Impact of androgen deprivation therapy and androgen receptor pathway inhibitors on cardiac structure and function evaluated by echocardiography in males with prostate cancer: a systematic review and meta-analysis.

Incidence, Management, and Prevention of Gynecomastia and Breast Pain in Patients with Prostate Cancer Undergoing Antiandrogen Therapy: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

The current guidelines for treating metastatic castration-sensitive prostate cancer (mCSPC) recommend treatment intensification of androgen deprivation therapy (ADT) with the addition of an androgen receptor pathway inhibitor (ARPI), with or without docetaxel. However, the adoption of these treatment options has been slow, leading to therapeutic inertia. This real-world study was conducted to investigate the occurrence of adverse events (AEs) among treated patients diagnosed with mCSPC in the United States. This retrospective claim review estimated the occurrence of AEs among patients with mCSPC from January 2014 to June 2021 in the PharMetrics® Plus data set. The study focused on 10 common AEs (fatigue/asthenia, gastrointestinal [GI] AEs, skin/nail/hair AEs, immunodeficiency/thrombocytopenia, hot flash, sexual function AEs, anemia, hypertension, pain, and edema) known to occur in ≥10% of patients and ≥2% more prevalent than those treated with ADT alone as selected from the US Food and Drug Administration prescribing information and published results from clinical trials. Proportions of patients experiencing these AEs at Day 90, 180, and then every 180 days until month 30 during the follow-up period were estimated using cumulative hazard plots. Results were adjusted using inverse probability of treatment weighting (IPTW) across four treatment groups: ADT alone, ADT + nonsteroidal anti-androgen (NSAA) (bicalutamide, nilutamide, or flutamide), ADT + docetaxel, and ADT + ARPIs (abiraterone, apalutamide, or enzalutamide). ADT-alone cohort was the reference group for all comparisons. A total of 4145 patients were included (ADT alone: 2318, ADT + NSAA: 632, ADT + docetaxel: 471, ADT + ARPIs: 724). At baseline, median (interquartile range [IQR]) age was 64.3 (60.1-73.1) years; most common sites of metastasis were bone only (n = 1886, 45.5%) and node only (n = 1237, 29.8%); most used medications were pain medications (n = 2182, 52.6%) and corticosteroids (n = 1213, 29.3%). Median (IQR) duration of follow-up 10.2 (6.1-16.6) months in ADT alone, 6.7 (4.1-11.5) months in ADT + NSAA, 5.1 (4.3-5.9) months in ADT + docetaxel, and 11.0 (6.6-17.0) months in ADT + ARPI cohort. The reported AEs increased over time for all assessed AEs, across all treatment groups. Compared with ADT alone, no statistically significant difference in the proportion of patients with AEs was seen in the ADT + ARPI or ADT + NSAA cohorts at months 3 and 12; a significantly higher proportion of patients in the ADT + docetaxel cohort experienced 6 of the 10 assessed AEs at month 3 (fatigue/asthenia, GI AEs, skin/nail/hair AEs, immunodeficiency/thrombocytopenia, hot flash, anemia). During the follow-up period, on IPTW analysis, compared with ADT alone, a significantly higher proportion of patients experienced AEs with seven AEs in the ADT + docetaxel group (fatigue/asthenia, GI AEs, skin/nail/hair AEs, immunodeficiency/thrombocytopenia, hot flash, anemia, edema; p < 0.001 for all seven), three AEs in the ADT + ARPI group (hot flash, p = 0.05; anemia, p = 0.01; edema, p = 0.019), and one AE in the ADT + NSAA group (anemia, p = 0.029). The proportion of patients with sexual function AE did not significantly differ between the treatment groups and ADT alone. Results of this large, real-world study demonstrated that all treatment groups experienced an increase in the rates of AEs over time, including ADT alone. Most AE rates with ADT + ARPIs were comparable with ADT + NSAA and not significantly different from ADT alone. ADT + docetaxel cohort was associated with significantly higher rates for all AEs over time except hypertension, sexual dysfunction, and pain. This study provides real-world evidence on AEs, beyond controlled clinical trials, and may assist healthcare providers to make better-informed decisions about disease management among patients with mCSPC.

Androgen Receptor Pathway Inhibitor Monotherapy in Prostate Cancer: Safety, Oncologic Outcomes, and Quality of Life-A Systematic Review and Meta-analysis.

ABSTRACTObjectiveThis study evaluated treatment patterns and factors associated with androgen deprivation therapy (ADT) intensification with androgen receptor pathway inhibitors (ARPI) and/or docetaxel among older men with mHSPC in the United States.MethodsThe study utilized a retrospective cohort of 6850 older men (age ≥ 67 years) diagnosed with mHSPC between July 2016 and December 2019 from the Surveillance, Epidemiology, and End Results Medicare‐linked database. Men must maintain continuous enrollment in Medicare fee‐for‐service Parts A/B/D for ≥ 12 months before mHSPC diagnosis and ≥ 6 months after diagnosis. Initial treatment was classified as ADT alone, ADT + ARPI, or ADT + docetaxel. Factors associated with initial treatment were examined using multivariable multinomial logistic regression.ResultsThe study cohort (mean age = 76.6 years, SD = 7.0) was mostly non‐Hispanic white (77.7%), followed by non‐Hispanic Black (8.4%) and Hispanic (6.5%). 30.4% received no systemic drug therapy within 6 months of mHSPC diagnosis, 47.1% received ADT alone, 14.8% received ADT + ARPI, and 5.9% received ADT + docetaxel. Among men treated with ADT, there was an increase in ADT + ARPI treatment from 19.0% to 30.0% and a concomitant decline in ADT monotherapy from 72.1% to 62.6% between 2017 and 2019, while ADT + docetaxel treatment marginally decreased from 8.8% to 7.3%. In multinomial logistic regression, men with de novo mHSPC were more likely to receive ADT + docetaxel (aOR = 2.73, 95% CI = [2.07, 3.60]) or ADT + ARPI (aOR = 1.56, 95% CI = [1.32, 1.84]); whereas men with higher frailty index were less likely to receive ADT + docetaxel (aOR = 0.93, 95% CI = [0.91, 0.95]) or ADT + ARPI (aOR = 0.97, 95% CI = [0.96, 0.98]). Specifically, ADT + ARPI was less likely to be utilized among the lower socio‐economic status groups.ConclusionsThree in 10 older men with mHSPC received no systemic treatment. Although there was a gradual uptake of ARPIs, monotherapy with ADT was still highly prevalent, suggesting the integration of intensified treatment is still suboptimal. Targeted interventions are necessary to enhance guideline adherence among older and frail men with mHSPC.

Observational Health Data Analysis of the Cardiovascular Adverse Events of Systemic Treatment in Patients with Metastatic Hormone-sensitive Prostate Cancer: Big Data Analytics Using the PIONEER Platform.

Limited real-world data exist on the effectiveness of treatment intensification (TI) with androgen receptor pathway inhibitors (ARPI) in de novo metastatic castration-sensitive prostate cancer (mCSPC). This study compared outcomes of TI or first-generation nonsteroidal antiandrogens (NSAAs) to androgen-deprivation therapy (ADT) alone in US patients with de novo mCSPC. Veterans Affairs patients with de novo mCSPC (February 2018-June 2020) confirmed via chart review were grouped into ADT alone, ADT + NSAAs, or ADT + ARPI cohorts using predefined recruitment quotas. Outcomes included inverse probability of treatment weighting (IPTW)-adjusted overall survival (OS), progression to metastatic castration-resistant prostate cancer (mCRPC), and prostate-specific antigen (PSA) response. A total of 384 patients were identified (ADT alone: 163, ADT + NSAA: 101, ADT + ARPI: 120). Median follow-up was 37.2, 38.1, and 34.8 months for ADT alone, ADT + NSAA, and ADT + ARPI, respectively. Compared with ADT alone, ADT + ARPI showed significantly better OS (HR [95% CI]: 0.61 [0.43 to 0.87], p = 0.007), lower risk of progression to mCRPC (0.46 [0.33 to 0.66], p < 0.001), and higher PSA response rate (PSA decline of ≥50% and ≥90% from baseline, and to <0.2 ng/mL and <0.1 ng/mL any time during first-line treatment; all p < 0.05). Outcomes with ADT + NSAA did not differ from ADT alone. ADT + ARPI was the most common second-line mCSPC and first-line mCRPC treatment. First-line ADT + ARPI was associated with significantly improved outcomes vs ADT alone in de novo mCSPC. These real-world results align with the benefits demonstrated in trials, supporting integration of TI with ARPIs into clinical practice to improve survival outcomes in patients with de novo mCSPC.

TPS5129 Background: Management of patients (pts) with mCSPC remains a challenge due to its incurable nature and heterogeneous response to androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI). Recent analyses of phase III ADT + ARPI trials show that mCSPC with suboptimal PSA response (≥0.2ng/ml at 6-12 months) have poor prognosis, short time to castration-resistance (CRPC) and 30-36 month median overall survival (OS). While docetaxel could also be utilized in mCSPC, there is equipoise about its use in ARPI-treated pts because of 1) an absence of randomized data for docetaxel in this setting, 2) toxicity of docetaxel with impact on quality of life for pts, and 3) selection of docetaxel treatment by disease volume rather than disease biology. CCTG-PR26 (TRIPLE-SWITCH) is a joint CCTG-SWOG trial run through the NCI National Clinical Trials Network. This study investigates whether adding docetaxel prior to development of CRPC, regardless of disease volume, will improve OS in ARPI-treated mCSPC pts that show evidence of suboptimal response. Methods: This international, open-label, randomized phase III trial compares standard ADT + ARPI against the addition of docetaxel to ADT + ARPI in mCSPC pts with suboptimal PSA response, defined as PSA ≥0.2 ng/mL after 6-12 months of ADT and ≥4 months of ARPI. Stratification will be based on PSA levels, ARPI type, presence of liver metastasis, disease recurrence status, and time since ADT initiation. Arm 1 will continue standard ADT + ARPI (abiraterone acetate with prednisone, apalutamide, enzalutamide or darolutamide). Arm 2 will receive docetaxel 75mg/m 2 IV every 3 weeks for up to 6 cycles in addition to continuing standard ADT + ARPI. Sample size is 830 pts in order to detect a targeted 33% improvement in overall survival (hazard ratio 0.75) using a 1-sided 0.025 level test with 85% power. Key eligibility criteria are: ≥18 years, histologically confirmed prostate adenocarcinoma, metastatic disease present and confirmed by conventional imaging (CT and/or bone scan), PSA ≥5.0 ng/mL prior to ADT, receipt of ADT for 6-12 months and ARPI for ≥4 months, PSA ≥0.2 ng/mL within 14 days of enrolment, adequate organ and marrow function, ECOG performance status 0-2, eligible for docetaxel chemotherapy, no evidence of disease progression or biochemical progression on ADT prior to enrolment. Primary endpoint is overall survival. Secondary endpoints include PSA response, PSA kinetics, and clinical progression free-survival. Correlative studies will explore the prognostic and predictive value of circulating tumor DNA (ctDNA) and the association between molecular signatures in primary prostate cancer tissue and clinical outcomes. Enrolment has been initiated in January 2025 and is ongoing. Clinical trial information: NCT06592924 .

Canada’s Drug Agency (CDA-AMC) recommends that Nubeqa be reimbursed by public drug plans for use in combination with androgen deprivation therapy (ADT) for the treatment of metastatic castration-sensitive prostate cancer (mCSPC) if certain conditions are met. A subcommittee of the pan-Canadian Oncology Drug Review Expert Review Committee (pERC) determined that Nubeqa plus ADT demonstrates acceptable clinical value versus other androgen receptor pathway inhibitors (ARPIs) plus ADT in patients with mCSPC. This determination was sufficient for the pERC subcommittee to recommend that Nubeqa plus ADT be reimbursed. Given that Nubeqa is expected to be an alternative to other ARPI plus ADT regimens, acceptable clinical value refers to at least comparable value versus apalutamide plus ADT, enzalutamide plus ADT, and abiraterone acetate and prednisone plus ADT. Evidence from a pivotal phase III clinical trial demonstrated that darolutamide plus ADT resulted in clinically meaningful improvements compared with placebo plus ADT in outcomes that are relevant for the management of mCSPC, including time to progression to more advance disease. Although limited by imprecision, evidence from an indirect comparison suggested similar effects for darolutamide plus ADT versus the other ARPI plus ADT regimens. Nubeqa should only be covered for patients who currently meet the eligibility criteria used by each of the public drug plans for the other ARPI plus ADT regimens used in the treatment of mCSPC.

169 Background: Combination therapies, such as androgen deprivation therapy (ADT) + androgen receptor pathway inhibitor (ARPI) +/- docetaxel, were shown to improve overall survival (OS) in pts with mHSPC. However, some pts are still characterized by EP. EMETPRO study analyzed these pts and their response to treatments administered at progression. Methods: EMETPRO is a multicenter, retrospective registry of pts with EP mHSPC defined as pts who have progression ≤ 6 months (m) under combination therapies (ADT + docetaxel or ADT + ARPI) or ≤ 9 m from ADT alone start. The primary endpoint is progression-free survival (PFS) calculated from the start of first-line (1°L) treatment for mCRPC in the entire population and in the different treatments sub-cohorts based on the treatment received in mHSPC. Secondary endpoints included OS calculated from the start of treatment for mHSPC and from the start of 1°L treatment for mCRPC. Results: From May 2005 to May 2023 431 pts were enrolled in the study. Median age was 69 years. Molecular analyses were available in 195 (45.2%) pts (Table). 206 (47.8%) pts received ADT alone for mHSPC while 123 (28.6%) and 77 (17.8%) pts received ADT + docetaxel and ADT + ARPI, respectively. 80 (38.8%) and 66 (32.0%) pts treated with ADT alone in mHSPC received ARPI or docetaxel as 1°L mCRPC treatment, respectively. 77 (62.6%) and 13 (10.6%) pts treated with ADT+ docetaxel in mHSPC received ARPI or cabazitaxel in mCRPC, respectively. 46 (59.7%) and 7 (9.1%) pts treated with ADT+ ARPI in mHSPC received docetaxel or a second ARPI in mCRPC, respectively. 14 pts (3.2%) received olaparib or radioligand treatments as 1°L mCRPC therapy. The median PFS from the start of 1°L treatment for mCRPC was 6.5, 4.9, and 5.4 m for pts that received ADT, ADT + docetaxel and ADT + ARPI, respectively. The median OS from mHSPC was 27.0, 20.0, and 19.5 m, in the same groups while the median OS from 1°L treatment for mCRPC was 18.5, 12 and 14.6 m, respectively. The 1°L therapy received in the mCRPC setting and the molecular profile did not correlate with PFS or OS. Conclusions: Pts with EP mHSPC are characterized by poor outcomes regardless of treatment received at progression. The best 1°L mCRPC therapy to use in these pts remains a crucial unmet clinical need. Future studies evaluating novel mechanisms (e.g. olaparib or lutetium PSMA) or intensification strategies (e.g. cabazitaxel and/or carboplatin) in this setting are urgently needed. Baseline characteristics. Number (N°) of pts 431 GS≥8 at mHSPC, N° (%) 278 (64.5) High-volume disease (CHAARTEED), N° (%) 302 (70.1) N° of pts with germline testing results 63 Alterations detected, N° (%) 24 (38.1) BRCA alterations detected, N° (%) 13 (20.6) N° of pts with somatic testing results 181 DNA damage response and repair gene alterations, No. (%) 47 (26.0) At least one TP53/PTEN/RB1 gene mutation detected, No. (%) 84 (46.4)

e17082 Background: Severalguidelines recommended the use of androgen receptor pathway inhibitors (ARPIs) and/or docetaxel along with ADT for mHSPC based on improved clinical outcomes demonstrated in clinical trials. Given the evolving treatment landscape since 2016, there is a need to understand the translation of clinical evidence and guidelines into clinical practice. Therefore, we examined the use of, and factors associated with intensification beyond ADT in men with mHSPC. Methods: A retrospective cohort of men treated for mHSPC was selected from private insurance claims of the Komodo Research Dataset (Jan 2017-Sep 2023). Men with mHSPC were identified based on their earliest claim for metastasis on or after prostate cancer diagnosis date without evidence of castration resistance. Index date was the earliest claim of ADT following mHSPC. Continuous insurance coverage for ≥ 12 months pre- (baseline) and ≥ 4 months post-index was required. Intensification beyond ADT was defined as the addition of ARPIs, docetaxel or both within ±4 months of the index date. Multinomial regression was conducted to examine factors associated with ADT intensification. Results: The study cohort comprised of 10,717 men with mHSPC with a median age of 65 years. Most had de novo mHSPC (62%), bone-only metastases (49%), hypertension (68%), diabetes (29%), and received opioids (59%) at baseline. Overall, in addition to ADT, 28% received ARPI (abiraterone: 18%, androgen receptor inhibitors: 10%), 9% docetaxel and 2.5% ARPI + docetaxel. From 2017 to 2023, there has been an increase in the intensification of ADT with ARPI from 13% to 47% and with docetaxel + ARPI from 0.8% to 15%, while the use of ADT + docetaxel declined from 12% to 3% and ADT alone from 74% to 36%. Key factors (age, comorbidity, de novo mHSPC, bone metastases) associated with intensification with either docetaxel or ARPI are listed in Table. Conclusions: There was a linear increase in intensification with ARPI and/or docetaxel in mHSPC between 2017-2023 in the US. Findings highlight a gradual uptake of guideline-recommended treatment for men with mHSPC, while over a third are still receiving ADT alone. [Table: see text]

5092 Background: Combination therapy has improved treatment of metastatic hormone sensitive prostate cancer (mHSPC). Doublets include androgen deprivation therapy (ADT) plus docetaxel (DOC) or the androgen receptor pathway inhibitors (ARPIs) abiraterone, enzalutamide, apalutamide, or darolutamide. There have been no large clinical trials that compare DOC to ARPIs in mHSPC. This study evaluates overall survival and time to castration-resistance in patients with de novo (synchronous) mHSPC in the Veterans Health Administration treated with combination therapy. Methods: Veterans were identified with initial diagnosis of ‘distant’ prostate cancer. All veterans had ADT initiated within 4 months of diagnosis and followed until September 2023. First combination therapy with DOC from 7/2016-6/2021 or ARPI from 7/2017-6/2021 were included if initiated within 4 months after ADT. Volume of disease was determined from chart review and castration-resistance (mCRPC) by a combination of natural language processing and administrative data. Real-world progression-free survival (rwPFS) was determined as time to mCRPC or death. Kaplan-Meier time to event analyses and Cox proportional hazard modeling with age, Black race, Charlson comorbidity index, prostate specific antigen, body mass index, and weight change in the year prior was used for analyses. Results: 1,226 patients with de novo mHSPC were identified with median age of 71.5 years and 349 (28.6%) were Black. High volume disease was identified in 929 (76.0%) and low volume in 293 (24.0%). DOC was used in 341 (27.9%) and ARPIs in 881 (72.1%). Veterans with high volume disease had shorter overall survival (OS) than low volume (23.8 vs. 64.1 months, p&lt;0.001). Overall, there was no difference in OS between DOC and ARPI (36.4 vs. 38.9 months, p=0.68), however DOC was associated with a shorter rwPFS (16.5 vs 22.1 months, p&lt;0.001). In high volume disease, there was no difference in OS between DOC and ARPI (33.8 vs. 32.5 months, p=0.68), however DOC was associated with a shorter rwPFS (14.9 vs 19.2 months, p=0.002). In a multivariable model of patients with high volume disease, there was no difference in OS observed between initial treatment with DOC and ARPIs (aHR 0.83, 95% CI 0.69-1.00). Conclusions: In veterans with de novo mHSPC, no difference in OS were observed between combination treatment with DOC or ARPI in patients with low or high-volume mHSPC. ARPIs were associated with longer progression free survival. Due to a lack of clinical trials comparing DOC and ARPI therapy, these data may guide selection of combination therapy for mHSPC.[Table: see text]

20 Background: Clinical features of people with mHSPC may affect their outcomes from the addition of ARPIs to androgen deprivation therapy (ADT). The STOPCAP Collaboration is seeking IPD to reliably investigate potential ARPI effect modifiers and determine who benefits more from an ARPI vs docetaxel plus ADT doublet. Methods: Full methods are in registered protocols (CRD42023431331; CRD4202540066). We sought IPD for completed trials examining effects of ARPIs for mHSPC. Initially, we examined ARPI effects using intention-to-treat, two-stage, common-effect meta-analysis of hazard ratios (HRs), adjusted for a core set of covariates and use of concomitant docetaxel. Main effects were based on overall survival (OS). Interaction effects were based on progression-free survival (PFS) to maximise power, then OS whenever PFS interactions were found (P&lt;0.10). Within clinically-relevant subgroups, ARPI and docetaxel doublet effects were compared using two-stage, contrast-based, random-effects network meta-analysis (NMA). Results: By October 2024, we had updated IPD from five trial comparisons: LATITUDE, STAMPEDE A vs G, SWOG-1216, ENZAMET, and STAMPEDE A vs J. Based on these (2882 events/5472 pts), adding an ARPI to ADT improved OS (HR=0.69, 95% CI=0.64-0.74). Four trial comparisons (excluding SWOG-1216) provided PFS data (2781 events/4161 pts) and showed improved PFS (HR=0.49, 95% CI=0.45-0.53). The relative benefit of ARPIs on PFS increased with younger age (interaction p=0.034), higher BMI (interaction p=0.048), and lower burden of metastases (interaction p=0.096). These effects were similar for OS (age interaction p=0.035; BMI interaction p=0.031; volume interaction p=0.25). The age effect was most pronounced in the abiraterone trials. Combining IPD from the ARPI + ADT and docetaxel + ADT trials (GETUG-AFU-15, CHAARTED, STAMPEDE A vs C) in NMA suggested that overall, an ARPI doublet may improve OS more than a docetaxel doublet (HR=0.85, 95% CI=0.70-1.03). However, when the NMA was confined to participants with high-volume, synchronous disease, where docetaxel is most efficacious (but excluding SWOG-1216, for which these data were not available), effects on OS were: HR=0.89, 95% CI=0.74-1.06. Conclusions: Our preliminary results suggest that people with mHSPC who are younger, have a higher BMI, or have low volume disease, may benefit more from ARPIs. ARPI and docetaxel doublets seem similarly effective in high-volume, synchronous disease. We will present updated analyses, incorporating recently received PEACE 1 IPD, for a clearer picture of ARPI effects, including subgroup-specific effects. Ongoing collection of IPD from other key trials will allow robust comparison of ARPI doublet with triplet therapy (including docetaxel), guiding more personalised treatment.

Purpose: Standard treatment for metastatic castration-resistant prostate cancer (mCRPC) includes androgen receptor (AR) pathway inhibitors (ARPIs), such as androgen deprivation therapy or enzalutamide. Despite prolonged survival with ARPI therapies, resistance is nearly universal, highlighting the urgent need to identify new resistance mechanisms and therapeutic targets. Methods: We combined systems-level and experimental approaches to identify and test actionable network nodes linked to ARPI resistance as therapeutic vulnerabilities in prostate cancer. Systems-level analyses were performed using weighted gene co-expression network analysis and Bayesian network inference. Networks were overlaid with experimental data, including ENCODE ChIP-Seq data. The in vitro efficacy of pocebrodib was evaluated in a series of enzalutamide-sensitive and -resistant prostate cancer cell lines using CellTiter-Glo, colony forming assays and 3D spheroid assays. The in vivo activity of pocebrodib was evaluated in patient-derived xenografts. Proteomics and acetylomics was used to interrogate the potential mechanisms of action for pocenbrodib. Results were validated by RT-qPCR, western blotting and flow cytometry. Knockdown studies were performed using non-targeting and SCP2-targeting siRNAs. Results: Multi-layer network inference pinpointed the CREB binding protein (CBP)/p300 complex as a key regulatory node associated with patient outcomes and ARPI resistance. Consistent with this observation, preclinical testing of the CBP/p300 inhibitor, pocebrodib, demonstrated efficacy in both enzalutamide-sensitive and -resistant lines in vitro, with IC50s of ∼1 μM. Cell growth inhibition was accompanied by downregulation of AR activity, as indicated by RNA-Seq and RT-qPCR. Pocenbrodib also demonstrated tumor growth inhibition of both enzalutamide-sensitive and -resistant patient-derived xenografts and a durable response in a patient with ARPI-resistant prostate cancer as part of the Phase I COURAGE study. Proteomics and acetylomics identified differential acetylation of both histone and non-histone proteins, including a subset of histone acetylation events altered in enzalutamide-resistant cells that are restored upon treatment with pocenbrodib. These analyses also identified enrichment of fatty acid metabolism proteins, including the sterol carrier protein 2 (SCP2) and fatty acid synthase (FASN), suggesting CBP inhibition may cause cells to sense loss of acetyltransferase activity as a reduction in free acetyl-coA, leading to alteration in fatty acid metabolism as a feedback response. Conclusion: Inhibition of the CBP/p300 axis by pocenbrodib is a promising new approach to treat ARPI-resistant prostate cancer. Future studies are aimed at clinical evaluation of pocenbrodib and exploration of downstream signaling axes to identify key biomarkers of response to pocenbrodib. Citation Format: Ananya Dutta, Beatrice C. Thomas, Pelumi Olawuni, Erik Soderblom, Eric Schadt, Bonnie Dougherty, Andrew J. Armstrong, Jason A. Jason A. Somarelli. Targeting the AR co-activator CBP/p300 in metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6920.

65 Background: Intensified androgen deprivation therapy (ADT) with an androgen receptor pathway inhibitor (ARPI) and/or docetaxel has led to improved outcomes for metastatic hormone-sensitive prostate cancer (mHSPC) in multiple clinical trials. Achievement of an undetectable PSA nadir has been associated with improved clinical outcomes, but real-world data across treatment regimens are limited. Methods: We evaluated PSA response and outcomes for patients with mHSPC treated with ADT monotherapy (mono), ADT + ARPI, and ADT + docetaxel in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). All patients with mHSPC enrolled in IRONMAN between 2017 and August 2023 in the United States, Canada, Spain, and England were included. Patients treated with triplet therapy were excluded due to small numbers. Undetectable PSA nadir, defined as PSA &lt;0.2 ng/mL, was evaluated at 6 and 12 months after treatment start. In this real-world study, relapse was defined as meeting one of the following criteria: PSA progression (≥25% PSA increase from nadir and absolute increase &gt;2 ng/mL), treatment change preceded by new metastasis location, or change to a neuroendocrine prostate cancer regimen. Rates of relapse were calculated using Kaplan Meier estimates, with confidence intervals based on standard errors calculated using the Greenwood formula. Results: Among 1,377 eligible patients, treatment was most commonly ADT + ARPI (n=775) followed by ADT mono (n=375) and ADT + docetaxel (n=227). In the overall population, PSA nadir &lt;0.2 ng/mL was achieved in 40% (n=554) at 6 months and 51% (n=702) at 12 months. Rates of PSA nadir &lt;0.2 ng/mL at 6 months were: 51% for ADT + ARPI, 27% for ADT mono, and 26% for ADT + docetaxel. At 12 months, rates of PSA nadir &lt;0.2 ng/mL increased to: 63% for ADT + ARPI, 38% for ADT mono, and 32% for ADT + docetaxel. During a median follow-up of 18 months, 291 patients (21%) experienced disease relapse; 19% experienced PSA progression. The percentage of patients in each treatment group with disease relapse at months 12, 24, and 36 of treatment are shown (Table); treatment groups are divided by whether patients had achieved PSA nadir &lt;0.2 ng/mL in 6 months. Conclusions: In this non-randomized, real-world registry, patients with mHSPC who achieved a PSA nadir &lt;0.2 ng/mL had a lower relapse rate than patients who did not, regardless of treatment. Percentage (95% CI), [number at risk] of patients with relapse at timepoint. Treatment Month 6 Month 12 Month 24 Month 36 ADT Monotherapyn=375 PSA &lt;0.2 ng/mL 0%(0, 0)[60] 1.7%(0, 5.0)[31] 11%(0, 24)[15] PSA ≥0.2 ng/mL 18%(11, 24)[80] 41%(30, 51)[38] 45%(33, 55)[19] ADT + ARPIn=775 PSA &lt;0.2 ng/mL 2.2%(0.6, 3.8)[288] 9.7%(5.9, 13)[166] 18%(12, 24)[76] PSA ≥0.2 ng/mL 21%(16, 26)[178] 42%(35, 49)[81] 50%(42, 58)[37] ADT + Docetaxeln=227 PSA &lt;0.2 ng/mL 8.2%(0.2, 16)[44] 22%(8.9, 33)[29] 36%(18, 50)[14] PSA ≥0.2 ng/mL 34%(25, 43)[69] 62%(50, 72)[21] 73%(59, 82)[12]

Advances in the treatment of metastatic prostate cancer