Metastatic Castration-sensitive Prostate Cancer Research Articles

Real-world clinical outcomes among patients with metastatic castration-sensitive prostate cancer initiating apalutamide.

Aim: To describe overall survival, time to castration resistance and castration resistance-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) initiating apalutamide in a US oncology network.Patients & methods: Patients with mCSPC initiating apalutamide on or after 17 September 2019 from an electronic health record-derived deidentified database were included. Patients were followed from apalutamide initiation and were censored at the earlier of end of clinical activity or data availability (31 October 2022).Results: At 12 and 24 months, overall survival rates were 91.0 and 88.3%, rates of castration sensitivity were 85.7 and 72.1%, and castration resistance-free survival rates were 80.2 and 65.9%, respectively.Conclusion: Real-world clinical outcomes of patients with mCSPC treated with apalutamide were comparable to results from the phase III TITAN trial.

Prognostic outcomes in Japanese patients with metastatic castration-sensitive prostate cancer: Comparative assessments between conventional androgen deprivation therapy (ADT) and ADT with novel androgen receptor signal inhibitor.

The objective of this study was to compare the prognostic outcomes between metastatic castration-sensitive prostate cancer (mCSPC) patients receiving conventional androgen deprivation therapy (ADT) and those receiving ADT plus a novel androgen-receptor signaling inhibitor (ARSI) in routine clinical practice in Japan. This was conducted as a retrospective multicenter study including 581 mCSPC patients, consisting of 305 receiving ADT alone or in combination with bicalutamide (group 1) and 276 receiving ADT plus one of the following ARSIs: abiraterone acetate, apalutamide, or enzalutamide (group 2). Prognostic outcomes between these 2 groups were comprehensively compared. In the entire cohort, prostate-specific antigen-progression-free survival (PSA-PFS) in group 2 was significantly longer than that in group 1, while no significant difference was noted in overall survival (OS) between the two groups. In patients corresponding to the LATITUDE high-risk group, however, both PSA-PFS and OS in group 2 were significantly longer than those in group 1. Of several factors examined, the following were identified as independent predictors of poor PSA-PFS in the entire cohort as well as the LATITUDE high-risk group: high C-reactive protein, high lactate dehydrogenase, high alkaline phosphatase, high Gleason score, and group 1. Furthermore, it was possible to precisely classify both the entire cohort and LATITUDE high-risk group into 3 risk groups regarding PSA-PFS according to the positive numbers of independent factors: positive for ≤1 factor, favorable; 2 factors, intermediate; and ≥3 factors, poor. Combined use of ARSIs with ADT could improve the prognostic outcomes of mCSPC patients, particularly those in the LATITUDE high-risk group, in real-world clinical practice in Japan.

Apalutamide plus androgen deprivation therapy in clinical subgroups of patients with metastatic castration-sensitive prostate cancer: a subgroup analysis of the randomised clinical TITAN study

Background. Whether disease burden in patients with metastatic castration-sensitive prostate cancer (mCSPC) predicts treatment outcomes is unknown. We assessed apalutamide treatment effect in TITAN patients with mCSPC by disease volume, metastasis number and timing of metastasis presentation.Methods. These protocol-defined and post hoc analyses of the phase III randomised TITAN study evaluated clinical outcomes in patients receiving 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy (ADT). Subgroups were defined by volume (high: visceral and ≥1 bone metastases or ≥4 bone lesions with ≥1 beyond vertebral column/pelvis), development of metastases per conventional imaging (synchronous: at initial diagnosis; meta-chronous: after localised disease) and oligometastases (≤5 bone-only metastases) or polymetastases (>5 in bone ± other locations or ≤5 in bone plus other locations). Overall survival (OS), radiographic or second progression-free survival, and time to prostate-specific antigen progression or castration resistance were assessed using Cox proportional hazards models.Results. Of 1052 patients, 63 %, 81 %, 54 %, 27 %, 5.7 %, and 8.0 % had high-volume, synchronous, synchronous/high-volume, synchronous/low-volume, metachronous/high-volume, and metachronous/low-volume disease, respectively. The OS benefit favoured apalutamide plus ADT versus ADT alone in synchronous/high-volume (hazard ratio (HR) 0.68; 95 % confidence interval (CI) 0.53–0.87; p = 0.002), synchronous/low-volume (HR 0.65; 95 % CI 0.40–1.05; p = 0.08), metachronous/high-volume (HR 0.69; 95 % CI 0.33–1.44; p = 0.32) and metachronous/low-volume (HR 0.22; 95 % CI 0.09–0.55; p = 0.001) subgroups. Apalutamide improved other clinical outcomes regardless of subgroup, with similar safety profiles. Most favourable outcomes were observed in oligometastatic disease.Conclusion. TITAN patients derived a robust benefit with apalutamide plus ADT regardless of disease volume and timing of metastasis presentation without differences in safety, supporting early apalutamide intensification in mCSPC.

Treatment escalation and de-escalation of de-novo metastatic castration-sensitive prostate cancer.

Androgen receptor signaling inhibitors combined with androgen deprivation therapy have become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC), regardless of tumor volume or risk. However, survival of approximately one-third of these patients has not improved, necessitating further treatment escalation. On the other hand, for patients with oligometastatic mCSPC, there is an emerging role for local radiation therapy. Although data remain scarce, it is expected that treatment of both primary tumor as well as metastasis-directed therapy may improve survival outcomes. In these patients, systemic therapy may be de-escalated to intermittent therapy. However, precise risk stratification is necessary for risk-based treatment escalation or de-escalation. In addition to risk stratification based on clinical parameters, research has been conducted to incorporate genomic and/or transcriptomic data into risk stratification. In future, an integrated risk model is expected to precisely stratify patients and guide treatment strategies. Here, we first review the transition of the standard treatment for mCSPC over the last decade and further discuss the newest concept of escalating or de-escalating treatment using a multi-modal approach based on the currently available literature.

Creatine supplementation and resistance training to preserve muscle mass and attenuate cancer progression (CREATINE-52): a protocol for a double-blind randomized controlled trial

BackgroundMuscle mass is important for metastatic prostate cancer survival and quality of life (QoL). The backbone of treatment for men with metastatic castration sensitive prostate cancer (mCSPC) is androgen deprivation therapy (ADT) with an androgen signaling inhibitor. ADT is an effective cancer treatment, but it facilitates significant declines in muscle mass and adverse health outcomes important to mCSPC survivors, such as fatigue, and reductions in physical function, independence, insulin sensitivity, and QoL. In non-metastatic CSPC survivors, resistance training (RT) preserves muscle mass and improves these related health outcomes, but the biggest barrier to RT in CSPC survivors of all stages is fatigue. Creatine monohydrate supplementation coupled with RT (Cr + RT) may address this barrier since creatine plays a critical role in energy metabolism. Cr + RT in cancer-free older adults and other clinical populations improves muscle mass and related health outcomes. Evidence also suggests that creatine supplementation can complement cancer treatment. Thus, Cr + RT is a strategy that addresses gaps in survivorship needs of people with mCSPC. The purpose of this parallel, double-blind randomized controlled trial is to test the effects of 52-weeks of Cr + RT compared with placebo (PLA) and RT (PLA + RT) on muscle mass, other related health outcomes, and markers of cancer progression.MethodsWe will carry out this trial with our team’s established, effective, home-based, telehealth RT program in 200 mCSPC survivors receiving ADT, and evaluate outcomes at baseline, 24-, and 52-weeks. RT will occur twice weekly with elastic resistance bands, and an established creatine supplementation protocol will be used for supplementation delivery. Our approach addresses a major facilitator to RT in mCSPC survivors, a home-based RT program, while utilizing a supervised model for safety.DiscussionFindings will improve delivery of comprehensive survivorship care by providing a multicomponent, patient-centered lifestyle strategy to preserve muscle mass, improve health outcomes, and complement cancer treatment (NCT06112990).

Prostate cancer across four countries in the Middle East: a multi-centre, observational, retrospective and prognostic study.

Prostate cancer (PC) is the second most prevalent cancer in males, with a steadily increasing incidence in the Middle East (ME). The aim of this study was to capture real-world data on the characteristics, disease progression, and treatment patterns among PC patients in the ME. This was a retrospective, observational, multi-centre study conducted across ten hospitals/research centers in Lebanon, Kingdom of Saudi Arabia, Iraq and Kuwait. Data were abstracted from medical records of 615 male patients who were diagnosed with PC between January 2012 and the site initiation date (December 2018-May 2019) and received at least one PC treatment/intervention. The observation period ranged between 84 and 88 months. Data were collected on demographics, clinical characteristics, time to progression to the subsequent clinical state or therapy (progression from localised/locally advanced PC to castration and to metastatic PC (metastatic castration-sensitive PC (mCSPC) or metastatic castration-resistant PC (mCRPC)), progression from mCSPC to mCRPC, and mCRPC patients' progression to first subsequent line of therapy), treatment patterns, and mortality. Most patients had localised/locally advanced PC (57.7%), followed by mCSPC (37.4%), and mCRPC (4.1%) at the time of inclusion in the study. Most patients were at tumours, nodes and metastases (TNM) stage IIIa (40.1%) or TNM stage IVb (27.8%) at study entry. Median time to metastatic disease, castration-resistance and next line therapy was 84 months (95% CI: 68-84), 41 months (95% CI: 30-56) and 7 months (95% CI: 0-41), respectively. The mortality rate was 3.6%. Disease progression was most common among patients with mCSPC (35.1%) or mCRPC (14.8%), and treatment discontinuation was most common among patients with mCRPC (36.6% treatments discontinued). The results show that most patients were at an advanced TNM stage at study entry, suggestive of a lack of awareness regarding PC. Disease progression was most common among patients with metastatic disease, reflecting the challenge of treating metastatic disease and highlighting the need for novel treatments.

Current Systemic Therapy in Men with Metastatic Castration-Sensitive Prostate Cancer.

This review aims to explore the evolving landscape of treatments available for metastatic castration-sensitive prostate cancer (mCSPC) patients. In less than a decade, evidence was chronologically provided that (1) systemic treatment intensification with docetaxel improves outcomes, including survival, in men with mCSPC, (2) then that these outcomes are also improved when a second-generation androgen receptor pathway inhibitor (ARPI) is combined with androgen deprivation therapy (ADT), and (3) using a "triplet systemic therapy," which consists in the combination of ADT, an ARPI and docetaxel, further improves outcomes, including survival. Radiotherapy to the prostate combined with ADT alone is now recommended in men with low-volume mCSPC. Combining prostate radiotherapy and intensified systemic treatment including abiraterone may be synergistic as suggested in the PEACE-1 trial. Also, the role of metastases-directed local therapies (mostly stereotactic radiotherapy) is currently being assessed in phase 3 trials. Finally, the integration of biomarkers (e.g. BRCA2 gene alterations, PTEN loss, PSMA expression) for decision making is not currently established, though trials are also currently underway. Importantly, most evidence currently available was obtained in men with de novo metastases, while for those with metastatic relapse after definitive local treatment, the role of treatment intensification is less well established. Treatment intensification is nowadays the standard of care for patients with de novo mCSPC as it leads to outcomes improvement, including survival, and the standard of care is evolving almost on a yearly basis.

Psoas mass index at the level of the third lumbar vertebra on computed tomography is a prognostic predictor for metastatic castration-sensitive prostate cancer.

Computed tomography-defined low skeletal muscle mass is associated with oncological outcomes in patients with prostate cancer. However, its association with the outcomes of hormone-treated metastatic castration-sensitive prostate cancer remains unclear. We aimed to determine the association between metastatic castration-sensitive prostate cancer and psoas muscle parameters. We retrospectively reviewed 121 patients with N1 and/or M1 metastatic castration-sensitive prostate cancer who underwent primary androgen deprivation therapy between 2005 and 2021, either by administration of luteinizing hormone-releasing hormone agonist/antagonist or by surgical castration accompanied by bicalutamide, a first-generation antiandrogen. Before treatment administration, the psoas muscle index at the level of the third lumbar vertebra (psoas muscle area [cm2]/height2 [m2]) and the mean Hounsfield units of the psoas muscle were evaluated using non-contrast computed tomography and in relation to oncological outcomes. The median follow-up was 56.9months. Furthermore, during follow-up, 82 (67.7%) and 53 (43.8%) patients progressed to castration-resistant prostate cancer and died, respectively. Multivariate analysis of castration-resistant prostate cancer-free survival and overall survival showed significant differences in the Gleason score, clinical N-stage, and psoas muscle index (median cutoff: 3.044 cm2/m2). Pretreatment psoas muscle index is an independent predictor of poor castration-resistant prostate cancer-free survival and overall survival in patients with N1 and/or M1 metastatic castration-sensitive prostate cancer.

Genomic profiling and clinical utility of circulating tumor DNA in metastatic prostate cancer: SCRUM-Japan MONSTAR SCREEN project

BackgroundCirculating tumor DNA (ctDNA) testing has emerged as a novel tool for cancer precision medicine. This study investigated the genomic profiling and clinical utility of ctDNA in metastatic prostate cancer.MethodsThis is a nation-wide prospective observational study. Patients treated with systemic treatment for metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) were included. ctDNA was analyzed using FoundationOne Liquid®CDx at enrollment. In a subset of patients, ctDNA after disease progression and tissue prior to the initiation of treatment were examined using FoundationOne Liquid®CDx and FoundationOne®CDx, respectively.ResultsThe frequency of AR alterations and homologous recombination repair (HRR) defect was higher in mCRPC compared with mCSPC. Tumor mutational burden was correlated between tissue and ctDNA at pre-treatment, as well as ctDNA between at pre-treatment and at post-treatment. Patients with HRR defect were associated with shorter time to castration resistance in androgen deprivation therapy/combined androgen blockade, but not in androgen receptor pathway inhibitor, compared with patients without HRR defect in mCSPC. Time to treatment failure in patients with AR amplification or AR mutation was shorter compared with patients without AR alterations in mCRPC.ConclusionsThis study revealed valuable findings for the clinical care of metastatic prostate cancer. Especially, predictive factors such as HRR defect in mCSPC should be validated in the future.

Emerging racial disparities among Medicare beneficiaries and Veterans with metastatic castration-sensitive prostate cancer

BackgroundPrevious studies have shown that Black men receive worse prostate cancer care than White men. This has not been explored in metastatic castration-sensitive prostate cancer (mCSPC) in the current treatment era.MethodsWe evaluated treatment intensification (TI) and overall survival (OS) in Medicare (2015–2018) and Veterans Health Administration (VHA; 2015–2019) patients with mCSPC, classifying first-line mCSPC treatment as androgen deprivation therapy (ADT) + novel hormonal therapy; ADT + docetaxel; ADT + first-generation nonsteroidal antiandrogen; or ADT alone.ResultsWe analyzed 2226 Black and 16,071 White Medicare, and 1020 Black and 2364 White VHA patients. TI was significantly lower for Black vs White Medicare patients overall (adjusted odds ratio [OR] 0.68; 95% confidence interval [CI] 0.58–0.81) and without Medicaid (adjusted OR 0.70; 95% CI 0.57–0.87). Medicaid patients had less TI irrespective of race. OS was worse for Black vs White Medicare patients overall (adjusted hazard ratio [HR] 1.20; 95% CI 1.09–1.31) and without Medicaid (adjusted HR 1.13; 95% CI 1.01–1.27). OS was worse in Medicaid vs without Medicaid, with no significant OS difference between races. TI was significantly lower for Black vs White VHA patients (adjusted OR 0.75; 95% CI 0.61–0.92), with no significant OS difference between races.ConclusionsGuideline-recommended TI was low for all patients with mCSPC, with less TI in Black patients in both Medicare and the VHA. Black race was associated with worse OS in Medicare but not the VHA. Medicaid patients had less TI and worse OS than those without Medicaid, suggesting poverty and race are associated with care and outcomes.

Radiographic Progression Without Corresponding Prostate-specific Antigen Progression in Patients with Metastatic Castration-sensitive Prostate Cancer Receiving Apalutamide: Secondary Analysis of the TITAN Trial

Background and objectiveIn prostate cancer treated with androgen deprivation therapy (ADT), the initial sign of treatment resistance is often prostate-specific antigen (PSA) progression, followed by radiographic progression. However, the association between these two forms of progression remains unclear, especially in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with androgen receptor pathway inhibitors. We sought to evaluate the association between radiographic progression, PSA progression, and outcomes of apalutamide therapy in mCSPC. MethodsWe analyzed individual participant-level data for patients randomized within the TITAN trial who experienced radiographic progression during follow-up (N = 326). This study investigated radiographic progression without simultaneous or preceding PSA progression, as defined by the Prostate Cancer Working Group 2 (discordant progression), and explored the association of such progression with radiographic progression-free survival. Key findings and limitationsAmong the patients who developed radiographic progression, 115 (35.3%) had been treated with apalutamide plus ADT (the apalutamide group) and 211 (64.7%) with placebo plus ADT (the placebo group). Discordant progression occurred in 52.2% of patients (60 of 115) in the apalutamide group and 27.5% (58 of 211) in the placebo group (p < 0.001). A multivariable logistic regression analysis showed that discordant progression was associated with apalutamide treatment. We found evidence of an association between discordant progression and shorter radiographic progression-free survival. Conclusions and clinical implicationsThis study found that nearly half of the patients with mCSPC treated with apalutamide who experienced radiographic progression developed it without corresponding PSA progression, suggesting that heavy reliance on PSA monitoring may be inadequate for assessing disease activity in this context. Patient summaryIn patients who have metastatic castration-sensitive prostate cancer (mCSPC) and are being treated with apalutamide, radiographic images may show cancer progression even if prostate-specific antigen tests indicate no change. This highlights the importance of regular imaging when using apalutamide to manage mCSPC.

Expert Perspectives on Controversies in Castration-Sensitive Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 1.

Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

Minimally invasive cytoreductive radical prostatectomy, exploring the safety and feasibility of a single-port or multi-port robotic platform

BackgroundConsolidative resection or cytoreductive radical prostatectomy (CRP) may benefit men with non-organ confined prostate cancer. We report the safety, feasibility, and outcomes of robot-assisted laparoscopic CRP using a single-port (SP) or multi-port (MP) platform.MethodsWe reviewed consecutive men with clinical node positive or metastatic castrate-sensitive prostate cancer who underwent IRB-approved CRP and extended pelvic lymph node dissection using the da Vinci SP or MP Surgical Systems (Intuitive Surgical, Sunnyvale, CA) from 2015–2022. Perioperative data and Clavien-Dindo 90-day complications were recorded.ResultsTwenty-four men with a median age of 61 (IQR 56—69) years and prostate-specific antigen of 32.1 (IQR 21.9—62.3) ng/mL were included. Clinical N1, M1, or N1 + M1 disease were detected in 8 (33%), 9 (38%), 7 (29%) patients, respectively. There was no difference in positive margins, 41% vs. 29% (P = 0.67), lymph node yield, 21 (IQR 14–28) vs. 20 (IQR 13.5–21) nodes (P = 0.31), or estimated blood loss, 150 mL (IQR 100–200) vs. 50 mL (IQR 50–125) (P = 0.06), between the MP and SP cohorts, respectively. Hospital length of stay was significantly shorter for the SP group, same-day discharge (IQR 0–0), compared to MP, 1-day (IQR 1–1), P < 0.001. One grade III bowel obstruction and lymphocele occurred in the MP cohort. No major complications occurred in the SP cohort.ConclusionRobot-assisted laparoscopic CRP is safe and feasible for select men with advanced castrate-sensitive prostate cancer.

Abstract 1136: Tumor genomic and transcriptomic profiling of patients (pts) with metastatic castration sensitive prostate cancer (mCSPC) who do versus do not achieve an optimal PSA response to androgen deprivation therapy intensification (ADTi)

Abstract Background: Pts with mCSPC receiving ADTi and achieving PSA nadir ≤0.2 ng/mL (PSA-L) have better overall survival (OS) compared to those with a PSA nadir &amp;gt; 0.2 ng/mL (PSA-H). We investigate differences in genomic and transcriptomic profiling between PSA-L and PSA-H. Methods: In this IRB-approved retrospective study, eligibility criteria included confirmed mCSPC receiving ADTi and having comprehensive genomic profiling (CGP) performed by a CLIA-certified lab (Foundation Medicine and Tempus). Transcriptomic profile was evaluated from Tempus cohort. Pts were divided into 2 groups: PSA-L and PSA-H based on achieving a PSA nadir ≤0.2 ng/mL at any time during treatment course. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p values (q values) for each differentially expressed gene. These results were subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R studio v4.2. Results: 248 pts were eligible for genomic analysis (PSA-L=166, PSA-H=82). The top 5 most commonly altered genes were TMPRSS2, TP53, PTEN, APC, and SPOP. Genomic analysis did not reveal significant differences between PSA-L and PSA-H. 78 pts were eligible for transcriptomic analysis (PSA-L=55, PSA-H=23). Table shows differences in the expression of pathways between PSA-L and PSA-H. Conclusion: While there were no significant differences in genomic aberrations between PSA-L and PSA-H, gene expression profiling showed significant variations in crucial pathways, particularly the AR pathway, which might explain the better outcomes in PSA-L. After external validation, these findings may help personalize medicine prior to initiation of therapy. Differential gene set expression scores in PSA-L vs. PSA-H Pathway Normalized Enrichment Score (NES)* p-value q-value TNF-α signaling via NFKB 2.5 &amp;lt;0.01 &amp;lt;0.01 Androgen Response 1.7 &amp;lt;0.01 &amp;lt;0.01 Estrogen Response 1.7 &amp;lt;0.01 &amp;lt;0.01 Interferon-α 1.5 &amp;lt;0.01 &amp;lt;0.01 Bile Acid Metabolism -1.5 &amp;lt;0.01 &amp;lt;0.01 Coagulation -1.7 &amp;lt;0.01 &amp;lt;0.01 Epithelial Mesenchymal Transition -1.9 &amp;lt;0.01 &amp;lt;0.01 Citation Format: Vinay Mathew Thomas, Beverly Chigarira, Georges Gebrael, Chadi Chehade, Arshit Narang, Nicolas Sayegh, Nishita Tripathi, Yeonjung Jo, Clara Tandar, Ayana Srivastava, Richard Ji, Emre Dal, Gliceida Galarza Fortuna, Haoran Li, Benjamin L. Maughan, Umang Swami, Neeraj Agarwal. Tumor genomic and transcriptomic profiling of patients (pts) with metastatic castration sensitive prostate cancer (mCSPC) who do versus do not achieve an optimal PSA response to androgen deprivation therapy intensification (ADTi) [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 1136.

Abstract 2560: Genomic biomarkers of survival in patients (pts) with metastatic castrate-sensitive prostate cancer (mCSPC) undergoing androgen deprivation therapy (ADT) intensification (ADTi)

Abstract Background: ADTi with androgen receptor pathway inhibitors (ARPI) with or without docetaxel improves survival outcomes in pts with mCSPC. Even with ADTi, 20% of these pts progress within a year and experience poor overall survival (OS). Identifying baseline genomic biomarkers predicting poor survival outcomes in pts receiving ADTi remains an unmet need. Methods: In this IRB-approved retrospective study, pts with a new diagnosis of mCSPC who underwent comprehensive genomic profiling of primary prostate tissue or metastatic site or cell-free DNA and treated with ADTi (ADT with ARPI or docetaxel) were included. Genomic alterations with an incidence &amp;gt; 5% were included in the analysis. Study endpoints: progression-free survival (PFS) was defined from the start of therapy for mCSPC to progression (per PCWG-2) or death from any cause. OS was defined from the start of therapy for mCSPC to the date of death from any cause or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for age at mCSPC diagnosis, disease volume (high vs. low), Gleason score (≥ 8 vs. &amp;lt; 8), Log2PSA at baseline, and initial timing of metastasis (de novo vs. non de novo). A subgroup analysis by intensification treatment received (ARPI vs. docetaxel) was also performed. Missing baseline characteristics such as volume of disease, Gleason score, and Log2PSA were multiply imputed on 50 chained equations using “mice” package in R. All the analyses were done using R version 4.3.1. Results: A total of 289 pts were included in the study. The baseline characteristics of the cohort will be presented in the meeting. The alterations included in the analysis were TP53 (31.8%), TMPRSS2 (30.4%), PTEN (17%), APC (10.4%), SPOP (9%), RB1 (6.2%), BRCA2 (5.2%), and CDK12 (5.2%). In the multivariable analysis, TP53 (HR 1.87, 95% CI 1.29-2.72, p = 0.001), RB1 (HR 2.56, 95% CI 1.45-4.53, p = 0.001), PTEN (HR 1.77, 95% CI 1.15-2.72, p = 0.009), and BRCA2 (HR 2.68, 95% CI 1.47-4.89, p = 0.002) were associated with significantly shorter PFS while TP53 (HR 1.78, 95% CI 1.1-2.88, p = 0.019), RB1 (HR 4.78, 95% CI 2.53-9.02, p &amp;lt; 0.001), and PTEN (HR 2.37, 95% CI 1.37-4.1, p = 0.003) were associated with significantly worse OS. Results of the subgroup analysis by intensification treatment (ARPI vs. docetaxel) will also be presented in the meeting. Conclusions: In this real-world study, we identified genomic biomarkers that could be associated with shorter PFS and OS in pts with mCSPC treated with ADTi. Upon external validation, these results may aid in developing a clinical-genomic risk stratification model, patient counseling, and treatment selection. Citation Format: Arshit Narang, Georges Gebrael, Chadi Hage Chehade, Nicolas Sayegh, Yeonjung Jo, Beverly Chigarira, Nishita Tripathi, Ayana Srivastava, Clara Tandar, Benjamin L. Maughan, Umang Swami, Neeraj Agarwal. Genomic biomarkers of survival in patients (pts) with metastatic castrate-sensitive prostate cancer (mCSPC) undergoing androgen deprivation therapy (ADT) intensification (ADTi) [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 2560.

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.

Bone-Modifying Agents in Patients With High-Risk Metastatic Castration-Sensitive Prostate Cancer Treated With Abiraterone Acetate

The association between the use of bone-modifying agents (BMAs) and the outcomes among patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with abiraterone acetate plus prednisone (AAP) remains unclear. To investigate the association between BMA use and the outcomes of patients with mCSPC receiving AAP. In this cohort study, a post hoc analysis of individual participant data from the LATITUDE trial was performed. The LATITUDE trial, a phase 3 randomized clinical trial, aimed to assess the efficacy of AAP and androgen deprivation therapy (ADT) vs dual-placebo and ADT in patients with high-risk mCSPC (data cutoff, August 15, 2018). Eligible patients had newly diagnosed prostate cancer with metastases and at least 2 of 3 high-risk factors (Gleason score ≥8, presence of ≥3 lesions on bone scan, or presence of measurable visceral metastasis). The trial was conducted at 235 sites in 34 countries. Data for the present study were evaluated from July 18 to September 23, 2023. Use of BMAs was defined as the administration of bisphosphonates and denosumab within 90 days before and after randomization. The primary outcomes were time to skeletal-related events (SREs) and overall survival (OS). An SRE was defined as a clinical or pathological fracture, spinal cord compression, palliative radiation to bone, or surgery involving bone. Differences in these outcomes were examined using the restricted mean survival time from inverse probability of treatment weighting-adjusted Kaplan-Meier curves, estimated until the last event was observed (longest time observed, 63.9 months). Treatment × covariate interactions were analyzed using weighted Cox proportional hazards regression models for the total cohort. In the total cohort of 1199 patients (956 [79.7%] younger than 75 years), 597 (49.8%) received AAP and ADT, including 474 (79.4%) younger than 75 years and 384 (64.3%) with more than 10 bone metastases (AAP cohort); 602 (50.2%) were treated with dual placebo and ADT, including 482 (80.1%) younger than 75 years and 377 (62.6%) with more than 10 bone metastases (ADT cohort). In the AAP cohort, 132 patients (22.1%) received BMAs, while in the ADT cohort, 131 (21.8%) did. Zoledronic acid was the most frequently administered BMA in both the AAP (93 [70.5%]) and the ADT (88 [67.2%]) cohorts. During the median follow-up of 51.8 (IQR, 47.2-57.0) months in the AAP cohort, BMA use was associated with a longer time to SRE (difference, 7.8 [95% CI, 4.2-11.3] months) but not with OS (difference, 1.6 [95% CI, -2.5 to 5.8] months). In the ADT cohort, BMA use was associated with both time to SRE (difference, 9.3 [95% CI, 5.2-13.3] months) and OS (difference, 5.5 [95% CI, 3.2-9.8] months). No evidence was found that the outcomes of BMA varied by AAP or ADT (hazard ratio for time to SRE, 0.99 [95% CI, 0.48-2.08]; P = .99 for interaction; hazard ratio for OS, 1.31 [95% CI, 0.88-1.96]; P = .18 for interaction). The findings of this cohort study suggest that use of BMAs was associated with a longer time to SRE in patients with high-risk mCSPC treated with ADT, with or without AAP, suggesting that BMA use might provide benefits to this population.

Demonstrating Bioequivalence for Two Dose Strengths of Niraparib andAbiraterone AcetateDual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.

The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs. This open-label randomized BA/BE study (NCT04577833) was conducted at 14 sites in the USA and Europe. The study had a sequential design, including a 21-day screening phase, a pharmacokinetic (PK) assessment phase comprising three periods [namely (1) single-dose with up to 1-week run-in, (2) daily doseon days 1-11, and (3) daily dose ondays 12-22], an extension where both niraparib and AA as single-agent combination (SAC; reference) or AA alone was continued from day 23 until discontinuation, and a 30-day follow-up phase. Patients were randomly assigned in a parallel-group design (four-sequence randomization) to receive a single oral dose of niraparib 100 mg/AA 1000 mg as a LS-DAT or SAC in period 1, and patients continued as randomized into a two-way crossover design during periods 2 and 3 where they received niraparib 200 mg/AA 1000 mg once daily as a RS-DAT or SAC. The design was powered on the basis of crossover assessment of RS-DAT versus SAC. During repeated dosing (periods 2 and 3, and extension phase), all patients also received prednisone/prednisolone 5 mg twice daily. Plasma samples were collected for measurement of niraparib and abiraterone plasma concentrations. Statistical assessment of the RS-DAT and LS-DAT versus SAC was performed on log-transformed pharmacokinetic parameters data from periods 2 and 3 (crossover) and from period 1 (parallel), respectively. Additional paired analyses and model-based bioequivalence assessments were conducted to evaluate the similarity between the LS-DAT and SAC. For the RS-DAT versus SAC, the 90% confidence intervals (CI) of geometric mean ratios (GMR) for maximum concentration at a steady state (Cmax,ss) and area under the plasma concentration-time curve from 0-24 h at a steady state (AUC 0-24h,ss) were respectively 99.18-106.12% and 97.91-104.31% for niraparib and 87.59-106.69 and 86.91-100.23% for abiraterone. For the LS-DAT vs SAC, the 90% CI of GMR for AUC0-72h of niraparib was 80.31-101.12% in primary analysis, the 90% CI of GMR for Cmax,ss and AUC 0-24h,ss of abiraterone was 85.41-118.34% and 86.51-121.64% respectively, and 96.4% of simulated LS-DAT versus SAC BE trials met the BE criteria for both niraparib and abiraterone. The RS-DAT met BE criteria (range 80%-125%) versus SAC based on 90% CI of GMR for Cmax,ss and AUC 0-24h,ss. The LS-DAT was considered BE to SAC on the basis of the niraparib component meeting the BE criteria in the primary analysis for AUC 0-72h; abiraterone meeting the BE criteria in additional paired analyses based on Cmax,ss and AUC 0-24h,ss; and the percentage of simulated LS-DAT versus SAC BE trials meeting the BE criteria for both. NCT04577833.

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.

Real-World Incidence and Severity of Hypertension Caused by Abiraterone Acetate in Patients With Metastatic Prostate Cancer.

Abiraterone acetate (AA) is used in treatment of patients with metastatic prostate cancer. Despite the survival advantage, AA is associated with hypertension due to mineralocorticoid excess syndrome. We conducted a single-center retrospective analysis to evaluate the real-world incidence and severity of AA-induced hypertension. Electronic health records were used to collect baseline characteristics and prostate cancer history. Patient data, including blood pressure at each 4 (±2)-week interval, were collected for 24 weeks after the initiation of AA therapy. The primary endpoint was the incidence and severity of AA-induced hypertension. The secondary endpoints include effect of different prednisone dosing regimens and prostate cancer types on hypertensive incidence and the impact of clinical pharmacists' involvement in managing AA-induced hypertension. A total of 142 patients who met our inclusion criteria received AA for metastatic prostate cancer, 73 (51.4%) with metastatic castration-resistant prostate cancer (mCRPC), and 69 (48.6%) with metastatic castration-sensitive prostate cancer (mCSPC). Of all, 43.7% experienced all-grade hypertension, and 28.2% experienced grade 3-4 hypertension. There was no difference in incidence of hypertension between patients receiving 5 mg of prednisone daily and those receiving 5 mg of prednisone twice daily. All-grade hypertension occurred in 39.7% of mCRPC and 47.8% of mCSPC patients (P = 0.33). Thirty-two percent of patients were actively managed by a clinical pharmacist and had an overall trend of reduced hypertension severity after 12 weeks. This single-center, retrospective cohort study found that real-world metastatic prostate cancer patients who received AA had substantially higher incidence and severity of hypertension compared with clinical trials regardless of prednisone dose. In patients with mCRPC and mCSPC, the role of prednisone dose in hypertension incidence and severity warrants further investigation. Overall, results indicate the need for closely monitoring hypertension and optimization of anti-hypertensive therapy by multidisciplinary teams in metastatic prostate cancer patients receiving AA.