Castration Resistance Research Articles

Abstract 7286: Optimizing prediction of metastatic castration-resistant prostate cancer: Multimodal fusion of clinicopathological and genomic features with machine learning

Abstract Background: Transitioning from metastatic castration-sensitive prostate cancer (mCSPC) to its resistant variant poses risks of intensified medication, toxic side effects, and financial burdens for men undergoing treatment. Our study proposes a multimodal approach that integrates clinical, pathological, and genomic features to optimize prediction of metastatic castration-resistant prostate cancer (mCRPC) events. By applying machine learning (MML) techniques to multimodal data, we aim to stratify these patients based on the risk of developing mCRPC, contributing to the development of safer and personalized treatment strategies. Methods: We analyzed a large cohort of patients with mCSPC (n=399) with a minimum of 36 month follow-up, annotated with clinical, pathological, and genomic features, encompassing relevant variables such as disease volume, PSA, metastases timing, variant classification, Grade Group, fraction of genome altered, MSI score, mutation counts, karyotypes, tumor mutational burden, and purity. Using a multimodal machine learning framework, we extracted informative features and employed eight distinct machine learning algorithms: K-Nearest Neighbor, Support Vector Machine, Decision Tree, and Logistic Regression, Support Vector Machine with RBF Kernel, Random Forest, and Gradient Boosting, in addition to a Deep Neural Networks architecture for building predictive models in supervised binary classification experiments. The models' performance was evaluated on separate training (80%) and testing sets (20%), and standard evaluation metrics, such as the area under the receiver operating characteristic curve (AUROC), and accuracy, were computed. Correlations were utilized to explore the relationships between features, and permutation analysis was employed to determine the importance of predictors. All raw data included in the analysis are available on cBioPortal database. The study is supported by the NIH-NCI-T32 for Next Generation Pathologists Program at our institution. Results: Of the 399 mCSPC patients, 56% developed castration resistance, 50% had Grade Group 5 disease, and 69% exhibited missense mutations. In a series of 8 experiments, the Support Vector Machine with RBF Kernel ensemble model and SVC exhibited the highest performance with an AUROC score of 0.77, while the remaining models tested in the study demonstrated AUROC scores ranging from 0.62 to 0.75. Notably, the fraction of altered genome emerged as the top-ranked predictor, displaying the highest importance score. Conclusions: Our study demonstrates the strong predictive performance of MML models in accurately identifying mCRPC events by leveraging routine clinical, pathological, and genomic data, offering valuable guidance for optimizing patient stratification and tailoring personalized therapeutic interventions. Citation Format: Mohammad K. Alexanderani, Francesca Khani, Matthew Greenblatt, Brian Robinson, Massimo Loda, Luigi Marchionni. Optimizing prediction of metastatic castration-resistant prostate cancer: Multimodal fusion of clinicopathological and genomic features with machine learning [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 7286.

Abstract 3297: Discovery and evaluation of GT19870, a GSPT1/Myc molecular glue drug (MGD) with oral bioavailability for targeting c-Myc and n-Myc-addictive blood cancer and solid tumors

Abstract c-Myc and n-Myc are oncogenic transcriptional factors driving tumor initiation, progression and poor prognosis in a variety of blood cancers and solid tumors, such as acute myeloid leukemia (AML), B-cell malignancies, castration resistance prostate cancer (mCRPC), small cell lung cancer and (SCLC) and neuroblastoma. Both c-Myc and n-Myc dysregulations have been directly linked to the poor clinical outcome in some of these cancers which are addictive to deregulated Myc proteins. Therefore, it is highly warranted to discover and develop novel therapeutical agents for targeting Myc-addictive cancers. GT19870 was discovered through a SAR effort for Myc degradation with improved bioavailability (F % 92.52) from GT19630, a GSPT1/Myc degrader series 1-4by using phenotypic screenings with c-Myc-addictive HL-60 AML cells and growth factor-dependent hematopoiesis progenitor TF-1 cells, followed by c-Myc ELISA and Western blot assays. GT19870 selectively inhibited the proliferation of HL60 cells with an IC50 of 2.6 nM as compared to an IC50 of 70.03 nM (26.5-fold selectivity) and effectively degraded c-Myc protein with an IC50 of 2.54 nM and IC90 <10 nM in HL-60 cells, as compared to an IC90>30 nM in CD3/CD28-stimulated PBMC assays. GT19870, as a MGD, was confirmed to selectively degrade GSPT1, a neo-substrate, by proteomic and Western Blot assays. Further, GT19870 was tested in SCLC, triple negative breast cancer (TNBC) and brain cancer cell panels, in which GT1987 was revealed potent anti-proliferation activities with an IC50<50 nM in 9 of 19 SCLC, 8 of 13 TNBC, and 7 of 24 brain cancer cell lines tested. Importantly GT19870 was also shown potent antitumor activities with IC50 of ≦5.4 nM in 8 of 8 SCLC patient derived organoids. Furthermore, GT19870 (salt form-GT19884) was demonstrated to induce target-engaged (c-Myc and n-Myc) tumor regression in AML, SCLC, mCRPC and neuroblastoma xenograft and PDX models with in a dose ranges of 3-12 mpk/qd/po. In brief, GT19870 is an oral MGD degrading GSPT1/c-Myc/n-Myc. This novel MGD has been demonstrated target-engaged antitumor activities in vitro and in vivo with selectivity of c-Myc degradation in c-Myc-addictive cancer cells as compared to growth factor-stimulated TF-1 cells and CD3/CD28 activated PBMC. GT19870 has been progressing IND enabling stage.

Metastases-directed radiotherapy in castration resistant oligo metastatic prostate cancer: A multicentric retrospective study from the French group COLib

Oligometastases aredefined as a number of detectable metastases less or equal to 5. In castrate-resistant oligo metastatic prostate Cancer (CR oligoM PC), Metastases-Directed Ablative radiotherapy (MDRT) is poorly investigated. Our study retrospectively reviewed the cases of CR oligoM PC treated with MDRT in 8 French high-volume radiotherapy centers.OS and PFS are defined as the delay between the first day of MDRT and death (OS) or progression according to PCWG criteria (PFS). OS and PFS are evaluated according to Kaplan Meyer, curves are compared with log rank test. Logistic regression was used to identify predictive factors for outcome: bone versus node metastasis, ISUP grade, PSA doubling Time (PSADT) at the time of MDRT, time to castration resistance.107 patients were included in the study, among those 197 metastases received MDRT. For the overall population, the median follow-up was 25.2 months (1,4–145). OS was 93 % at 2 years and 81,4% at 3 years. At 2 years, 100 % of patients with node-only metastasis were alive versus 88,7% among those who have bone metastases (p = 0,72). The median PFS was 12,6 months (IC 95 % [9,6; 17]), with no difference among patients with node only disease versus the rest of the cohort.The PFS was 18,2 months (10,0; 32,4) in patients with PSADT >6 months versus 10,7 months (8,9; 14,3) when PSADT was inferior to 6 months. However, this difference did not reach significant.We did not find a correlation neither between ISUP grade (1–2 versus 3–4-5) and PFS, nor between hormone-sensitivity duration and PFS.Patients receiving MDRT for CR oligoM PC have a good prognosis with 81,6% OS at 3 years. PSA DT longer than 6 months could be related to better PFS. MDRT strategy could postpone the onset of new systemic treatment with median PFS >1 year.

Microbiome Dysbiosis Is Associated with Castration Resistance and Cancer Stemness in Metastatic Prostate Cancer.

Prostate cancer is the second leading cause of death in males in America, with advanced prostate cancers exhibiting a 5-year survival rate of only 32%. Castration resistance often develops during the course of treatment, but its pathogenesis is poorly understood. This study explores the human microbiome for its implications in castration resistance and metastasis in prostate cancer. RNA sequencing data were downloaded for the bone and soft tissue biopsies of patients with metastatic castration-resistant prostate cancer. These included both metastatic and adjacent normal biopsies. These sequences were mapped to bacterial sequences, yielding species-level counts. A vast majority of species were found to be significantly underabundant in the CRPC samples. Of these, numerous were found to correlate with the expression of known markers of castration resistance, including AR, PI3K, and AKT. Castration resistance-associated signaling pathways were also enriched with these species, including PI3K-AKT signaling and endocrine resistance. For their implications in cancer aggression and metastasis, cancer stem cell markers were further explored for a relation to these species. EGFR and SLC3A2 were widely downregulated, with a greater abundance of most species. Our results suggest that the microbiome is heavily associated with castration resistance and stemness in prostate cancer. By considering the microbiome's importance in these factors, we may better understand the highly aggressive and highly invasive nature of castration-resistant prostate cancer, allowing for the needed improvements in the treatment of this disease.

Characterizing the real-world economic burden of metastatic castration-sensitive prostate cancer in the United States

Aims To describe healthcare resource utilization (HRU) and costs of patients with metastatic castration-sensitive prostate cancer (mCSPC). Methods Linked data from Flatiron Metastatic PC Core Registry and Komodo’s Healthcare Map were evaluated (01/2016-12/2021). Patients with chart-confirmed diagnoses for metastatic PC without confirmed castration resistance in Flatiron who initiated androgen deprivation therapy (ADT) monotherapy or advanced therapy for mCSPC in 2017 or later (index date) with a corresponding pharmacy or medical claim in Komodo Health were included. Advanced therapies considered were androgen-receptor signaling inhibitors, chemotherapies, estrogens, immunotherapies, poly ADP-ribose polymerase inhibitors, and radiopharmaceuticals. Patients with <12 months of continuous insurance eligibility before index were excluded. Per-patient-per-month (PPPM) all-cause and PC-related HRU and costs (medical and pharmacy; from a payer’s perspective in 2022 $USD) were described in the 12-month baseline period and follow-up period (from the index date to castration resistance, end of continuous insurance eligibility, end of data availability, or death). Results Of 871 patients included (mean age: 70.6 years), 52% initiated ADT monotherapy as their index treatment without documented advanced therapy use. During baseline, 31% of patients had a PC-related inpatient admission and 94% had a PC-related outpatient visit; mean all-cause costs were $2551 PPPM and PC-related costs were $839 PPPM with $787 PPPM attributable to medical costs. Patients had a mean follow-up of 15 months, during which 38% had a PC-related inpatient admission and 98% had a PC-related outpatient visit; mean all-cause costs were $5950 PPPM with PC-related total costs of $4363 PPPM, including medical costs of $2012 PPPM. Limitations All analyses were descriptive; statistical testing was not performed. Treatment effectiveness and clinical outcomes were not assessed. Conclusion This real-world study demonstrated a significant economic burden in mCSPC patients, and a propensity to use ADT monotherapy in clinical practice despite the availability and guideline recommendations of advanced life-prolonging therapies.

Lower baseline testosterone level is related to earlier development of castration resistance in metastatic prostate cancer: a multi-center cohort study.

In the era of concurrent combination therapy in metastatic hormone sensitive prostate cancer, the impact of the testosterone level before initiating androgen deprivation therapy on treatment outcome is still uncertain. We aimed to investigate its effect on time-to-castration-resistance in a metastatic hormone sensitive prostate cancer cohort. This is a multi-center retrospective study of 5 databases from China, Japan, Austria and Spain including 258 metastatic hormone sensitive prostate cancer patients with androgen deprivation therapy initiated between 2002 and 2021. Baseline testosterone was divided into high and low groups using 12 nmol/L as cutoff level. Primary outcome was time-to-castration-resistance. Secondary outcomes were survival functions. Kaplan-Meier method was employed to evaluate the correlation between baseline testosterone and time-to-castration-resistance. Subgroup analysis was performed to elucidate the effect of upfront combination-therapy and metastatic volume. Median age was 72 years. Median follow-up time was 31 months. Median pre-treatment prostate-specific-antigen level was 161 ng/mL. Majority of case were graded as International-Society-of-Urological-Pathology grade 5 (63.6%). 57.8% patients had high volume disease and 69.0% received upfront combination treatment. 44.6% of the cohort developed castration-resistance. The low testosterone group demonstrated shorter mean-time-to-castration-resistance (19.0 vs 22.4 months, p=0.031). The variance was more significant in patients without combination therapy (13.2 vs 26.3 months, p=0.015). Cancer-specific and overall survival were inferior in the low baseline testosterone level group without receiving combination therapy (p=0.001). Lower pre-treatment testosterone level is correlated to shorter time-to-castration resistance and worse survival in metastatic prostate cancer patients without upfront combination therapy. Those with low baseline testosterone should be encouraged to adopt combination therapy to delay progression.

Comparison of molecular analysis results determined by next-generation sequencing to immunohistochemical indicators and clinicopathological parameters in prostate adenocarcinomas.

Prostate cancer is a common cancer in males, frequently leading to mortality. Multiple genetic factors play roles in prostate cancer pathogenesis. Demonstration of pathological pathways and customised treatment options have been possible with next-generation sequencing. In this study, we aimed to evaluate the relationships of the changes in the prostate cancer pathways genes with the pathological, immunohistochemical and the clinical parameters. Retrospective cross-sectional study. Among the prostate needle biopsy materials investigated in Adnan Menderes University Faculty of Medicine, Department of Pathology, thirty-one cases, who had been analysed using the next-generation sequencing system, were included in this study. As a result of statistical analysis, a significant relationship was found between the pathogenic mutation detected in androgen receptor and Breast Cancer Gene 2 genes and tumour volume. In all cases with a pathogenic mutation in the androgen receptor gene, a pathogenic mutation in the Protein Tyrosine Phosphatase and Tensin Homolog gene was also observed and a significant relationship was found between them. Castration resistance was observed in cases with high tumour volume, and a statistically significant difference was found. A statistically significant relationship was found between tumour volume and Ki-67 expression. In addition, a significant relationship was observed between the castration resistance and Ki-67, c-erbB2 expressions. A statistically significant relationship was found between Ki-67 and c-erbB2. Regarding prognosis prediction and treatment, identifying the molecular changes in genes playing roles in prostate cancer with next-generation sequencing is very important.

How the Management of Biochemical Recurrence in Prostate Cancer Will Be Modified by the Concept of Anticipation and Incrementation of Therapy.

Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification into low- and high-risk cases for early progression in metastatic disease is necessary. At present, PSA-DT represents the best parameter to define low- and high-risk BCR PC, but real precision medicine is strongly suggested to define tailored management for patients with BCR. Before defining management, it is necessary to exclude the presence of low-volume metastasis associated with PSA progression using new-generation imaging, preferably with PSMA PET/CT. Low-risk BCR cases should be actively observed without early systemic therapies. Early treatment of low-risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such as the development of castration resistance before the appearance of metastases (non-metastatic castration-resistant PC). Patients with high-risk BCR benefit from early systemic therapy. Even with overall survival (OS) as the primary treatment endpoint, metastasis-free survival (MFS) should be used as a surrogate endpoint in clinical trials, especially in long survival stages of the disease. The EMBARK study has greatly influenced the management of high-risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy. In high-risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining an unchanged quality of life in the asymptomatic phase of the disease. The possibility of using ARSIs alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than with the intensification of the combination therapy. Continued use versus discontinuation of enzalutamide plus leuprolide intensified therapy upon reaching undetectable PSA levels needs to be better defined with further analysis. Real-world analysis must verify the significant results obtained in the context of a phase 3 study.

Remission Depth in Metastatic Hormone-Sensitive Prostate Cancer Is Associated With Prognosis in Patients With Initial Prostate-Specific Antigen Values Above 100 Ng/ML.

Recently, new drugs have caused a paradigm shift in the treatment of metastatic hormone-sensitive prostate cancer (HSPC). Meanwhile, research has identified several prognostic factors of metastatic HSPC. The present study focused on remission depth in metastatic HSPC and evaluated its association with remission depth. We analyzed 427 patients diagnosed with metastatic HSPC with serum initial prostate-specific antigen (PSA) > 100 ng/ml. The nadir serum PSA value was used as a marker of remission depth for each duration to castration resistanceby using receiver operating characteristic (ROC) curves.Cox proportional hazards regression was used to assess for any correlation of progression-free survival (PFS) and overall survival (OS) with the nadir PSA level. The cut-off value for the nadir PSA level per time to castration resistance (TTCR) at three, five, seven, and nine years was calculated. The nadir PSA value alone was able to predict prognosis because of its high sensitivity, high specificity, and high AUC in ROC analysis. The nadir PSA level can be an independent prognostic marker not only for TTCR but also for OS on multivariate analysis. We identified the cut-off value for nadir PSA per TTCR period in patients with metastatic HSPC. The nadir PSA value alone can predict prognosis; this demonstrates utility in routine clinical practice due to its simplicity and accuracy.

The impact of SPOP gene alterations in men with metastatic prostate cancer: Results from the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) consortium.

225 Background: Inactivating mutations in the SPOP gene, encoding speckled-type poxvirus and zinc-finger protein, are common among men with localized and metastatic prostate cancer, occurring at a frequency of 6-15%. Previous studies have suggested the presence of an inactivating mutation in SPOP results in increased sensitivity to androgen deprivation therapy (ADT). In this multi-institutional clinical-genomic database, we evaluated the impact of SPOP alterations on survival outcomes in men with metastatic prostate cancer. Methods: Retrospective data from the PROMISE Consortium were utilized for this analysis. Eligible patients had metastatic prostate cancer and had undergone standard of care next-generation sequencing (NGS). Patients with inactivating mutations in SPOP were defined as SPOP mutated, where. as those lacking such alterations were defined as SPOP wild-type. The primary endpoint was overall survival defined as the time from diagnosis of metastatic prostate cancer to death from any cause, censored at the date of last follow-up. Secondary endpoints included time from metastatic disease to castration resistance and time from castration resistance to death. Results: Of the 2097 patients with available NGS testing, 5.5% (n=115) had SPOP alterations. The median age at diagnosis was 63 years, 427 were Black, and 83 were Hispanic. At last assessment, 66% had bone metastases, 7% lung metastases, and 5% liver metastases. The most frequent co-occurring alterations in the SPOP-mutated group were: TP53 (30.4%), APC (25.2%), and AR (21.7%). 1832 patients were included in the survival analysis [n=96 (5.2%) with and n=1736 (94.8%) without SPOP alterations]. Median overall survival was numerically longer, though not statistically significant, in the SPOP-mutated compared SPOP-wild-type group (75.9 versus 59.5 months, p=0.12). In patients with metastatic disease, median time to castration resistance was 14.6 months in the SPOP-mutated group versus 12.2 months in the SPOP-wild-type group (p=0.30). Median time from metastatic castration resistant to death was 45.0 months in the SPOP-mutated group and 40.2 months in the SPOP-wild type group. Conclusions: Our hypothesis generating data support that SPOP-mutated prostate cancer likely represents a unique molecular subtype of prostate cancer that may confer prolonged survival. Future studies of novel androgen-receptor targeting treatments should be tested in this molecular population.

Latin American Challenges and Recommendations for Poly Adenosine Diphosphate Ribose Polymerase Inhibitor Treatment in Metastatic Castration Resistant Prostate Cancer: An Expert Overview.

In Latin America, prostate cancer is the third most common cancer overall and the most common in men, with the highest mortality rate of all cancers. In 2022, there were approximately 22,985 new prostate cancer cases and 61,056 deaths from prostate cancer in the region. Patients with metastatic disease that is resistant to cure by castration now have multiple therapeutic options, including poly-ADP ribose polymerase inhibitors. These treatment advances present new challenges, such as developing monitoring protocols for early detection of disease progression to castration resistance. The Americas Health Foundation organized a 3-day meeting with 8 regional oncologists and pathologists to create a paper on metastatic castration-resistant prostate cancer diagnosis and therapy, including the new poly-ADP ribose polymerase inhibitors. The panel examined metastatic castration-resistant prostate cancer in Latin America and recommended ways to improve patient care using published literature and their expertise. Gene mutations play an important role in prostate cancer development. Precision medicine innovations highlight the importance of genotyping DNA variants and tumor biomarkers for targeted treatment. Access to appropriate genetic testing is difficult, medications are available but expensive, and there is a lack of infrastructure and regulatory frameworks that prevent patients from benefiting from innovative therapies. The panel recommends developing a population database and biobank and creating tumor tissue collection, processing, and storage facilities. Multi-stakeholder collaboration is needed to integrate the information gathered, train staff, select target populations, improve patient accessibility, and reduce the cost burden of drugs, genetic counselors, and cancer geneticists in Latin America. Collaboration is essential among healthcare professionals, policymakers, patient advocacy groups, pharmaceutical companies, and international organizations to address these challenges and needs in Latin America.

Real-world survival of men with metastatic castration-sensitive prostate cancer (mCSPC) initiated on apalutamide (APA) or enzalutamide (ENZ) in an oncology database: ROME Study.

57 Background: Androgen receptor signaling inhibitors (ARSIs), including APA and ENZ, have demonstrated progression-free and overall survival benefits for men with mCSPC in the clinical trial setting, but data evaluating real-world treatment effectiveness remains limited. The aim of this study was to describe real-world survival among men with mCSPC who initiated APA or ENZ in the United States (US). Methods: In this retrospective longitudinal cohort study, clinical data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry Electronic DataMart (1/1/2013–05/31/2023) were used. Patients with chart-confirmed metastasis and without castration resistance were classified into two treatment cohorts based on earliest initiation of APA or ENZ on/after 12/16/2019 (index date). Patients had ≥12 months of clinical data pre-index and were followed from the index date until the earliest of 24 months post-index, end of clinical activity, or end of data availability. Patients’ date of death was obtained from electronic medical records, Social Security Death Index, or other confirmed sources. Using an intention-to-treat approach, Kaplan-Meier analysis was used to describe the proportion of patients surviving by 24 months post-index. An unadjusted Cox proportional hazards model was used to describe crude differences in survival rates between patients initiating APA and ENZ. Results: There were 234 APA (mean age: 73.2 years; 59.8% White, 13.7% Black) and 527 ENZ (mean age: 73.9 years; 55.2% White, 13.1% Black) patients included in this study (Table). APA median time on-treatment was 10.9 months over a median observation period of 13.3 months, while ENZ median time on-treatment was 11.1 months over a median 14.8 months observation period. By 24 months, a higher proportion of patients in the APA cohort survived than in the ENZ cohort (85.4% vs 73.9%; unadjusted hazard ratio=0.59, 95% confidence interval: 0.39, 0.95; p=0.030; Table). Conclusions: In this real-world analysis of patients with mCSPC, more patients treated with APA survived by 24 months following treatment initiation as compared to treatment with ENZ. While the current study reports unadjusted analyses, future studies adjusting for potential confounding variables should be conducted to confirm these findings in order to inform clinicians on treatment selection for patients with mCSPC. [Table: see text]

Survival Outcomes of APA as a Starting treatment: Impact in real-world patients with mCSPC (OASIS).

65 Background: Over the last decade,androgen receptor signaling inhibitors (ARSIs; apalutamide [APA], enzalutamide [ENZ], abiraterone acetate + prednisone [AAP]) in combination with androgen-deprivation therapy (ADT) have emerged as more effective life-prolonging treatment options for mCSPC. We examined the impact of ARSI starting therapy in mCSPC on long-term clinical outcomes in real-world clinical practice in the US. Methods: This retrospective, observational cohort study evaluated clinical outcomes in adult patients with mCSPC using the ConcertAI RWD 360 prostate cancer dataset. All patients with newly diagnosed mCSPC from 1 Jan 2018 to 30 Sept 2022 were enrolled and followed up until 31 Mar 2023. Among other outcomes, PSA50 and PSA90 (PSA response defined as a ≥50% and ≥90% decline from baseline, respectively) and undetectable PSA (PSA ≤0.2 ng/mL) were assessed using the Kaplan-Meier method. Relative risks of onset of castration resistance (CR) and death were estimated using multivariate Cox proportional hazard models adjusted for potential confounding factors (age, comorbidities, BMI, baseline PSA). Results: 165 patients with mCSPC started on APA + ADT, 643 started on ENZ + ADT, 1064 on AAP +ADT, 293 on docetaxel (DTX) + ADT, and 543 on ADT alone (Table). A higher proportion of patients initiating APA achieved PSA50, PSA90, or undetectable PSA compared with other treatments. CR-free survival was significantly longer in patients first treated with an ARSI + ADT than those treated with DTX + ADT or ADT alone. Reduced risk of developing CR was observed in patients starting with APA + ADT compared with ADT alone (adjusted hazard ratio [aHR] 0.36, 95% CI 0.19, 0.67; p=0.0016). OS was longer in patients started on ARSIs compared to ADT alone. Patients starting with APA + ADT were observed to have a lower risk of death compared with ENZ + ADT (aHR 0.48, 95% CI 0.23, 0.99; p&lt;0.05) or AAP + ADT (aHR 0.43, 95% CI 0.21, 0.90; p&lt;0.05). Conclusions: ADT alone continues to be used widely despite the availability of newer and more effective life prolonging therapies. Use of APA + ADT as starting treatment for mCSPC demonstrated significantly better clinical outcomes than other ARSIs, DXT + ADT, or ADT alone in real-world clinical practice in the US. [Table: see text]

Financial toxicity from PARP inhibitors in castrate-resistant prostate cancer.

54 Background: Approximately 5-10% of men with prostate cancer (PC) are eligible for treatment with PARP inhibitors. As an estimated 120,000 men living in the US have metastatic PC, between 6,000-12,000 men may be eligible for treatment with PARP inhibitors. Recently, several PARP inhibitors have been approved as single or combination therapies in the first-line castrate-resistant (CR) setting and later-line setting including: olaparib, olaparib plus abiraterone (AAP), and talazoparib plus enzalutamide. It is unclear if these newly approved therapies may be cost prohibitive for patients and/or health care systems. Methods: Using average sale price data from UpToDate for PARP inhibitors and novel hormone therapies (NHTs), we calculated the total cost of treatment for each single or combination therapy regimen. We used phase II/III clinical trial data to determine the median duration of treatment for each regimen. Results: The three approved PARP inhibitors have total costs in descending order as follows: AAP plus olaparib ($689,813.77), talazoparib plus enzalutamide ($388,390.46), and olaparib ($202,845.22). In comparison, in the PROfound trial, the cost of AAP alone was $192,140.37 and in the TALAPRO-2 trial, the cost of enzalutamide alone was $ 253,780.80. The difference in estimated cost between olaparib plus AAP versus talazoparib plus enzalutamide per patient is $37,970.29. Conclusions: Despite several new approved therapies in BRCA mutated and HRR mutated mPC, the total costs for PARP inhibitors remain prohibitive for health care institutions. The estimated difference between two newly approved PARP plus NHT regimens could translate in a difference of $455,643,480 in healthcare system costs if all eligible U.S. men received treatment with olaparib plus AAP over talazoparib plus enzalutamide. [Table: see text]

11-Ketotestosterone and time to castration resistance in patients with recurrent non-metastatic prostate cancer receiving androgen deprivation therapy.

209 Background: The contribution of 11-oxygenated androgens to disease progression in men receiving androgen deprivation therapy (ADT) for recurrent non-metastatic prostate cancer (PCa) remains unresolved. We hypothesized that evaluating circulating levels of 11-oxygenated androgens, such as the potent androgen receptor (AR) agonist 11-ketotestosterone (11KT), could serve as a potential predictor for the onset of castration resistance (CRPC). Methods: The multi-institutional prospective PROCURE cohort involves 2,026 patients who underwent radical prostatectomy for localized PCa. In this cohort, a subset of 145 patients who received ADT therapy for recurrent disease and had available plasma samples post-surgery were included in this study. The effect of therapy on steroid levels was assessed in paired samples obtained before and after the initiation of ADT (n=50), and samples from patients under combined ADT with AR pathway inhibitors, enzalutamide (n=10) and abiraterone (n =15). 11-oxygenated androgens (n=7) and canonical steroids, such as testosterone (T) and dihydrotestosterone (DHT), were quantified by mass spectrometry. Kaplan-Meier survival analyses were used to investigate relationships of androgen levels with the occurrence of CRPC. Results: 11-oxygenated androgens remained unaffected by ADT, which stands in contrast to the observed changes in T, DHT and other steroids. In men with castrated T levels, 11KT was the most abundant androgen. Elevated 11KT was associated with a sooner time to CRPC ( P=0.023). The 10-year CRPC event-free rate was 63% vs. 84% for 11KT levels above and below the median, respectively. The initiation of enzalutamide had no impact on 11-oxygenated androgen levels, whereas abiraterone significantly reduced 11KT levels owing to the adrenal origin of its precursor. Conclusions: Our findings indicate that 11KT is a significant component of the hormonal profile predictive of an earlier onset of CRPC and inhibition of its production by the CYP17A1 inhibitor abiraterone.

Analysis of real-world survival for patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or abiraterone acetate (ABI) in an oncology database: ROMA study.

58 Background: Androgen receptor signaling inhibitors (ARSI), including APA and ABI plus prednisone, are approved for the treatment of mCSPC. However, studies evaluating survival for these agents in clinical trials or the real-world have not been investigated. This study describes real-world survival among men with mCSPC who initiated APA or ABI in the United States (US). Methods: Data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry Electronic DataMart (1/1/2013–05/31/2023) was used to identify ARSI-naïve patients with chart-confirmed metastasis and without evidence of castration resistance at ARSI initiation. Patients were classified into two treatment cohorts based on the start date for APA or ABI (index date) on/after 9/17/2019. Patients had ≥12 months of clinical data pre-index and were followed from the index date until the earliest of 24 months post-index, end of clinical activity, or end of data availability. Patients’ date of death was obtained by integrating data from electronic medical records, the Social Security Death Index, and or other confirmed sources. Using an intention-to-treat approach, Kaplan-Meier analysis was used to describe the proportion of patients surviving by 24 months post-index. An unadjusted Cox proportional hazards model was used to describe crude differences in survival rates between patients initiating APA and ABI. Results: This study included 242 APA (mean age: 73.0 years; 60.3% White, 13.6% Black) and 607 ABI (mean age: 73.1 years; 57.3% White, 16.8% Black) patients. APA median time on-treatment was 11.4 months over a median observation period of 14.3 months. ABI median time on-treatment was 10.8 months over a median observation of 14.0 months. By 24 months, 85.7% of the APA cohort and 75.9% of the ABI cohort were living (unadjusted hazard ratio=0.60, 95% confidence interval: 0.38, 0.96; p=0.033; Table). Conclusions: In this study, we observed that more ARSI-naïve patients with mCSPC survived by 24 months after initiating APA than those who initiated ABI. While the current study presents unadjusted comparisons, additional causal analyses controlling for confounding variables should be conducted to confirm these initial findings. [Table: see text]

Real-world economic burden of patients with metastatic castration-sensitive prostate cancer (mCSPC).

64 Background: In patients with prostate cancer (PC), progression to a metastatic disease stage is associated with substantial decline in prognosis as well as incremental economic burden. There is limited real-world evidence combining clinical data and payer claims to evaluate economic outcomes of patients with mCSPC. This study described healthcare costs of patients with mCSPC before and after the initiation of advanced therapy. Methods: Linked data from the Flatiron Metastatic PC Core Registry and all-payer claims data from Komodo Health Solutions were evaluated (Jan 2016 to Dec 2021). Patients in Flatiron who initiated advanced therapy for mCSPC (index date) in 2017 or later and had a corresponding pharmacy or medical claim in Komodo, following evidence of metastasis in the absence of castration resistance were included. Advanced therapies considered were androgen-receptor signaling inhibitors, chemotherapies, estrogens, immunotherapies, poly ADP-ribose polymerase inhibitors, and radiopharmaceuticals. Patients were excluded if they initiated a clinical trial drug as their index regimen or had &lt;12 months of health insurance eligibility pre-index. All-cause and PC-related total costs (medical and pharmacy) per-patient-per-month (PPPM) were described from a payer’s perspective in the 12-month pre- and post-index period using 2022 US dollars. The post-index period was censored at evidence of castration resistance. Flatiron Health, Inc. did not participate in data analyses. Results: In total, 418 patients with mCSPC were identified (mean age 68 years, 56% white, 53% commercially insured, and 37% on Medicare). Pre-index androgen deprivation therapy was observed in 74% of patients. Pre-index, mean all-cause costs were $2,334 PPPM and PC-related costs were $964 PPPM with $90 PPPM attributable to PC-related pharmacy costs (Table). Post-index, patients averaged 14.5 months of follow-up, in which mean all-cause costs were $8,829 PPPM with PC-related costs of $7,232 PPPM, an increase of &gt;7 times compared to pre-mCSPC therapy initiation. Conclusions: This real-world study demonstrated that costs associated with disease progression in PC are significant and lead to a need for more innovative therapies and medical management in this patient population. Approaches that effectively slow disease progression at earlier stages of PC disease may result in better overall outcomes and lower overall costs associated with progression to metastatic disease. [Table: see text]

Bone Turnover Markers, n-Terminal Propeptide of Type I Procollagen and Tartrate-Resistant Acid Phosphatase Type 5b, for Predicting Castration Resistance in Prostate Cancer.

Bone is a common site of prostate cancer metastasis. Bone turnover markers n-terminal propeptide of type I procollagen (P1NP) and tartrate-resistant acid phosphatase type 5b (TRACP-5b) are highly sensitive to bone remodeling activity. However, their prognostic significance as markers of prostate cancer is unknown. This study retrospectively examined the usefulness of P1NP and TRACP-5b as prognostic biomarkers. Castration-resistant prostate cancer recurrence-free survival (CFS) was estimated using the Kaplan-Meier method. A predictive model for CFS was constructed using multivariate analysis. This study enrolled 255 patients diagnosed with prostate cancer at Kanazawa University Hospital. The median follow-up was 115.1 months. Patients with both high serum P1NP and TRACP-5b levels, defined as having a poor bone turnover category (BTC), had significantly shorter CFS. Multivariate analysis identified Gleason score, metastasis, and BTC poor as predictors for castration resistance in prostate cancer. Using these three factors, a prognostic model was established, categorizing patients into low-risk (no or one factor) and high-risk (two or three factors) groups. In the low-risk group, the median CFS was not reached, contrasting with 19.1 months in the high-risk group (hazard ratio, 32.23, p < 0.001). Combining P1NP and TRACP-5b may better predict castration resistance.

Integrating single-cell and bulk RNA sequencing data unveils antigen presentation and process-related CAFS and establishes a predictive signature in prostate cancer

BackgroundCancer-associated fibroblasts (CAFs) are heterogeneous and can influence the progression of prostate cancer in multiple ways; however, their capacity to present and process antigens in PRAD has not been investigated. In this study, antigen presentation and process-related CAFs (APPCAFs) were identified using bioinformatics, and the clinical implications of APPCAF-related signatures in PRAD were investigated.MethodsSMART technology was used to sequence the transcriptome of primary CAFs isolated from patients undergoing different treatments. Differential expression gene (DEG) screening was conducted. A CD4 + T-cell early activation assay was used to assess the activation degree of CD4 + T cells. The datasets of PRAD were obtained from The Cancer Genome Atlas (TCGA) database and NCBI Gene Expression Omnibus (GEO), and the list of 431 antigen presentation and process-related genes was obtained from the InnateDB database. Subsequently, APP-related CAFs were identified by nonnegative matrix factorization (NMF) based on a single-cell seq (scRNA) matrix. GSVA functional enrichment analyses were performed to depict the biological functions. A risk signature based on APPCAF-related genes (APPCAFRS) was developed by least absolute shrinkage and selection operator (LASSO) regression analysis, and the independence of the risk score as a prognostic factor was evaluated by univariate and multivariate Cox regression analyses. Furthermore, a biochemical recurrence-free survival (BCRFS)-related nomogram was established, and immune-related characteristics were assessed using the ssGSEA function. The immune treatment response in PRAD was further analyzed by the Tumor Immune Dysfunction and Exclusion (TIDE) tool. The expression levels of hub genes in APPCAFRS were verified in cell models.ResultsThere were 134 upregulated and 147 downregulated genes, totaling 281 differentially expressed genes among the primary CAFs. The functions and pathways of 147 downregulated DEGs were significantly enriched in antigen processing and presentation processes, MHC class II protein complex and transport vesicle, MHC class II protein complex binding, and intestinal immune network for IgA production. Androgen withdrawal diminished the activation effect of CAFs on T cells. NMF clustering of CAFs was performed by APPRGs, and pseudotime analysis yielded the antigen presentation and process-related CAF subtype CTSK + MRC2 + CAF-C1. CTSK + MRC2 + CAF-C1 cells exhibited ligand‒receptor connections with epithelial cells and T cells. Additionally, we found a strong association between CTSK + MRC2 + CAF-C1 cells and inflammatory CAFs. Through differential gene expression analysis of the CTSK + MRC2 + CAF-C1 and NoneAPP-CAF-C2 subgroups, 55 significant DEGs were identified, namely, APPCAFRGs. Based on the expression profiles of APPCAFRGs, we divided the TCGA-PRAD cohort into two clusters using NMF consistent cluster analysis, with the genetic coefficient serving as the evaluation index. Four APPCAFRGs, THBS2, DPT, COL5A1, and MARCKS, were used to develop a prognostic signature capable of predicting BCR occurrence in PRAD patients. Subsequently, a nomogram with stability and accuracy in predicting BCR was constructed based on Gleason grade (p = n.s.), PSA (p < 0.001), T stage (p < 0.05), and risk score (p < 0.01). The analysis of immune infiltration showed a positive correlation between the abundance of resting memory CD4 + T cells, M1 macrophages, resting dendritic cells, and the risk score. In addition, the mRNA expression levels of THBS2, DPT, COL5A1, and MARCKS in the cell models were consistent with the results of the bioinformatics analysis.ConclusionsAPPCAFRS based on four potential APPCAFRGs was developed, and their interaction with the immune microenvironment may play a crucial role in the progression to castration resistance of PRAD. This novel approach provides valuable insights into the pathogenesis of PRAD and offers unexplored targets for future research.

Therapeutic Approaches to Targeting Androgen Receptor Splice Variants.

Therapeutic options for advanced prostate cancer have vastly expanded over the last decade and will continue to expand in the future. Drugs targeting the androgen receptor (AR) signaling pathway, i.e., androgen receptor targeting agents (ARTAs), remain the mainstream treatments that are increasingly transforming the disease into one that can be controlled for an extended period of time. Prostate cancer is inherently addicted to AR. Under the treatment pressure of ARTA, molecular alterations occur, leading to the clonal expansion of resistant cells in a disease state broadly categorized as castration-resistant prostate cancer (CRPC). One castration resistance mechanism involves AR splice variants (AR-Vs) lacking the ligand-binding domain. Some AR-Vs have been identified as constitutively active, capable of activating AR signaling pathways without androgenic ligands. Among these variants, AR-V7 is the most extensively studied and may be measured non-invasively using validated circulating tumor cell (CTC) tests. In the context of the evolving prostate cancer treatment landscape, novel agents are developed and evaluated for their efficacy in targeting AR-V7. In patients with metastatic CRPC (mCRPC), the availability of the AR-V7 tests will make it possible to determine whether the treatments are effective for CTC AR-V7-positive disease, even though the treatments may not be specifically designed to target AR-V7. In this review, we will first outline the current prostate cancer treatment landscape, followed by an in-depth review of relatively newer prostate cancer therapeutics, focusing on AR-targeting agents under clinical development. These drugs are categorized from the standpoint of their activities against AR-V7 through direct or indirect mechanisms.