Prostate Cancer Clinical Trials Research Articles

Targeting the tumor microenvironment, a new therapeutic approach for prostate cancer.

A growing number of studies have shown that in addition to adaptive immune cells such as CD8 + T cells and CD4 + T cells, various other cellular components within prostate cancer (PCa) tumor microenvironment (TME), mainly tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs), have been increasingly recognized as important modulators of tumor progression and promising therapeutic targets. In this review, we aim to delineate the mechanisms by which TAMs, CAFs and MDSCs interact with PCa cells in the TME, summarize the therapeutic advancements targeting these cells and discuss potential new therapeutic avenues. We searched PubMed for relevant studies published through December 10 2023 on TAMs, CAFs and MDSCs in PCa. TAMs, CAFs and MDSCs play a critical role in the tumorigenesis, progression, and metastasis of PCa. Moreover, they substantially mediate therapeutic resistance against conventional treatments including anti-androgen therapy, chemotherapy, and immunotherapy. Therapeutic interventions targeting these cellular components have demonstrated promising effects in preclinical models and several clinical trials for PCa, when administrated alone, or combined with other anti-cancer therapies. However, the lack of reliable biomarkers for patient selection and incomplete understanding of the mechanisms underlying the interactions between these cellular components and PCa cells hinder their clinical translation and utility. New therapeutic strategies targeting TAMs, CAFs, and MDSCs in PCa hold promising prospects. Future research endeavors should focus on a more comprehensive exploration of the specific mechanisms by which these cells contribute to PCa, aiming to identify additional drug targets and conduct more clinical trials to validate the safety and efficacy of these treatment strategies.

Abstract 3665: Stratifying prostate cancer patients through circulating genes related to prostate cell subtypes, drug targets, and therapeutic resistance

Abstract Stratification remains an obstacle for the optimal treatment of prostate cancer (PCa) patients throughout the treatment trajectory. Targeting the androgen receptor (AR) kills the majority of luminal-like cells, which are AR-positive and express Prostate Specific Antigen (PSA). However, a subset of surviving AR-positive cells develop resistance to treatments while AR-negative cells of the neuroendocrine (NE) or stem-like phenotypes emerge through selection. We reported on the clinical relevance of cell-subtype genes in whole blood RNA of advanced PCa patients. Here, we studied an expanded panel of genes to include drug targets and therapeutic resistance as predictive biomarkers to stratify patients at diagnosis and at the advanced stage of disease.Genes were chosen based on literature review, results of clinical trials in PCa, and PCa transcriptomic data. Technical validation of TaqMan RT-qPCR assays was carried out for each gene, including rigorous testing of reproducibility. Whole blood RNA was extracted from 26 healthy controls with no prostatic disease, 16 patients prior to prostatectomy, and 43 blood samples from 28 metastatic cases. Gene overexpression was defined as the 99.5% confidence interval of expression in controls. Clinical data were retrieved from patients’ charts.A panel of 64 genes was built, showing overexpression in advanced PCa but low or no expression in normal blood (including whole blood, white and red blood cell populations and platelets). Testing in control blood showed no correlation with age. The proportions of patients’ white blood cells did not correlate with gene expression in their blood. Overall, up to 44/64 genes were overexpressed in at least one patient sample. Patients with prostatic intraductal carcinoma at prostatectomy showed more circulating genes, including more NE and stemness genes, and more PCa cell subtypes represented. Intermediate and high-risk patients showed more circulating NE genes. In metastatic patients, signatures of luminal, NE, stemness, and resistance to AR inhibitors or taxanes were associated with progression. PCa-specific luminal genes were associated with shorter overall survival. Treatment resistance genes correlated with lines of treatment and current taxanes. Two targetable NE genes were overexpressed in distinct categories of patients, suggesting that they may benefit from more specific treatments.In conclusion, phenotypic and functional differences in circulating gene patterns of PCa patients correlate with pathological features, treatments, progression. They may be clinically meaningful to stratify patients and predict therapeutic response. Circulating genes encoding drug targets may justify clinical trials to offer personalized treatments and impact on lethal PCa. Citation Format: Seta Derderian, Edouard Jarry, Arynne Santos, Mohanachary Amaravadi, Quentin Vesval, Lucie Hamel, Raphael Sanchez-Salas, Alexis Rompré-Brodeur, Wassim Kassouf, Raghu Rajan, Marie Duclos, Fadi Brimo, Armen Aprikian, Simone Chevalier. Stratifying prostate cancer patients through circulating genes related to prostate cell subtypes, drug targets, and therapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3665.

A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer.

Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC). Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed. In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion. Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.

Disparities in prostate cancer mortality and clinical trial availability across vulnerable populations.

24 Background: Clinical trials provide high-level evidence and test novel therapies that have significantly improved cancer outcomes. However, disparities in clinical trial participation and cancer mortality persist across race/ethnicity and vulnerable populations, notably in patients with prostate cancer (PCa). Adverse social determinants of health (SDOH) and systemic barriers may underlie these disparities. Identifying and overcoming these barriers may improve access to and representation in clinical trials, thereby promoting equitable advancement and applicability of science. For these reasons, we evaluate the association between clinical trial availability, cancer mortality, and population-level SDOH in PCa. Methods: Using custom data linkage from ClinicalTrials.gov, Surveillance Epidemiology and End Results (SEER) Registry, and the Centers for Disease Control and Prevention Social Vulnerability Index (SVI), we performed a cross-sectional analysis of county-level PCa clinical trial data, cancer incidence and mortality rates, and population-level SDOH. We included Phase 2 and Phase 3 interventional PCa clinical trials with start dates from 2007 to 2022. The total number of clinical trials over the study period was calculated per county and population-adjusted for 100,000 residents. Counties were stratified into quintiles based on SVI (i.e., least vulnerable to most vulnerable). Population-adjusted clinical trial availability, cancer incidence, and cancer mortality were compared across SVI quintiles. Multivariable logistic and linear regression analyses were performed to evaluate the association between SVI and clinical trial availability and cancer mortality, respectively. Results: The mean number of PCa trials per 100,000 residents was 25.6, with the most vulnerable counties having fewer clinical trials compared to the least vulnerable counties (mean 18.1 vs. 50.0, p<0.05). Further, the most vulnerable counties had a lower PCa incidence rate per 100,000 residents (mean 393.8 vs. 411.7, p<0.05), but a higher PCa mortality rate per 100,000 residents (mean 85.7 vs. 72.0, p<0.05). On multivariable regression analysis, the most vulnerable counties were associated with significantly decreased odds of having any PCa clinical trial (OR 0.3, 95% CI 0.2 – 0.4) and significantly increased PCa mortality (10.8, 95% CI 7.4 – 14.3), while the presence of any PCa clinical trial was associated with significantly decreased PCa mortality (-6.9, 95% CI -9.1 – -4.7). Conclusions: The most vulnerable counties were far less likely to have any PCa clinical trials despite having a significantly higher PCa mortality rate. The presence of a PCa clinical trial was associated with a reduction in PCa mortality. These vulnerable counties represent scientifically underserved populations that may benefit from equity-driven clinical trial enrollment and cancer care infrastructure expansion.

The frequency of use and enrollment impact of patient-centered outcomes in prostate cancer clinical trials.

115 Background: Cancer treatments should help patients live either longer or better by improving patient quantity or quality of life. However, some trial endpoints do not correlate with overall survival, and are not noticeable to patients. Selecting endpoints for clinical trials that reflect these goals could improve the discovery process by ensuring trial results are of direct interest to patients, and perhaps by improving enrollment rates to trials. However, how frequently prostate cancer clinical trials use patient-centered outcomes, and how outcome type impacts trial enrollment, is unknown. Methods: On October 23, 2022, we queried ClinicalTrials.gov for full text records of phase 2-3 prostate cancer trials started after January 1, 2007. We extracted primary outcomes and other trial characteristics using a custom Python script. Two reviewers categorized each outcome into categories (e.g., overall survival, response rate, patient reported measure). As previously studied, the only valid surrogate for overall survival is metastasis-free survival. We considered these two outcomes or any outcome directly noticeable to a patient to be a patient-centered outcome. For completed or terminated trials, we defined ‘sufficient accrual’ as attaining 85% of a trial’s goal enrollment. We identified associations between trial outcome types and sufficient trial enrollment with chi-square tests and logistic regression. Results: Of 1,717 prostate cancer trials, only 37% used a patient-centered outcome, with 6% using overall or metastasis-free survival. Among 318 Phase 3 trials, 49% used a patient-centered outcome and 26% used overall or metastasis-free survival. Of 731 completed or terminated prostate cancer trials, 55% of trials and 68% of phase 3 trials reached sufficient enrollment (85% of enrollment goal). On multivariable analysis, trials with an overall survival endpoint had higher odds of sufficient enrollment (OR 8.0 [95% CI 2.2-33.5], p < 0.01), but trials with any patient-centered outcome had lower odds of sufficient enrollment (OR 0.25 [95% CI 0.11-0.54], p < 0.01). Conclusions: Less than half of prostate cancer trials use an outcome that is clearly patient-centered (i.e., affecting overall survival or an outcome noticeable to a patient). Further work is needed to clarify the use, understanding, and effect of outcome selection in cancer trials. Realigning trial efforts with patient-centered goals could improve the efficiency, productivity, and applicability of clinical trials.

Toxicity-benefit analysis of advanced prostate cancer trials using weighted toxicity scoring.

110 Background: The weighted toxicity score (WTS) is a metric suitable for comparing the toxicity burden in experimental versus control arms of randomized controlled trials (RCTs). When compared against clinical endpoints, the WTS can be used to evaluate the cost versus benefit of anti-cancer agents. This study sought to apply the WTS to prostate cancer (PC) clinical trials. Methods: Select phase 3 PC RCTs with reported adverse event (AE) data were compiled. The WTS was computed for each trial arm and compared to reported hazard ratios (HRs) of primary and/or secondary endpoints (i.e., overall survival (OS) and progression-free survival (PFS)). Average WTSs for the experimental versus control arms were used to calculate the toxicity differential between treatment arms. Average HRs for OS and PFS were used to compare efficacy. Results: Sixteen RCTs were analyzed (investigational agents: androgen-receptor signaling inhibitors (ARSi) [n = 4], poly (ADP-ribose) polymerase inhibitors (PARPi) monotherapy [n = 3], ARSi + PARPi as well as ARSi + ARSi combination therapies [n = 3 each], and triple therapy [n=3]). The median number of distinct reported AEs across all studies was 18 (range, 9-61). Overall, toxicity and efficacy were greater among experimental than control arms (6.62 versus 4.00 median WTS; median HR for OS 0.71, median HR for PFS 0.61). The triple therapy studies observed the lowest increase in toxicity by adding an ARSi to control therapy (10.4%), associated with 52% lower risk of progression, and 29% lower risk of death. Comparably, the ARSi + PARPi trials noted the highest increase in toxicity (79.7%), with 32% lower risk of progression and 12% lower risk of death. The PARPi monotherapy, ARSi monotherapy, and ARSi + ARSi combination therapy studies reported increased toxicity due to experimental therapy in descending order (Table). Conclusions: The WTS enables toxicity versus benefit assessment for anti-cancer regimens. Clinical application of this metric may facilitate individualized treatment planning in advanced PC management. [Table: see text]

Gaussian Copula Regression Modeling for Marker Classification Metrics with Competing Risk Outcomes

Decisions regarding competing risks are usually based on a continuous-valued marker toward predicting a cause-specific outcome. The classification power of a marker can be summarized using the time-dependent receiver operating characteristic curve and the corresponding area under the curve (AUC). This paper proposes a Gaussian copula-based model to represent the joint distribution of the continuous-valued marker, the overall survival time, and the cause-specific outcome. Then, it is used to characterize the time-varying ROC curve in the context of competing risks. Covariate effects are incorporated by linking linear components to the skewed normal distribution for the margin of the marker, a parametric proportional hazards model for the survival time, and a logit model for the cause of failure. Estimation is carried out using maximum likelihood, and a bootstrap technique is implemented to obtain confidence intervals for the AUC. Information-criteria strategies are employed to find a parsimonious model. The performance of the proposed model is evaluated in simulation studies, considering different sample sizes and censoring distributions. The methods are illustrated with the reanalysis of a prostate cancer clinical trial. The joint regression strategy produces a straightforward and flexible model of the time-dependent ROC curve in the presence of competing risks, enhancing the understanding of how covariates may affect the discrimination of a marker.

Understanding the Termination of Urologic Cancer Clinical Trials: Insights and Challenges.

Clinical trials are valuable evidence for managing urologic malignancies. Early termination of clinical trials is associated with a waste of resources and may substantially affect patient care. We sought to study the termination rate of urologic cancer clinical trials and identify factors associated with trial termination. A cross-sectional search of ClinicalTrials.gov identified completed and terminated kidney, prostate, and bladder cancer clinical trials started. Trials were assessed for reasons for termination. Multivariable analyses were conducted to determine the significant factors associated with the termination. Between 2000 and 2020, 9,145 oncology clinical trials were conducted, of which 11.30% (n = 1,033) were urologic cancer clinical trials. Of the urologic cancer clinical trials, 25.38% (n = 265) were terminated, with low patient accrual being the most common reason for termination, 52.9% (n = 127). Multivariable analysis showed that only the university funding source odds ratio (OR) of 2.20 (95% CI, 1.45 to 3.32), single-center studies OR of 2.11 (95% CI, 1.59 to 2.81), and sample size of <50 were significant predictors of clinical trial termination OR of 5.26 (95% CI, 3.85 to 7.69); all P values are <.001. The termination rate of urologic cancer clinical trials was 25%, with low accrual being the most frequently reported reason. Trials funded by a university, single-center trials, and small trials (sample size <50) were associated with early termination. A better understanding of these factors might help researchers, funding agencies, and other stakeholders prioritize resource allocations for multicenter trials that aim to recruit a sufficient number of patients.

Abstract C054: Association of fatty acid synthase expression with FASN gene methylation and self-identified race in prostate cancer

Abstract Fatty acid synthase (FASN) catalyzes the synthesis of long-chain saturated fatty acids and is overexpressed during prostatic tumorigenesis; however, the mechanism of this upregulation remains unclear and could include gene amplification, epigenetic regulation or regulation by androgen receptor (AR). Though FASN is an attractive therapeutic target in prostate cancer and several clinical trials of FASN inhibitors are underway, prior studies have suggested racial disparities in FASN copy number and FASN protein expression exist in primary prostate cancer, which may have implications for the therapeutic efficacy of FASN inhibitors. FASN gene amplification may be more common in prostate cancers from self-identified Black (BL) patients than their White (WH) counterparts, and a recent study has suggested that FASN protein expression is also higher among primary prostate tumors from BL compared to WH men due to changes in the AR cistrome. Here, we examine FASN protein expression as measured by digitally quantified immunohistochemistry assay and reverse phase protein array analysis or FASN gene expression, comparing it to gene CpG methylation pattern by InfiniumEPIC profiling and whole genome bisulfite sequencing (WGBS) across multiple racially diverse primary and metastatic prostate cancer cohorts, including more than 1000 tumors. We demonstrate that the FASN gene body is hypomethylated and overexpressed in primary prostate tumors compared to benign tissue. FASN gene methylation shows a significant inverse correlation with FASN protein and gene expression in both primary and metastatic prostate cancer. However, in contrast to previous studies, we find no significant association of FASN expression or methylation with self-identified race or genetic ancestry in models that include ERG gene fusion status across two independent primary tumor cohorts. Taken together, these data support a potential epigenetic mechanism for FASN regulation in the prostate and suggest that FASN inhibitors may be equally efficacious in both BL and WH men with prostate cancer. Citation Format: Oluwademilade Dairo, Lia DePaula Oliveira, Ethan Schaffer, Thiago Vidotto, Adrianna Amaral De Aragao Mendes, Jiayun Lu, Jessica Hicks, Adam G. Sowalsky, Angelo M. De Marzo, Corrine E. Joshu, Brian Hanratty, Karen S. Sfanos, William B. Isaacs, Michael C. Haffner, Tamara L. Lotan. Association of fatty acid synthase expression with FASN gene methylation and self-identified race in prostate cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C054.

Abstract B118: Racial and ethnic minorities remain underrepresented in cancer clinical trials despite local cancer incidence

Abstract Introduction: Over the last two decades, racial and ethnic minorities have been underrepresented in cancer clinical trials. Some have suggested that location is a barrier to inclusion in cancer clinical trials. The aim of this project is to assess how diversity of cancer clinical trials reflect their surrounding communities. Methods: Cancer clinical trials for the top five most deadly cancers including lung, breast, prostate, colon and pancreatic were selected from ClinicalTrials.gov. Trials were excluded if they were conducted outside the US or in multiple NIH-designated health service areas (HSA). Location-specific enrollment fractions were determined by comparing the proportion of trial participants to the local cancer incidence. National Cancer Institute (NCI) and Centers for Disease Control and Prevention (CDC) state cancer profiles (statecancerprofiles.cancer.gov) were used to determine HSA-specific data of cancer incidence by race and ethnicity. Results: 904 cancer clinical trials were identified from 2008-2022, including lung (n=157), breast (n= 330), prostate (n=219), colon (n=111) and pancreas (n=87). Overall, reporting of race and ethnicity was poor with only 53.6% of total trials reporting race and 35.9% reporting ethnicity. Compared to the local cancer incidence surrounding trial centers, White patients were overrepresented (p&amp;lt;0.0001), whereas Black (p&amp;lt;0.0001), Asian/Pacific Islander (p&amp;lt;0.0001), American Indian/Alaskan (p&amp;lt;0.0001) and Hispanic (p=0.004) were underrepresented. Furthermore, Black patients were underrepresented across breast (p=0.009), prostate (p&amp;lt;0.0001), lung (p&amp;lt;0.0001), colon (p=0.027) and pancreas (p&amp;lt;0.0001) cancer clinical trials when compared to the local cancer incidence. Conclusion: Racial and ethnic minority patients remain underrepresented in cancer clinical trials when compared to local cancer incidence. These findings reaffirm that location is not the only barrier to cancer clinical trial participation. Further efforts are needed to reduce healthcare disparities and improve patient care. Citation Format: Kelly M. Herremans, Andrea N. Riner, Vignesh Vudatha, Devon C. Freudenberger, Jose G. Trevino. Racial and ethnic minorities remain underrepresented in cancer clinical trials despite local cancer incidence [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B118.

Prostate cancer clinical trials in low- and middle-income countries.

Prostate cancer is the second most common form of cancer and a leading cause of cancer-related death in men. In an era of evidence-based medicine, clinical trials play a critical role, and adherence to best practices is crucial in managing complicated and non-communicable diseases, such as prostate cancer. For this reason, extrapolating research conducted in high-income countries (HICs) to low-middle-income countries (LMICs) may lead to incorrect findings or treatment plans for patients in these areas. Unfortunately, clinical trials in LMICs face several challenges in terms of design, funding and recruitment. This study aimed to examine clinical trials on prostate cancer in LMICs, including the scope of these trials, the type of interventions being tested and funding sources. A search of the Cochrane Library Controlled Trials Registry was conducted between January 2010 and June 2021 using keywords including: 'prostate cancer', 'prostate adenocarcinoma' and 'prostate tumour'). The trials were classified into either HICs or LMICs based on the World Bank Atlas classification. A descriptive analysis was performed to determine the characteristics of the trials. A total of 3,455 clinical trials for prostate cancer have been conducted globally, with 542 (15.68%) conducted LMICs. Most of these trials (89%) were registered in upper-middle-income countries, with none being conducted in low-income countries. The majority of trials were prospective studies (98.1%), with 65.2% being randomised and 57% being phase III. Of the trials, 48.4% aimed to recruit fewer than 500 participants. The main source of funding was pharmaceutical companies in 78.1% of the cases, followed by institutional funds (16.1%) and public funds (5.8%). At the time of the search query, 74.6% of the trials were inactive, with 37% completed, 5% terminated due to insufficient funding and 75% terminated due to medical inefficacy or poor accrual. The majority of trials (88.2%) were interventional, with only 6% focusing on screening and prevention, and 2% designed for palliative care. This study sheds light on the challenges faced in conducting clinical trials for prostate cancer in LMICs. The findings underline the need for improved support from international organisations and pharmaceutical companies to bridge the gaps in prostate cancer research and facilitate collaboration between researchers in LMICs and other countries.

Carboplatin in Patients With Metastatic Castration-Resistant Prostate Cancer Harboring Somatic or Germline Homologous Recombination Repair Gene Mutations: Phase II Single-Arm Trial.

Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While polyadenosine 5'diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations. The primary objective is to assess the objective response rate of 3 weekly carboplatin treatments in patients with mCRPC harboring deleterious mutations in the HRR pathway genes and previously treated with a taxane or a novel antiandrogen agent. The secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin. Patients diagnosed with mCRPC harboring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary end point will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrollment. Secondary outcomes include progression-free survival-soft-tissue disease progression (by response evaluation criteria in solid tumors, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy-Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0). The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date. All 49 participants will be enrolled according to plan. This prospective phase II trial represents a critical step toward addressing the therapeutic gap in patients with mCRPC harboring HRR pathway mutations, particularly in demographic regions with limited access to poly (ADP-ribose) polymerase inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally. Clinical Trials Registry of India CTRI/2023/04/051507; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=Njc0NjU=&Enc=&userName=. DERR1-10.2196/54086.

Surrogacy validation for time-to-event outcomes with illness-death frailty models.

A common practice in clinical trials is to evaluate a treatment effect on an intermediate outcome when the true outcome of interest would be difficult or costly to measure. We consider how to validate intermediate outcomes in a causally-valid way when the trial outcomes are time-to-event. Using counterfactual outcomes, those that would be observed if the counterfactual treatment had been given, the causal association paradigm assesses the relationship of the treatment effect on the surrogate outcome with the treatment effect on the true, primary outcome. In particular, we propose illness-death models to accommodate the censored and semicompeting risk structure of survival data. The proposed causal version of these models involves estimable and counterfactual frailty terms. Via these multistate models, we characterize what a valid surrogate would look like using a causal effect predictiveness plot. We evaluate the estimation properties of a Bayesian method using Markov chain Monte Carlo and assess the sensitivity of our model assumptions. Our motivating data source is a localized prostate cancer clinical trial where the two survival outcomes are time to distant metastasis and time todeath.

Prognostic Value of End-of-Treatment PSMA PET/CT in Patients Treated with 177Lu-PSMA Radioligand Therapy: A Retrospective, Single-Center Analysis.

Our objective was to evaluate the prognostic value of end-of-treatment prostate-specific membrane antigen (PSMA) PET/CT (PSMA-PET) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA radioligand therapy (PSMA-RLT). Methods: This was a single-center retrospective study. mCRPC patients who underwent PSMA-RLT with available baseline PSMA-PET (bPET) and end-of-treatment PSMA-PET (ePET) within 6 mo of the last PSMA-RLT cycle were eligible. Overall survival (OS) and prostate-specific antigen (PSA) progression status at the time of ePET (by Prostate Cancer Clinical Trials Working Group 3 criteria) were collected. PSMA-PET tumor segmentation was performed to obtain whole-body PSMA tumor volume (PSMA-VOL) and define progressive (≥20% increase) versus nonprogressive disease. Pairs of bPET and ePET were interpreted for appearance of new lesions. Response Evaluation Criteria in PSMA-PET/CT (RECIP) 1.0 were also applied to define progressive versus nonprogressive disease. The associations between changes in PSMA-VOL, new lesions, RECIP 1.0, and PSA progression status at the time of ePET with OS were evaluated by Kaplan-Meier analysis. Results: Twenty mCRPC patients were included. The median number of treatment cycles was 3.5 (interquartile range [IQR], 2-4). The median time between bPET and cycle 1 of PSMA-RLT was 1.0 mo (IQR, 0.7-1.8 mo). The median time between the last cycle of PSMA-RLT and ePET was 1.9 mo (IQR, 1.2-3.5 mo). Twelve of 20 patients (60%) had died at the last follow-up. The median follow-up time from ePET for survivors was 31.2 mo (IQR, 6.8-40.7 mo). The median OS from ePET was 11.4 mo (IQR, 6.8-30.7 mo). Patients with new lesions on ePET had shorter OS than those without new lesions (median OS, 10.7 mo [95% CI, 9.2-12.2] vs. not reached; P = 0.002). Patients with progressive PSMA-VOL had shorter OS than those with nonprogressive PSMA-VOL (median OS, 10.7 mo [95% CI: 9.7-11.7 mo] vs. not reached; P = 0.007). Patients with progressive RECIP had shorter OS than those with nonprogressive RECIP (median OS, 10.7 mo [95% CI, 9.7-11.7 mo] vs. not reached; P = 0.007). PSA progression at the time of ePET was associated with shorter OS (median, 10.9 mo [95% CI, 9.4-12.4 mo] vs. not reached; P = 0.028). Conclusion: In this retrospective study of 20 mCRPC patients treated with PSMA-RLT, progression on ePET by the appearance of new lesions, changes in PSMA-VOL, and RECIP 1.0 was prognostic for OS. Validation in larger, prospective multicentric clinical trials is warranted.

A Problem in NIH and Federally Funded Prostate Cancer Interventional Clinical Trials.

Obesity, diagnosed in 41.1% of African American (AA) men, is a risk factor for prostate cancer (PCa) recurrence, progression, and increased mortality. Obesity is associated with aggressive PCa only in AA men and not White American (WA) men. The overall health of AA PCa patients is also more likely to be adversely affected by comorbid type 2 diabetes (T2D), often an outcome of obesity and a cause of reduced odds of PCa survival. This evidence suggests that preventing and controlling comorbid obesity and T2D in AA men diagnosed with PCa should be a research funding priority. The aim of this study is to determine if federally funded PCa clinical trials controlled T2D and obesity. Completed interventional PCa clinical trials conducted in the USA, funded by the NIH or other federal agency, which included males aged 18-64years, and reported study protocols were included in the study. We examined the intervention modalities used in the trials to determine if any attempted to control obesity and T2D. Fifty-eight trials met the study inclusion criteria. Of these 11 were excluded from the analysis as they did not report AA men. A total of 5802 men participated in the remaining 47 trials. Of these, 917 (15.8%) were AA and 4885 (84.2%) were WA men. Forty (85.1%) trials used pharmaceutical medication therapies or other clinical procedures. None of the medications or clinical procedures used were indicated for treatment of obesity and T2D. 5 (10.6%) trials addressed treatment preferences, survivorship, coping, function, and incontinence among PCa patients. Only 2 (4.25%) trials examined weight loss and diet. None of the completed federally funded PCa clinical trials that included AA men used methods to control T2D. Only an insignificant number (4.25%) attempted to control obesity. This gap in therapeutic optimization to control these comorbid conditions indicates a critical area in need of federal funding priority.

The Effect of Racial Concordance on Patient Trust in Online Videos About Prostate Cancer

Black men have a higher risk of prostate cancer compared with White men, but Black adults are underrepresented in online content about prostate cancer. Across racial groups, the internet is a popular source of health information; Black adults are more likely to trust online health information, yet have more medical mistrust than White adults. To evaluate the association between racial representation in online content about prostate cancer and trust in the content and identify factors that influence trust. A randomized clinical trial was conducted from August 18, 2021, to January 7, 2022, consisting of a 1-time online survey. Participants included US men and women aged 40 years and older. Data were analyzed from January 2022 to June 2023. Participants were randomized to watch the same video script about either prostate cancer screening or clinical trials presented by 1 of 4 speakers: a Black physician, a Black patient, a White physician, or a White patient, followed by a questionnaire. The primary outcome was a published scale for trust in the information. χ2 tests and multivariable logistic regression were used to compare trust according to the video's speaker and topic. Among 2904 participants, 1801 (62%) were men, and the median (IQR) age was 59 (47-69) years. Among 1703 Black adults, a greater proportion had high trust in videos with Black speakers vs White speakers (72.7% vs 64.3%; adjusted odds ratio [aOR], 1.62; 95% CI, 1.28-2.05; P < .001); less trust with patient vs physician presenter (64.6% vs 72.5%; aOR, 0.63; 95% CI, 0.49-0.80; P < .001) and about clinical trials vs screening (66.3% vs 70.7%; aOR, 0.78; 95% CI, 0.62-0.99; P = .04). Among White adults, a lower proportion had high trust in videos featuring a patient vs physician (72.0% vs 78.6%; aOR, 0.71; 95% CI, 0.54-0.95; P = .02) and clinical trials vs screening (71.4% vs 79.1%; aOR, 0.57; 95% CI, 0.42-0.76; P < .001), but no difference for Black vs White presenters (76.8% vs 73.7%; aOR, 1.11; 95% CI, 0.83-1.48; P = .49). In this randomized clinical trial, prostate cancer information was considered more trustworthy when delivered by a physician, but racial concordance was significantly associated with trust only among Black adults. These results highlight the importance of physician participation and increasing racial diversity in public dissemination of health information and an ongoing need for public education about clinical trials. ClinicalTrials.gov Identifier: NCT05886751.

Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study

BackgroundInitial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration. ObjectiveTo present the final data from TRITON2. Design, setting, and participantsTRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy. Outcome measurements and statistical analysisThe primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint. Results and limitationsAs of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35–57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40–100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5–57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46–61%), 55% (23–83%), 3.4% (0.4–12), 6.7% (0.2–32%), 14% (0.4–58%), and 23% (5.0–54%), respectively. ConclusionsThe final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene. Patient summaryAlmost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations.

Abstract B058: Exploring the oncogenic role of six-transmembrane epithelial antigen of the prostate in the context of androgen receptor signaling

Abstract Prostate cancer is the second leading cause of death among American men, where pathogenesis is predominantly driven by dysregulation of the Androgen Receptor (AR). The current standard of care for metastatic disease includes a regime of androgen deprivation therapy (ADT) and AR antagonists, which increases survival to 24-48 months. Selective pressure of the therapy often leads to resurgence of AR activity resulting in castrate resistant disease, for which there are no curative treatment options. Moreover, once the disease has progressed to castrate resistance, AR directed therapies are no longer viable as a sole treatment option. Six-Transmembrane Epithelial Antigen of the Prostate 1-4 (STEAP) proteins are a family of ferric metalloreductases involved in maintaining iron homeostasis. STEAP expression is enriched in androgen sensitive and hormone refractory disease states, where increased expression correlates with high Gleason Score. STEAP proteins display greater intratumoral homogeneity at both primary and metastatic sites than the canonically used Prostate Specific Membrane Antigen (PSMA), indicating attractive diagnostic and therapeutic potential. Differential expression profiles have been observed among the STEAP family members depending on AR status in-vitro, suggesting a dependence on the AR signaling network. Previous literature indicates silencing of STEAPs in-vitro decreased cell viability and reduced proliferative, invasive, and migratory phenotypes; moreover in-vivo xenografts in which STEAPs are knocked down exhibited a significant reduction in tumor growth. Preliminary data suggests that treatment with Enzalutamide reduces the expression of STEAP proteins, implying a mechanistic link to the AR signaling axis. AMG509, a bispecific STEAP1-CD3 antibody, is the only STEAP directed therapeutic actively in clinical trials for prostate cancer (NCT04221542). There is limited mechanistic data regarding how STEAP directed therapies exert their anti-tumor function. Despite sharing similar architecture, localization, and biological implications, each STEAP protein retains unique functional roles within the cell. We plan to perform a systematic investigation on the oncogenic roles of individual STEAP protein in the context of AR dependent and independent prostate cancer models. In-vitro pharmacological AR manipulations will be used to evaluate changes in STEAP expression in multiple disease models. Genetic manipulations of STEAPs will be carried out under normal growth and ADT conditions to investigate the effects on growth, migration, oxidative stress, and cell cycle regulation. Given their principal role as ferric reductases, iron supplementation and iron drop-out will be examined in parallel. Novel treatment regimens will be explored using a combination of AR and STEAP directed therapeutics. Collectively, this study aims to uncover both the overlapping and distinct functions of STEAP proteins within the AR signaling axis and to illuminate their usefulness as a therapeutic target. Citation Format: Candice Bizzaro, Latese Evens, Moriah Cunningham, Jasibel Vasquez Gonzalez, Matthew Schiewer. Exploring the oncogenic role of six-transmembrane epithelial antigen of the prostate in the context of androgen receptor signaling [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 B058.

Abstract IA004: Metabolic mechanisms of prostate cancer progression that feed nuclear receptors

Abstract The androgen axis is central to prostate cancer physiology and therapy. Androgens are gonadal and extragonadal in origin, both of which stimulate the androgen receptor (AR). The use of medical castration (ADT), adrenal androgen ablation (i.e., abiraterone) and potent AR antagonists (i.e., enzalutamide, apalutamide, darolutamide), has yielded complex clinical states of prostate cancer, including disease states that are resistant to multiple forms of hormonal therapy. One of the major questions that arises is whether men can be identified who will benefit from earlier intensive hormonal therapy. Another question is whether alternative hormonal treatment strategies can be used to address resistance to the current generation of hormonal therapies. We propose that identification of steroid metabolic dependencies is part of the answer to both of these questions. Approximately half of men with prostate cancer inherit an activating missense in the first and rate-limiting enzyme that converts extragonadal precursor steroids to dihydrotestosterone (DHT). The “adrenal-permissive” HSD3B1(1245C) allele encodes for a 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) enzyme that increases tumor DHT synthesis from adrenal DHEA. Heterozygous or homozygous HSD3B1(1245C) inheritance confers poor outcomes after ADT. Furthermore, men with HSD3B1(1245C) inheritance and castration-resistant prostate cancer (CRPC) treated with abiraterone or enzalutamide still have poorer outcomes. Together, these data suggest that directly targeting this metabolic lesion is necessary for optimal therapy in these men. We recently discovered that phosphorylation of the 3βHSD1 tyrosine 344 by the BMX kinase is necessary for androgen biosynthesis and CRPC in xenograft models. These findings have led to the launch of the Maverick clinical trial in the Prostate Cancer Clinical Trials Consortium (PCCTC) that combines abiraterone plus BMX inhibition with abivertinib in men with CRPC. In sum, this accumulating body of evidence suggests that steroid metabolic dependencies should be considered as an essential part of cancer metabolism, particularly in the context of developmental therapeutics for prostate cancer. Citation Format: Nima Sharifi. Metabolic mechanisms of prostate cancer progression that feed nuclear receptors [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 IA004.

Using key stakeholder interviews to inform implementation of a cancer center collaborative intervention to improve clinical trial accruals.

e18650 Background: Cancer clinical trial (CT) participation rates in the US are low, especially among BIPOC populations. Patient enrollment to CTs is influenced by structural characteristics of the care delivery system, and the nature of individual needs and available resources. We are developing a multi-level intervention across 3 cancer centers in New York City by creating a collaborative pool of, and a referral system for breast, prostate, and liver cancer CTs to increase overall participation, particularly among BIPOC populations. To inform implementation of this intervention, we explored key stakeholder perceptions and attitudes around CT enrollment process across 3 hospitals within one such cancer center. Methods: We conducted semi-structured interviews with 23 key stakeholders to determine the attitudinal and structural factors affecting CT accrual at 1 cancer center and its 2 community hospital affiliates. Stakeholders included oncologists, nurses, informaticists, oncology leadership and research staff, identified using a targeted and snowball sampling approach. Guided by the Behavioral Model of Health Service Use, we identified themes related to enabling, predisposing, and need factors, and coded transcripts until theme saturation in Dedoose. Results: Key approaches to improve CT participation focused on these structural enabling themes: increased availability of CTs, personnel to screen and enroll patients, well-timed and technology-assisted clinician notification of a potential CT match (within or outside home institution), along with an institutional culture encouraging stakeholder engagement, provider outreach, and care coordination. Important predisposing and enabling themes related to stakeholders’ beliefs about patients included: financial access, knowledge and perceptions about CTs, language barriers, motivation, and medical mistrust. Knowledge about open trials, and skepticism or enthusiasm about CTs were important predisposing themes related to clinicians. Need theme affecting implementation was clinician judgment about their patients’ eligibility for CT evaluated based on functional status, comorbidities, age, advanced cancer stage, progression of disease, change in therapy, and drug targets. Conclusions: We identified actionable enabling, predisposing, and need factors that serve as barriers to CT accrual and to successful implementation of our intervention. Major findings were structural and attitudinal, including lack of staffing resources for clinicians, and financial assistance and access for patients. Updated information about open CTs, implementation of e-screening tools for patient enrollment, addressing clinician skepticism for enrollment by increased recognition for their research efforts, as well as delivery of culturally sensitive patient education around CTs may improve CT enrollment.