) marked by recent emergence of therapies such as radioconjugates and PARP inhibitors, outcomes remain poor for many patients. Future care improvements will require innovative treatments and simplifying treatment planning. The goal of this study is to understand how the evolving treatment landscape has impacted care and outcomes in patients with aPC using real world (rw) data. This study evaluates outcomes of mCRPC patients who have advanced to a 3rd line of therapy (L3) with prior exposure to both an androgen receptor signaling inhibitor (ARSI) therapy and a taxane or platinum-based chemotherapy, in any aPC disease setting. Methods: mCRPC patients in the Flatiron Database who progressed to L3 with pre-L3 exposure to both an ARSI (abiraterone, enzalutamide, apalutamide, and darolutamide) and chemotherapy (cabazitaxel and docetaxel) were eligible for inclusion. Patients whose mCRPC diagnosis occurred between Dec 2010 and Nov 2023 were included. As the objective was to study the aPC treatment landscape, patients with prior exposure to therapies approved in the mCRPC disease setting such as radioconjugates, PARP inhibitors, radiation, investigational and palliative drugs were excluded. Outcomes were reported as median real-world overall survival (rwOS) indexed to start of L3 treatment, and median rw time to next treatment (rwTTNT) from the start of L3 to the beginning of L4 treatment. Results: 660 patients met all inclusion criteria and had at least one year of treatment history in the aPC disease setting. Median follow up time (indexed to L3 start) for all patients was 7.55 months. Median rwOS for all patients was 10.8 months (95% CI 9.9 - 12.2), while median rwTTNT was 5 months (95% CI 4.6 - 5.4). The most common L3 therapy class was chemotherapy, followed by ARSIs (Table). To aid in treatment planning strategies, drug sequence patterns were also analyzed. Frontline ARSIs were followed by second line chemotherapy for most of the patients (n = 349; 53%). Conclusions: Relatively short survival times and short durations on L3 therapies for aPC demonstrate a high unmet need, with therapeutic options dominated by ARSIs and chemotherapy. Recently approved radioconjugate therapies, like Pluvicto â, have reported median OS 15.3 months (Fallah, 2023) in prostate-specific membrane antigen (PSMA)-positive patients, which is greater than the 10.8 months observed in general mCRPC population analyzed in this study. These findings underscore the need to develop effective therapies and treatment strategies that are tailored for advanced prostate cancer. [Table: see text]

A Comprehensive Review and Androgen Deprivation Therapy and Its Impact on Alzheimer's Disease Risk in Older Men with Prostate Cancer.

Prostate cancer (PCa) is one of the most prevalent malignancies affecting males worldwide. Despite reductions in mortality rates due to advances in early identification and treatment methods, PCa remains a major health concern. Recent research has shed light on a possible link between PCa and Alzheimer's disease (AD), which is a significant neurological ailment that affects older males all over the world. Androgen deprivation therapy (ADT), a cornerstone therapeutic method used in conjunction with radiation and palliative care in advanced metastatic PCa cases, is critical for disease management. Evidence reveals a relationship between ADT and cognitive impairment. Hormonal manipulation may cause long-term cognitive problems through processes such as amyloid beta (Aβ) aggregation and neurofibrillary tangles (NFTs). Fluctuations in basal androgen levels can upset the delicate balance of genes that are sensitive to androgen levels, contributing to cognitive impairment. This detailed review dives into the various aspects of PCa aetiology and its relationship with cognitive decline. It investigates the discovery of particular biomarkers, as well as microRNAs (miRNAs), which play important roles in pathogenic progression. The review attempts to identify potential biomarkers associated with ADT-induced cerebral changes, including Aβ oligomer buildup, NFT formation, and tauopathy, which can contribute to early-onset dementia and cognitive impairment. Besides it further aims to provide insights into innovative diagnostic and therapeutic avenues for alleviating PCa and ADT-related cognitive sequelae by unravelling these complicated pathways and molecular mechanisms.

Abstract CT222: Efficacy and safety of ceralasertib in the PLANETTE study in patients (pts) with ATM-altered advanced solid tumors (ASTs) or metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Ceralasertib, a potent, selective ATR inhibitor, is synthetically lethal in ATM-deficient preclinical models. This Phase 2a study (NCT04564027) assessed ceralasertib monotherapy in previously treated pts with ATM-altered tumors. Methods: Adult pts had ASTs excluding NSCLC (Cohort [Co] A; data cutoff [DCO] Dec 21 2022) or mCRPC (Co B; DCO Apr 28 2023) and germline/somatic ATM pathogenic/likely pathogenic variants (PVs) by local assessment. ATM alterations were centrally confirmed by FMI F1CDx in tumor and/or FMI F1 liquid CDx in circulating tumor DNA, and/or by ATM protein deficiency by immunohistochemistry (cutoff ≤5%). Primary endpoints were objective response rate (ORR) in Co A and composite response rate (CRR) in Co B. Safety was a secondary endpoint. Results: The initial starting dose of 240 mg BID PO ceralasertib on Days 1-14 of a 28-day cycle was reduced to 160 mg BID due to hematologic toxicity. Results are reported for 30 pts in Co A and 15 pts in Co B with a starting dose of 160 mg BID. In Co A, the 28 pts with centrally confirmed ATM alterations (93.3% [28/30] with ATM PV and 36.7% [11/30] ATM-deficient) had an ORR of 7.1% (80% CI: 1.9, 17.9): 1 complete response in breast cancer (ongoing at 12 mos) and 1 partial response in endometrial cancer (ongoing at 9 mos), both ATM-deficient. In Co B, the 13 pts with centrally confirmed ATM alterations (73.3% [11/15] with ATM PV and 46.7% [7/15] ATM-deficient) had a CRR of 7.7% (80% CI: 0.8, 26.8): 1 pt with conversion of circulating tumor cell count from unfavorable to favorable (ongoing at 3 mos) with unknown ATM expression. The safety profile was manageable (Table). Steady-state ceralasertib plasma concentrations exceeded the IC90 for ~23 hrs/day. Conclusion: Responses to ceralasertib monotherapy were limited in ATM-altered tumors, despite reaching target plasma levels. Alternative pt selection and combination treatment strategies are being explored. TABLE 1: NAND Efficacy, safety of ceralasertib 160 mg BID on D1-14 of D28 cycle in pts with ATM-altered ASTs/mCRPC Cohort A: ASTs Cohort B: mCRPC Efficacy Response rate in pts with centrally confirmed ATM alterations, % (80% CI)* N=28 7.1 (1.9, 17.9)† N=13 7.7 (0.8, 26.8)‡ Response rate in pts with centrally confirmed ATM PVs, % (80% CI) N=28 7.1 (1.9, 17.9) N=11 9.1 (1.0, 31.0) Response rate in pts with centrally confirmed ATM-deficiency, % (80% CI) N=11 18.2 (4.9, 41.5) N=7 0.0 (0.0, 28.0) Safety, n (%) N=30 N=15 TEAEs 30 (100) 15 (100) Grade ≥3 TEAEs 15 (50.0) 8 (53.3) TRAEs 21 (70.0) 13 (86.7) Grade ≥3 TRAEs 6 (20.0) 5 (33.3) Serious TEAEs 4 (13.3) 4 (26.7) Serious TRAEs 2 (6.7) 1 (6.7) TEAEs leading to discontinuation 1 (3.3)§ 0 TEAEs leading to death 0 0 TEAEs (any grade) occurring in ≥20% of pts in either cohort, n (%) N=30 N=15 Nausea 13 (43.3) 8 (53.3) Abdominal pain 9 (30.0) 1 (6.7) Anemia 8 (26.7) 7 (46.7) Fatigue 8 (26.7) 5 (33.3) Asthenia 8 (26.7) 2 (13.3) Decreased appetite 7 (23.3) 3 (20.0) *Centrally confirmed ATM-altered patients were patients with either ATM PV confirmed by FMI F1CDx in tumor and/or by FMI F1 liquid CDx in circulating tumor DNA and/or ATM protein-deficient by immunohistochemistry assay at Ventana with cut-off ≤5%. Thus, ATM PV patients could also have ATM protein-deficiency. †Objective response by RECIST v1.1, in centrally confirmed ATM-altered patients. ‡Composite response: by RECIST v1.1 for soft tissue and visceral lesions and PCWG3 criteria for bone lesions; confirmed conversion of circulating tumor cell count from ≥5/7.5 mL blood to <5/7.5 mL; or confirmed prostate-specific antigen decline of >50%, in centrally confirmed ATM-altered patients. §Discontinuation due to decreased appetite classified as a serious adverse event. ASTs, advanced solid tumors; CI, confidence interval; mCRPC, metastatic castration-resistant prostate cancer; PV, pathogenic variant; pts, patients; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event Citation Format: Rahul Aggarwal, Antoine Italiano, Susan Domchek, Oscar Goodman, Sophie Postel-Vinay, Jesus Garcia-Donas, Tanya Dorff, Zachery Reichert, Philippe Cassier, Neal Shore, Catherine Marshall, Graeme Parr, Itziar Irurzun-Arana, Neel Shah, Natalia Lukashchuk, Olga Murina, Daniel Slade, Bienvenu Loembé, Emma Dean, Elhan Sanai, Wassim Abida. Efficacy and safety of ceralasertib in the PLANETTE study in patients (pts) with ATM-altered advanced solid tumors (ASTs) or metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT222.

Preliminary reliability of the FACT-RNT in standard-of-care Lu-PSMA therapy of metastatic castration-resistant prostate cancer.

99 Background: The Functional Assessment of Cancer Therapy-Radionuclide Therapy (FACT-RNT) was recently developed as the first patient-reported outcome (PRO) measure designed to monitor RNT-relevant symptoms and toxicities for patients with advanced metastatic castrate-resistant prostate cancer (mCRPC). This study aimed to examine preliminary reliability of the FACT-RNT in patients receiving RNT as part of standard of care. Methods: Patients scheduled to start 177Lu-PSMA-617 for advanced mCRPC December 2022 – August 2023 who were fluent in English or Spanish completed the FACT-RNT on day 1 of each RNT cycle administered at UCLA. The FACT-RNT is a 15-item measure assessing symptoms and toxicities on a 0-4 scale; total scores range from 0-60, with higher scores indicating better quality of life. Reliability was assessed in R using data from cycles 1-4 with Cronbach’s alpha test of internal consistency, Guttman’s Lamba 6 test of split-half reliability, inter-item correlations, and test-retest reliability. Results: Patients (N=43) were, on average, 69 years old (SD = 9, range = 51-91) at RNT cycle 1, were mostly non-Hispanic (79%) and White (58%) with Gleason score ≥ 7 (67%) at diagnosis. Patients had undergone surgery (35%), chemotherapy (98%), radiation (65%), hormone therapy (100%), and/or immunotherapy (28%). Some patients who recently began therapy were not yet due for follow-up cycles, and 9 (21%) died during the study period. Completion of the FACT-RNT ranged from n=43 (Cycle 1) to n=19 (Cycle 4). The FACT-RNT total score ranged from 18-60 across cycles. Internal consistency reliability ranged from 0.82 (good) to 0.91 (excellent), and split-half reliability ranged from 0.92 to 0.99 (excellent). Average inter-item correlations were acceptable for scaling purposes (all exceeding 0.20). Within-subject correlations between scores were r=0.75 for cycles 2 vs. 3 and r=0.94 for cycles 3 vs. 4, indicating good measurement stability across cycles. Conclusions: In preliminary analyses, the FACT-RNT demonstrates good to excellent internal consistency across the first four cycles, moderate to strong consistency of measuring a common underlying construct, and good measurement stability. Findings support reliability of the FACT-RNT and its use in future research.

1809P Dynamics of plasma tumour DNA and copy number alterations in advanced metastatic castration-resistant prostate cancer (mCRPC) patients treated with cabazitaxel: A prospective biomarker trial

1809P Dynamics of plasma tumour DNA and copy number alterations in advanced metastatic castration-resistant prostate cancer (mCRPC) patients treated with cabazitaxel: A prospective biomarker trial

Unleashing novel horizons in advanced prostate cancer treatment: investigating the potential of prostate specific membrane antigen-targeted nanomedicine-based combination therapy.

Prostate cancer (PCa) is a prevalent malignancy with increasing incidence in middle-aged and older men. Despite various treatment options, advanced metastatic PCa remains challenging with poor prognosis and limited effective therapies. Nanomedicine, with its targeted drug delivery capabilities, has emerged as a promising approach to enhance treatment efficacy and reduce adverse effects. Prostate-specific membrane antigen (PSMA) stands as one of the most distinctive and highly selective biomarkers for PCa, exhibiting robust expression in PCa cells. In this review, we explore the applications of PSMA-targeted nanomedicines in advanced PCa management. Our primary objective is to bridge the gap between cutting-edge nanomedicine research and clinical practice, making it accessible to the medical community. We discuss mainstream treatment strategies for advanced PCa, including chemotherapy, radiotherapy, and immunotherapy, in the context of PSMA-targeted nanomedicines. Additionally, we elucidate novel treatment concepts such as photodynamic and photothermal therapies, along with nano-theragnostics. We present the content in a clear and accessible manner, appealing to general physicians, including those with limited backgrounds in biochemistry and bioengineering. The review emphasizes the potential benefits of PSMA-targeted nanomedicines in enhancing treatment efficiency and improving patient outcomes. While the use of PSMA-targeted nano-drug delivery has demonstrated promising results, further investigation is required to comprehend the precise mechanisms of action, pharmacotoxicity, and long-term outcomes. By meticulous optimization of the combination of nanomedicines and PSMA ligands, a novel horizon of PSMA-targeted nanomedicine-based combination therapy could bring renewed hope for patients with advanced PCa.

Antitumor activity of alkylphospholipid edelfosine in prostate cancer models and endoplasmic reticulum targeting

Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men worldwide. While the five-year survival in local and regional prostate cancer is higher than 99%, it falls to about 28% in advanced metastatic prostate cancer. The ether lipid edelfosine is considered the prototype of a family of promising antitumor drugs collectively named as alkylphospholipid analogs. Here, we found that edelfosine was the most potent alkylphospholipid analog in inducing apoptosis in three different human prostate cancer cell lines (LNCaP, PC3, and DU145) with distinct androgen dependency, and differing in tumor suppressor phosphatase and tensin homolog (PTEN) and p53 status. Edelfosine accumulated in the endoplasmic reticulum of prostate cancer cells, leading to endoplasmic reticulum stress and cell death in the three prostate cancer cells. Inhibition of autophagy potentiated the pro-apoptotic activity of edelfosine in LNCaP and PC3 cells, where autophagy was induced as a survival response. Edelfosine induced a slight and transient inhibition of AKT in PTEN-negative LNCaP and PC3 cells, but not in PTEN-positive DU145 cells. Daily oral administration of edelfosine in murine prostate restricted AKT kinase transgenic mice, expressing active AKT in a prostate-specific manner, and in a DU145 xenograft mouse model resulted in significant tumor regression and apoptosis in tumor cells. Taken together, these results show a significant in vitro and in vivo antitumor activity of edelfosine against prostate cancer, and highlight the endoplasmic reticulum as a novel and promising therapeutic target in prostate cancer.

Consultation-Liaison Case Conference: Suicidal Ideation in a Patient at the End-of-Life.

Psychiatric comorbidities are common among patients approaching the end of life, often necessitating the involvement of consultation-liaison psychiatrists. We present the case of a patient with advanced metastatic prostate cancer and a complicated hospital course who made suicidal remarks and requested a hastened death. This common and challenging clinical scenario requires a multidisciplinary approach. In this article, experts in consultation psychiatry, palliative care, and psycho-oncology describe helpful diagnostic and therapeutic strategies for such cases. The key learning points are the differential diagnoses in end-of-life patients endorsing suicidal ideation, the psychiatric management of oncological and palliative care patients, the implementation of a safe discharge plan, and the role of the consultation-liaison psychiatrist in hospice care.

Abstract B067: CRM1 inhibitor selinexor induces DNA damage repair-related vulnerability in prostate cancer cells

Abstract Background: Advanced metastatic prostate cancer is the second leading cause of death in men in the United States. Androgen deprivation therapy has been used as a front-line therapy; however, despite initial success, it fails subsequently and results in the development of castration-resistant prostate cancer. Due to these unmet therapeutic needs, there is an urgency to identify novel targets to develop next-generation therapeutics. Chromosome region maintenance 1 (CRM1) is one of the seven members of mammalian export proteins that function to export the proteins using nuclear export signal (NES). Several tumors, including prostate cancer, overexpress CRM1 to efflux tumor suppressor proteins to the cytoplasm and exhibit dysregulated nuclear export. CRM1-mediated export can lead to functional inactivation of p53, cyclinD1, p16, p21, and p27. Essential DNA repair proteins such as Rad51 and BRCA1 exhibit leucine-containing hydrophobic residues rich in NES and are known to be shuttled by CRM1. Based on this, we hypothesize that CRM1 inhibition may affect the expression, kinetics, localization, and stability of DNA repair network proteins. Methods: Androgen receptor-positive and negative prostate cancer cells were treated with Selinexor. The dose of the drug and duration was dependent on the endpoint measurement. Cell death was monitored using MTT assay and western blot measurement of cleaved PARP. Total RNA and cell lysate were collected to measure the relative levels of BRCA-1, RAD51, p53, and other members of the DNA repair pathway (HR and NHEJ). DNA damage was estimated using the number of micronuclei and immunofluorescence staining for γ-H2AX and COMET assay. Results: Selinexor treatment in prostate cancer cells affects the functioning of the DNA repair network and can be combined with inhibitors of DNA repair proteins. Citation Format: Rajendra Kumar, Janet Mendonca, Yuhan Yang, Abhishek Shetty, Lillian Wilson, Kavya Boyapati, Deven Topiwala, Keerti Soundappan, Eleni Panagopoulos, Michael Carducci, Sushant Kachhap. CRM1 inhibitor selinexor induces DNA damage repair-related vulnerability in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B067.

Minor intron splicing is critical for survival of lethal prostate cancer

The evolutionarily conserved minor spliceosome (MiS) is required for protein expression of ∼714minor intron-containing genes (MIGs) crucial for cell-cycle regulation, DNA repair, and MAP-kinase signaling. We explored the role of MIGs and MiS in cancer, taking prostate cancer (PCa) as an exemplar. Both androgen receptor signaling and elevated levels of U6atac, a MiS small nuclear RNA, regulate MiS activity, which is highest in advanced metastatic PCa. siU6atac-mediated MiS inhibition in PCa invitro model systems resulted in aberrant minor intron splicing leading to cell-cycle G1 arrest. Small interfering RNA knocking down U6atac was ∼50% more efficient in lowering tumor burden in models of advanced therapy-resistant PCa compared with standard antiandrogen therapy. In lethal PCa, siU6atac disrupted the splicing of a crucial lineage dependency factor, the RE1-silencing factor (REST). Taken together, we have nominated MiS as a vulnerability for lethal PCa and potentially other cancers.

Treatment of Advanced Metastatic Prostate Cancer Using Molecular-Targeted Therapy: Radioligand Lutetium-177 Prostate-Specific Membrane Antigen.

This study investigates the predicting factors of the biochemical response and survival of patients with advanced metastatic prostate cancer who underwent therapy with radioligand lutetium-177 (177Lu)-prostate-specific membrane antigen (PSMA), often referred to as [177Lu]Lu-PSMA. This study is areview of theprevious literature. This study included articles published in the last 10 years in the English language. According to the literature review, treatment with [177Lu]Lu-PSMA has a positive impact on prostate-specific antigen (PSA) within the first cycle and a negative impact on lymph node metastasis. There is a plausible positive impact on PSA after multiple cycles and performance status and a negative impact on visceral metastasis. In conclusion, the reviews show that treatment with [177Lu]Lu-PSMA in patients with castration-resistant prostate cancer is beneficial in reducing PSA and metastasis.

Cardiovascular Complications in Patients with Prostate Cancer: Potential Molecular Connections.

Cardiovascular diseases (CVDs) and complications are often seen in patients with prostate cancer (PCa) and affect their clinical management. Despite acceptable safety profiles and patient compliance, androgen deprivation therapy (ADT), the mainstay of PCa treatment and chemotherapy, has increased cardiovascular risks and metabolic syndromes in patients. A growing body of evidence also suggests that patients with pre-existing cardiovascular conditions show an increased incidence of PCa and present with fatal forms of the disease. Therefore, it is possible that a molecular link exists between the two diseases, which has not yet been unraveled. This article provides insight into the connection between PCa and CVDs. In this context, we present our findings linking PCa progression with patients' cardiovascular health by performing a comprehensive gene expression study, gene set enrichment (GSEA) and biological pathway analysis using publicly available data extracted from patients with advanced metastatic PCa. We also discuss the common androgen deprivation strategies and CVDs most frequently reported in PCa patients and present evidence from various clinical trials that suggest that therapy induces CVD in PCa patients.

Reversible epigenetic alterations mediate PSMA expression heterogeneity in advanced metastatic prostate cancer.

Prostate-specific membrane antigen (PSMA) is an important cell surface target in prostate cancer. There are limited data on the heterogeneity of PSMA tissue expression in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the mechanisms regulating PSMA expression (encoded by the FOLH1 gene) are not well understood. Here, we demonstrate that PSMA expression is heterogeneous across different metastatic sites and molecular subtypes of mCRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13 of 52 (25%) cases had no detectable PSMA and 23 of 52 (44%) cases showed heterogeneous PSMA expression across individual metastases, with 33 (63%) cases harboring at least 1 PSMA-negative site. PSMA-negative tumors displayed distinct transcriptional profiles with expression of druggable targets such as MUC1. Loss of PSMA was associated with epigenetic changes of the FOLH1 locus, including gain of CpG methylation and loss of histone 3 lysine 27 (H3K27) acetylation. Treatment with histone deacetylase (HDAC) inhibitors reversed this epigenetic repression and restored PSMA expression in vitro and in vivo. Collectively, these data provide insights into the expression patterns and regulation of PSMA in mCRPC and suggest that epigenetic therapies - in particular, HDAC inhibitors - can be used to augment PSMA levels.

Prostate cancer bone metastases biology and clinical management (Review).

Prostate cancer (PCa) is one of the most prominent causes of cancer-related mortality in the male population. A highly impactful prognostic factor for patients diagnosed with PCa is the presence or absence of bone metastases. The formation of secondary tumours at the bone is the most commonly observed site for the establishment of PCa metastases and is associated with reduced survival of patients in addition to a cohort of life-debilitating symptoms, including mobility issues and chronic pain. Despite the prevalence of this disease presentation and the high medical relevance of bone metastases, the mechanisms underlying the formation of metastases to the bone and the understanding of what drives the osteotropism exhibited by prostate tumours remain to be fully elucidated. This lack of in-depth understanding manifests in limited effective treatment options for patients with advanced metastatic PCa and culminates in the low rate of survival observed for this sub-set of patients. The present review aims to summarise the most recent promising advances in the understanding of how and why prostate tumours metastasise to the bone, with the ultimate aim of highlighting novel treatment and prognostic targets, which may provide the opportunity to improve the diagnosis and treatment of patients with PCa with bone metastases.

Perioperative outcomes of radical prostatectomy for advanced stage, node positive, and metastatic prostate cancer.

270 Background: Historically, surgical management with radical prostatectomy (RP) has been a definitive treatment option only for localized prostate cancer (PCa). However, recent studies suggest an overall survival benefit to treating the primary tumor with radiation therapy in metastatic PCa (mPCa). Therefore, RP may have a role in treating mPCa, but the perioperative safety of that remains unclear. Here, we aim to compare the perioperative outcomes of RP for locally advanced, node positive, and metastatic PCa using the National Surgical Quality Improvement Project (NSQIP) database. Methods: RPs performed between 2019-2020 were identified in NSQIP and the corresponding Prostatectomy-Targeted Participant Use File. Cases were grouped into six distinct categories: T1N0M0-T2N0M0; T3N0M0; T4N0M0; T1-3N1M0; T4N1M0; and T1-4N0-1M1. Baseline age, race, and medical comorbidities were compared between the groups. Patients were then further grouped into T1-2N0M0 versus T3-4N0M0 cases to compare the effect of locally advanced disease, TanyN1M0 versus TanyN0M0 to compare the effect of node-positivity, and TanyN0M1 versus TanyN0M0 to compare the effect of metastases. 30-day outcomes, operative time, hospital length-of-stay, 30-day mortality, readmissions, reoperations, major complications, minor complications, and surgery-specific complications were compared between groups. Results: Pathologic staging was available for 5,248 RPs. Baseline demographics were largely similar, with the exceptions of increased Black race, diabetes, and smoking in the node-positive-group and increased age in the T4 group. There was a slightly higher rate of minor complications in the locally advanced (T3-4N0M0) versus localized (T1-2N0M0) group, but no significant difference in major complications, 30-day mortality, readmissions, or rectal injuries. In comparison to node-negative patients (T1-4N0M0), node-positivity (T1-4N1M0) was associated with longer operative time, LOS, and incidence of 30-day renal failure, but was otherwise not associated with a higher rate of any complication. Compared to non-metastatic cases (T1-4N0M0), metastatic cases (T1-4N0M1) were associated with a higher rate of bleeding, prolonged-NG-tube use, ureteral obstruction, and LOS. Conclusions: RP for patients with locally advanced, node positive, and metastatic prostate cancer appears to be safe; it is not associated with significantly higher rates of 30-day mortality or major complications compared to RP for localized prostate cancer. Given the potential survival benefit in treating the primary tumor in advanced disease, there may be a role for RP in treating patients with advanced PCa.

Abstract B050: Reproducible and effective preclinical models of prostate cancer metastasis established with PDXs

Abstract Metastatic castration resistant prostate cancer (mCRPC) is a lethal disease. Understanding the intricacy of this disease and developing targeted treatment is hampered by the lacking of clinically relevant animal models. LuCaP patient-derived xenografts (PDXs), established from advanced metastatic prostate cancer, are a large cohort that encompass the molecular and cellular heterogeneity of mCRPC. We have established four prostate cancer metastasis models from three androgen receptor (AR) positive lines (LuCaP136, LuCaP167 and LuCaP23.1) and one AR negative line LuCap145.2. The three AR positive LuCap lines metastasized to vertebrae and long bones with differing bone-associated histology while the AR negative LuCap145.2 metastasize to brain and spinal cord. The bone metastasis phenotypes of the models encompass: osteolytic (LuCaP136), mixed bone destruction and new bone formation (LuCaP167), and a highly osteoblastic histology (LuCaP23.1). LuCap136 and LuCap167 also metasize to soft tissues including adrenal, kidney and liver. Castration responses were studied on LuCap136 and LuCap167 models. Although both models are castration resistant, LuCap136 model initially are sensitive to castration with decreased tumor progression, and AR down-regulated in the metastatic sites. In contrast, tumor progression was not affected after castration in LuCap167 model. AR and ARV7 were up-regulated in metastatic cells. In summary, the LuCap PDX lines have the capacity for systemic growth in clinically accurate metastatic sites. In addition, the two AR positive models show different castration response which may be driven by different pathways. Understanding the complexity of these pathways would guide optimal selection of drug combinations to achieve the best outcome for patients with mCRPC. Citation Format: JuanJuan I. Yin, Asha Daryanani, Aian Alilin, Ross Lake, Kathy Kelly. Reproducible and effective preclinical models of prostate cancer metastasis established with PDXs [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B050.

Development of PARP Inhibitors in Targeting Castration-Resistant Prostate Cancer.

Prostate cancer is a genetically heterogenous disease and a subset of prostate tumors harbor alterations in DNA damage and repair (DDR) genes. Prostate tumor DDR gene alterations can arise via germline or somatic events and are enriched in high-grade and advanced disease. Alterations in genes in the homologous recombination (HR) repair pathway are associated with sensitivity to PARP inhibition in breast and ovarian cancer, and data from recently completed randomized trials also demonstrate benefit of PARP inhibitor therapy in patients with advanced metastatic castration-resistant prostate cancer (mCRPC) and tumor HR gene alterations. PARP inhibitors have been investigated in first-line mCRPC in biomarker-selected and unselected populations, and are currently under study in earlier disease states in patients with DDR gene alterations. This chapter focuses on the current state of PARP inhibitor development in prostate cancer with particular emphasis on biomarkers and combination therapy approaches.

LncRNA weighted gene co-expression network analysis reveals novel biomarkers related to prostate cancer metastasis

BackgroundMost prostate cancer patients die from metastasis and lack accurate efficacious biomarkers to monitor the disease behavior, optimize treatment and assess prognosis. Herein, we aimed to identify meaningful lncRNA biomarkers associated with prostate cancer metastatic progression.MethodsBy repurposing microarray probes, 11,624 lncRNAs in prostate cancer were obtained from Gene Expression Omnibus database (GSE46691, N = 545; GSE29079, N = 235; GSE94767, N = 130). Weighted gene co-expression network analysis was applied to determine the co-expression lncRNA network pertinent to metastasis. Hub lncRNAs were screened. RNA-seq and clinical data from the Cancer Genome Atlas prostate cancer (TCGA-PRAD) cohort (N = 531) were analyzed. Transwell assay and bioinformatic analysis were performed for mechanism research.ResultsThe high expression levels of nine hub lncRNAs (FTX, AC005261.1, NORAD, LINC01578, AC004542.2, ZFAS1, EBLN3P, THUMPD3-AS1, GAS5) were significantly associated with Gleason score and increased probability of metastatic progression. Among these lncRNAs, ZFAS1 had the consistent trends of expression in all of the analysis from different cohorts, and the Kaplan-Meier survival analyses showed higher expression of ZFAS1 was associated with shorter relapse free survival. In-vitro studies confirmed that downregulation of ZFAS1 decreased prostate cancer cell migration.ConclusionWe offered some new insights into discovering lncRNA markers correlated with metastatic progression of prostate cancer using the WGCNA. Some may serve as potential prognostic biomarkers and therapeutic targets for advanced metastatic prostate cancer.

Prostate specific membrane antigen binding radiopharmaceuticals: Current data and new concepts.

Prostate specific membrane antigen (PSMA) represents a validated target for prostate cancer therapeutics. The phase III VISION study with 177lutetium (177Lu)-PSMA-617 represented a pivotal step forward and the FDA has now approved this agent in advanced metastatic castrate-resistant prostate cancer (mCRPC). A number of other PSMA targeted radiopharmaceuticals are now under development. Some of these agents are targeted to PSMA via monoclonal antibodies such as J591 and TLX591. Others are targeted to PSMA via small molecules such as PSMA-617, PSMA I&T, MIP-1095, etc. In addition to the use of various ligands, multiple isotopes are now in clinical trials. Beta emitters in development include 177Lu, 131iodide (131I), and 67copper (67Cu). Targeted alpha emitters potentially include 225actinium (225Ac), 227thorium (227Th), and 212lead (212Pb). Phase III trials are underway with both 177Lu-PSMA-617 and 177Lu-PSMA I&T in mCRPC. Single dose phase I trials are complete with 225Ac-J591 but additional data are need to launch a phase III. Data are promising with 225Ac-PSMA-617 but concerns remain over salivary and renal toxicity. Tandem therapies are also considered combining both beta and alpha-targeted therapy. Taken together the field of PSMA targeted radiopharmaceuticals is rapidly developing. The targeted alpha therapies are particularly promising and several developmental paths forward are being considered in the near future.