Abiraterone Acetate Prednisone Research Articles

Abstract 3572: Role of the gut microbiome in androgen production and prostate cancer treatment resistance

Abstract Metastatic prostate cancer is often treated via a combination of androgen deprivation therapy (ADT) and the androgen receptor axis-targeted therapies abiraterone acetate + prednisone (AA/P) or enzalutamide. Unfortunately, most individuals undergoing these treatments develop resistance, termed “castration resistance”, through an unknown mechanism. Previous studies demonstrate a potential link between the gut microbiota and the treatment efficacy of endocrine therapy in metastatic castration resistant prostate cancer (mCRPC). This may be due in part to gut bacterial communities with the machinery to synthesize androgens using mechanisms distinct from human cells. For example, the bacterial desAB genes (e.g., “desmolase”) that were first described in the gut commensal bacterial species Clostridium scindens convert cortisol and prednisone to the androgenic metabolites 11β-hydroxyandrost-4-ene-3,17-dione (11OHAD) and ∆1-adrenosterone (∆1-AT), respectively. We hypothesize that androgen synthesis by the gut microbiota promotes treatment resistance to AA/P in advanced prostate cancer. This study aims to determine if androgen-converting gut bacterial species as well as circulating and fecal androgen levels correlate with AA/P treatment response in individuals with mCRPC using a combination of metagenomics and metabolomics. We further aim to demonstrate the relationship between gut bacterial androgen production and prostate cancer treatment response using an in vivo mouse model. Metagenomic sequencing showed an imbalance in microbial communities and identified the presence of androgen-synthesizing bacteria such as C. scindens in fecal samples of individuals undergoing treatment with AA/P. We also demonstrate that the relative abundance of C. scindens, as well as other species reported to generate androgens, are significantly enriched during metastatic disease progression on AA/P. Furthermore, targeted quantitative PCR of the bacterial desmolase (desA) gene demonstrated that absolute levels of desmolase are significantly higher in AA/P non-responders relative to AA/P responders, and trended higher in individuals with rising prostate-specific antigen (PSA) versus stable PSA while on AA/P. Targeted LC/MS/MS analyses of fecal samples demonstrated the presence of testosterone, dihydrotestosterone, 11OHAD, ∆1-AT, and other androgen metabolites in association with rising PSA levels in the AA/P cohort. Furthermore, we demonstrate that C. scindens converts hydrocortisone and prednisone into 11OHAD and ∆1-AT, respectively, in vitro at 48- and 72h post-treatment, which recapitulates prior published studies. Finally, we have established a prostate cancer mouse model using a VCaP xenograft in which tumor growth was significantly inhibited by abiraterone acetate in comparison to treatment with ADT alone. Additional studies will use this mouse model to study the effects of androgen metabolism by gut bacteria on AA/P efficacy. Overall, this study ascertains the ability of the human gut microbiota to harbor androgen-synthesizing bacteria, which in turn can be an alternative source of androgens that could impact the efficacy of the anti-androgen therapies used to treat metastatic prostate cancer. Citation Format: Angelica I. Cruz Lebron, Pedro A. Balbuena-Almodóvar, Luke Mummert, Sarah Ernst, Mark Markowski, Michelle Rudek, Jason Ridlon, Karen S. Sfanos. Role of the gut microbiome in androgen production and prostate cancer treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3572.

Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

Interaction of age and benefit of treatment intensification in advanced prostate cancer: An aggregate meta-analysis of 14 randomized trials.

118 Background: Treatment intensification (TI) for men with advanced prostate cancer consistently demonstrates improvements in overall survival (OS) when compared to androgen deprivation therapy (ADT) alone. However, TI increases morbidity and may contribute to worsening other-cause mortality. Herein, we aim to determine if there is an interaction of age and TI on OS in men with advanced prostate cancer. Methods: A systematic literature search in MEDLINE, Embase, and conference proceedings were searched to identify contemporary randomized phase 3 trials in advanced prostate cancer evaluating the role of TI with chemotherapy and/or androgen receptor-signaling inhibition (ARSI) between 1/1/2010-9/1/2023. Trials in metastatic hormone-sensitive prostate cancer (mHSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) were included given potential for competing risks; mCRPC trials were excluded. Meta-analyses were performed with random-effect modeling. Meta-regression was performed using Hartung-Knapp methods in mHSPC trials accounting for drug (docetaxel, abiraterone acetate/prednisone (AAP), non-AAP ARSIs (apalutamide, enzalutamide, or darolutamide)), use of RT to primary, percent high volume disease, percent synchronous metastatic disease, and median PSA. Age was dichotomized as < or ≥ 70 in 8 trials, and < or ≥ 65 in 6 trials. Results: Fourteen trials with 16 randomized comparisons (n=17,765 patients) were included. A total of 9,229 younger and 7,458 older men were included in age-specific analyses. Overall, TI significantly improved OS (HR 0.72, 95%CI 0.69-0.76, p<0.0001), which was consistent irrespective of disease state (mHSPC HR 0.72, 95%CI 0.78-0.77; nmCRPC HR 0.74, 95%CI 0.66-0.83). There was a significant interaction between age and TI on OS (p-interaction <0.001); TI in younger men significantly improved OS (HR 0.65, 95%CI 0.59-0.72, p<0.0001). Older men derived less benefit from TI, but TI did improve OS (HR 0.80, 95%CI 0.74-0.87, p<0001). In subgroup of older men in mHSPC trials, a significant treatment effect difference based on drug class was observed (p=0.047); AAP (HR 0.92, 95%CI 0.78-1.10, p=0.38), docetaxel (HR 0.86, 95%CI 0.70-1.05, p=0.13), and non-AAP ARSIs (HR 0.71, 95%CI 0.63-0.81, p<0.001). On meta-regression of mHSPC trials, age remained an independent variable associated with TI benefit (p=0.005). Limitations include the post-hoc nature of this aggregate meta-analysis and use of dichotomized age. Conclusions: TI improves OS for men with mHSPC and nmCRPC, but a significant interaction between age and TI on OS was identified. Further work leveraging individual patient data is needed to understand drivers of this observation, including impact of treatment compliance, comorbid conditions, adrenal suppression, outcomes in different prognostic groups, and competing risks in older patients.

FORMULA-509: A Multicenter Randomized Trial of Post-Operative Salvage Radiotherapy (SRT) and 6 Months of GnRH Agonist with Either Bicalutamide or Abiraterone Acetate/Prednisone (AAP) and Apalutamide (Apa) Post-Radical Prostatectomy (RP)

FORMULA-509 was designed to evaluate whether adding six months of AAP and Apa to a GnRH Agonist could improve outcomes compared to six months of bicalutamide plus GnRH Agonist for patients with unfavorable features receiving SRT for a detectable PSA post-RP. FORMULA-509 is an investigator-initiated, multi-center, open-label, randomized trial. Patients had PSA ≥0.1 post-RP and one or more unfavorable features (Gleason 8-10, PSA >0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time <10 months, negative margins, persistent PSA, gross local/regional disease, or Decipher High Risk). All patients received SRT plus 6 months of GnRH agonist and randomization was to concurrent bicalutamide 50 mg or AAP 1000 mg/5 mg + Apa 240 mg QD. Radiation to pelvic nodes was required for pN1 and optional for pN0. The primary endpoint was PSA progression-free survival (PFS) and secondary endpoint was metastasis-free survival (MFS) determined by conventional imaging. The study was powered to detect a HR of 0.50 for PFS and a HR of 0.30 for MFS, each with 80% power and one-sided type I error of 0.05. Stratification was by PSA at study entry (>0.5 vs.≤0.5) and pN0 vs pN1. Analyses within these subgroups were pre-planned and utilized two-sided p-values. Three hundred forty-five participants (332 evaluable) from 9 sites were randomized from 11/24/2017 to 3/25/2020 (172 bicalutamide, 173 AAP/Apa). Median follow-up was 34 (6-53) months; 29% were pN1 and 31% had PSA >0.5 ng/mL. The HR for PFS was 0.71 (90% CI 0.49-1.03), stratified one-sided log-rank p = 0.06 (3-year PFS was 68.5% bicalutamide vs 74.9% AAP/Apa). The HR for MFS was 0.57 (90% CI 0.33-1.01), stratified one-sided log rank p = 0.05 (3-year MFS was 87.2% bicalutamide vs 90.6% AAP/Apa). In a pre-planned analysis by stratification factors, AAP/Apa was significantly superior for patients with PSA >0.5 for PFS [HR 0.50, (95% CI 0.27-0.95), p = 0.03 (2-sided); 3-year PFS 46.8% bicalutamide vs. 67.2% AAP/Apa] and for MFS [HR 0.32 (95% CI 0.13-0.84), p = 0.02 (2-sided); 3-year MFS 66.1% bicalutamide vs. 84.3% AAP/Apa.] No statistically significant benefit was detected in pre-planned analyses of stratification subgroups defined by PSA≤0.5, pN0, or pN1. Adverse events were consistent with the known safety profiles of the agents being studied, with more rash and hypertension in the AAP/Apa arm. Although this primary analysis did not meet the pre-specified threshold for statistical significance, it does strongly suggest that the addition of AAP/Apa instead of bicalutamide to SRT+6 months of GnRH Agonist may improve PFS and MFS, particularly in the subgroup of patients with PSA>0.5 where a pre-planned subgroup analysis by stratification factors observed a statistically significant benefit for both PFS and MFS. (NCT03141671).

Randomized Phase II Multicenter Trial of Abiraterone Acetate With or Without Cabazitaxel in the Treatment of Metastatic Castration-Resistant Prostate Cancer.

Improving clinical outcomes with novel drug combinations to treat metastatic castration-resistant prostate cancer (mCRPC) is challenging. Preclinical studies showed cabazitaxel had superior antitumor efficacy compared with docetaxel. Gene expression profiling revealed divergent effects of these taxanes in cycling cells. mCRPC are RB deficient rendering them hypersensitive to taxanes. These data suggested that upfront treatment with cabazitaxel with abiraterone may affect therapeutic response. We designed a phase II randomized noncomparative trial of abiraterone acetate/prednisone (AAP) or AAP and cabazitaxel (AAP + C) in men with mCRPC to address this hypothesis. This trial of 81 men with mCRPC determined the radiographic progression-free survival (rPFS), prostate-specific antigen (PSA) progression-free survival, overall objective response, and safety of AAP or AAP + C. Equally allocated patients received AAP followed by switching to cabazitaxel upon radiographic progression (arm 1) or upfront with AAP + C (arm 2). Patients were stratified into high-/low-risk groups by the Halabi nomogram. Real-time assessment of RB status and circulating tumor cell (CTC) analysis to correlate with clinical outcomes was exploratory. Both treatment arms were well-tolerated. Median rPFS in AAP was 6.4 months (95% CI, 3.8 to 10.6) and median overall survival (OS) 18.3 months (95% CI, 14.4 to 37.6), respectively. Fifty-six percent of patients showed ≥50% decline in PSA. Median rPFS in AAP + C was 14.8 months (95% CI, 10.6 to 16.4), and median OS 24.5 months (95% CI, 20.4 to 35.0). There was a ≥50% decline in PSA in 92.1% of men. Neither RB expression in pretherapy tumor biopsy, CTC, or tissue explants identified those who may benefit from AAP + C. AAP + C was safe with improved rPFS, OS duration, and a higher proportion of PSA declines. This suggests that AAP + C given earlier rather than sequentially may benefit some men. Further work is needed to identify this population.

Dynamic assessment of serum chromogranin A and treatment response with abiraterone acetate in metastatic castration-resistant prostate cancer.

Elevated serum chromogranin A (CGA) is associated with intrinsic or treatment-related neuroendocrine differentiation (NED) in men with metastatic castration-resistant prostate cancer (mCRPC). Fluctuations in serum CGA during treatment of mCRPC have had conflicting results. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with abiraterone acetate (AA) therapy. Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial with uniform serum CGA processing performed before initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded), therefore 71 patients were analyzed. All patients underwent a composite response assessment at 12-weeks. Kaplan-Meier estimates and Cox Regression models were used to calculate the association with time-to-treatment failure analyses and overall survival. An increase in chromogranin was associated with a lower risk of treatment failure (hazard ratio [HR]: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6-16.0) and an elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). An increase in CGA was not found to be associated with OS (HR: 0.71, 95% CI: 0.42-1.21, p = 0.207). An elevated baseline CGA/PSA ratio was not associated with OS (HR: 0.62, 95% CI: 0.37-1.03, p = 0.062). An increase in PSA after 12 weeks of treatment was associated with an increased risk of treatment failure (HR: 4.14, CI: 2.21-7.73, p = < 0.0001) and worse OS (HR: 2.93, CI: 1.57-4.45, p = < 0.0001). We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in patients with mCRPC were associated with a favorable response to AA/P with no changes in survival. There may be limited clinical utility in serum CGA testing to evaluate for lethal NED as AA/P did not induce lethal NED in this cohort. This highlights that not all patients with an increasing CGA have a worse OS.

Efficacy and safety of abiraterone acetate plus prednisone and androgen deprivation therapy +/- docetaxel in older patients (≥70 years), with de novo metastatic-castration sensitive prostate cancer, compared to younger patients (&lt;70 years): The PEACE-1 trial.

20 Background: Metastatic castration-sensitive prostate cancer (mCSPC) primarily affects older men (OM). In this post-hoc analysis we investigated the safety and efficacy of abiraterone acetate + prednisone (AAP) in older (≥ 70 years) and younger (&lt; 70 years) patients in PEACE-1. Methods: Men with de novo mCSPC were allocated to standard of care (SOC), SOC + AAP, SOC + radiotherapy (RXT), or SOC + AAP + RXT in this 2x2 design phase 3 trial. SOC was initially androgen deprivation therapy (ADT) alone, then from Oct 2015 onwards, the use of docetaxel (D) was authorized as part of SOC (at the investigator’s discretion until 2017, then, following the publication of LATITUDE and STAMPEDE trials, accrual was restricted to men receiving ADT+ D). Efficacy and safety in OM included in PEACE-1 were analyzed with the same methods used in the overall trial (Lancet 2022; 399: 1695-1707). Results: A total of 741 younger men (YM) (63%) and 431 OM (37%) were randomized. OM presented with more altered PS (ECOG 1-2) (36% vs 26% p=0.0003) and less frequent use of docetaxel (D) as part of SOC (66% vs 51% p&lt;0.0001) than YM. Hypertension (56,5% vs 38,2%, p&lt;0,001) and diabetes mellitus type 2 (15,5% vs 11%, p=0,029) were significantly more frequent in OM. Median time to AAP discontinuation was shorter (30.0 months [95%CI= 22.1; 35.4] vs 41.4 [95%CI= 31.5; 54.0] independently of D use and more frequently due to adverse events or death in the older than younger population. The benefit of AAP on radiographic progression-free survival (rPFS) tended to decrease with age in the overall population: (HR 0.65, 95%CI 0.42-1.01) in OM vs (HR 0.49, 95%CI 0.35-0.69) for YM. The same trend was observed on overall survival (OS): (HR 0.95, 95%CI 0.72-1.25) for OM vs (HR: 0.73, 95%CI 0.58-0.92) for YM. On the other hand, in men fit to receive the SOC composed of ADT+D, the rPFS benefit of AAP was comparable in OM (HR 0.55, 95%CI 0.29-1.04) and in YM (HR 0.5, 95%CI 0.33-0.78). The OS benefit of AAP was: (HR 0.80, 95%CI 0.53-1.2) and (HR 0.71, 95%CI 0.52-0.95) in OM and YM, respectively. Safety data show that severe adverse events (grade 3-5) were more frequent in OM receiving AAP in comparison with YM (69% vs 61%) while there was no difference between older and YM not receiving AAP (48% vs 47%). Conclusions: This post-hoc analysis of PEACE-1 suggests that, in the overall population, OM derive a lower benefit, both in terms of rPFS and OS, from adding AAP to SOC versus YM. This decreased benefit is likely due to more toxicity leading to more frequent and earlier drug discontinuation. Importantly, in OM fit enough to receive ADT+D, the benefit of adding AAP to SOC was comparable to YM. Clinical trial information: NCT01957436 .

FORMULA-509: A multicenter randomized trial of post-operative salvage radiotherapy (SRT) and 6 months of GnRH agonist with or without abiraterone acetate/prednisone (AAP) and apalutamide (Apa) post-radical prostatectomy (RP).

303 Background: Six months of a GnRH agonist with SRT is a standard of care for patients with unfavorable features and a detectable PSA post-RP. FORMULA-509 was designed to evaluate whether adding six months of AAP and Apa to this regimen could improve outcomes. Methods: FORMULA-509 (NCT03141671) is an investigator-initiated, multi-center, open-label, randomized trial. Patients had PSA≥0.1 post-RP and one or more unfavorable features (Gleason 8-10, PSA&gt;0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time &lt;10 months, negative margins, persistent PSA, gross local/regional disease, or Decipher High Risk). All patients received SRT plus 6 months of GnRH agonist and randomization was to concurrent bicalutamide 50 mg or AAP 1000mg/5mg + Apa 240mg QD. Radiation to pelvic nodes was required for pN1 and optional for pN0. The primary endpoint was PSA progression-free survival (PFS) and secondary endpoint was metastasis-free survival (MFS) determined by conventional imaging. The study was powered to detect a HR of 0.50 for PFS and a HR of 0.30 for MFS, each with 80% power and one-sided type I error of 0.05. Stratification was by PSA at study entry (&gt;0.5 vs.≤0.5) and pN0 vs pN1. Analyses within these subgroups were pre-planned. Results: 345 participants (332 evaluable) from 9 sites were randomized from 11/24/2017 to 3/25/2020 (172 bicalutamide, 173 AAP/Apa). Median follow-up was 34 (6-53) months; 29% were pN1 and 31% had PSA &gt;0.5 ng/mL. The HR for PFS was 0.71 (90% CI 0.49-1.03), stratified one-sided log-rank p=0.06 (3-year PFS was 68.5% bicalutamide vs 74.9% AAP/Apa). The HR for MFS was 0.57 (90% CI 0.33-1.01), stratified one-sided log rank p=0.05 (3-year MFS was 87.2% bicalutamide vs 90.6% AAP/Apa). In a pre-planned analysis by stratification factors, AAP/Apa was significantly superior for patients with PSA &gt;0.5 for PFS [HR 0.50, (90% CI 0.30-0.86), p=0.03 (2-sided); 3-year PFS 46.8% bicalutamide vs. 67.2% AAP/Apa] and for MFS [HR 0.32 (90% CI 0.15-0.72), p=0.01 (2-sided); 3-year MFS 66.1% bicalutamide vs. 84.3% AAP/Apa.] No statistically significant benefit was detected in pre-planned analyses of stratification subgroups defined by PSA≤0.5, pN0, or pN1. Adverse events were consistent with the known safety profiles of the agents being studied, with more rash and hypertension in the AAP/Apa arm. Conclusions: Although this primary analysis did not meet the pre-specified threshold for statistical significance, it does strongly suggest that the addition of AAP/Apa to SRT+6 months of ADT may improve PFS and MFS, particularly in the subgroup of patients with PSA&gt;0.5 where a pre-planned subgroup analysis by stratification factors observed a statistically significant benefit for both PFS and MFS. Clinical trial information: NCT03141671 .

Plasma progastrin-releasing peptide level shows different predictive profiles for treatment response by androgen receptor axis-targeted agents in patients with metastatic castration-resistant prostate cancer.

The neuroendocrine (NE) pathway cannot be ignored as a mechanism for castration-resistant prostate cancer (CRPC) progression. The neuromediator, gastrin-releasing peptide (GRP) may be involved in the aberrant activation of the normal androgen receptor (AR) and increased AR variants. This study focused on plasma levels of progastrin-releasing peptide (ProGRP) and examined the treatment outcomes with androgen receptor axis-targeted (ARAT) agents. One hundred patients with metastatic CRPC were enrolled. Enzalutamide (ENZ) or abiraterone acetate/prednisone (AA/P) were administered to 50 patients each in a nonrandomized manner as a first-line or later choice. Plasma ProGRP levels were determined using a chemiluminescent enzyme immunoassay, and data were collected prospectively. The study endpoints were prostate-specific antigen (PSA) response and survival estimates. In the ENZ series, ProGRP levels correlated with the maximum PSA change from baseline (high ProGRP: -34.5% vs. low ProGRP: -85.7% p= .033). PSA progression-free survival (PFS), radiographic/symptomatic (r/s) PFS, and overall survival (OS) in patients with high ProGRP were significantly worse than those in patients with low ProGRP (median PSA-PFS: 3.3 vs. 10.0months, p =.001, r/s PFS: 5.0 vs. 15.0months, p< 0.001, and OS 17.5 vs. 49.0months, p< .001, respectively). In addition, ProGRP showed an independent predictive value for all survival estimates in multivariate analyses. In the AA/P series, ProGRP levels did not correlate with the PSA change or predict PSA-PFS and r/s PFS, but they maintained a significant difference in OS (19.0 vs. 48.0months, p= .003). Plasma ProGRP provides a consistent predictive value for OS in metastatic CRPC patients who underwent therapy with ARAT agents. Meanwhile, ProGRP showed different predictive profiles for PSA- and r/s PFS between ENZ and AA/P. These findings clinically suggest a mechanism for CRPC progression involving the NE pathway via the GRP. The underlying mechanism of different predictive profiles by the ARAT agent should be explored in future research.

Does Clinical Evidence of Heterogeneity Impact Treatment Selection? A Case Study of Abiraterone for Metastatic Prostate Cancer.

Two pivotal randomized controlled trials (RCTs) demonstrate that abiraterone acetate + prednisone (AAP) combined with androgen deprivation therapy (ADT) significantly extends the survival of men with metastatic hormone-sensitive prostate cancer (mHSPC) compared with ADT alone. Their subgroup analyses indicate that the survival benefit is significant for younger men but not older men. We aimed to assess whether publication of the RCTs was associated with differential real-world AAP utilization by age groups. Using TriNetX electronic medical records data collected from 43 healthcare organizations across the United States, we performed a difference-in-differences event study among men with newly diagnosed mHSPC observed from June 2014 to June 2019. Eligible subjects were identified based on a comprehensive published algorithm. We analyzed the change in utilization rate of AAP before versus after publication of the RCTs among men aged &lt;70 years versus ≥70 years, adjusting for demographic factors and clinical conditions. Our study included 6,888 men with newly diagnosed mHSPC with 12,738 observations, of whom 46% were aged &lt;70 years. The prepublication trends of AAP utilization were similar between the age groups, whereas publication of the RCTs was associated with a 3.5% higher adjusted uptake rate of AAP among younger men (95% CI, 1.2%-5.8%) relative to older men. This estimate reflects an uptake rate nearly 3 times higher than would have been expected had younger men followed the same utilization trends as older men. The estimates remained consistent throughout the postpublication period. Our study suggests that publication of the RCTs was associated with faster uptake of AAP among younger versus older men with newly diagnosed mHSPC, despite the absence of clinical guidance for differential treatment selection. This finding highlights the importance of confirmatory studies among older men, considering the uncertainties of subgroup analyses in RCTs.

Systemic Therapy for Metastatic Hormone-Sensitive Prostate Cancer: A Randomized Controlled Trial-Based Network Meta-Analysis.

To compare the effects of different treatment strategies for metastatic hormone-sensitive prostate cancer (mHSPC) using a network meta-analysis. English databases (PubMed, Embase, and medRxiv) and Chinese databases (Wanfang and CNKI) were searched for randomized controlled trials (RCTs) on the treatment of mHSPC from inception to June 1, 2021. The overall survival (OS) and failure-free survival (FFS) reported by the included studies were extracted from each study for network meta-analysis. Moreover, the priority ranks of the treatment methods were determined. A total of 18 RCTs with 14,682 patients were included in this study. Androgen-deprivation therapy (ADT) + apalutamide (APA) showed the highest probability of improving the OS (96.2%) and FFS (68.0%). In addition, the patients were stratified into ten subgroups as follows: low/high tumor burden (CHAARTED criteria); Gleason score ≤7/≥8; Eastern Cooperative Oncology Group (ECOG) = 0/≥1; with/without prechemotherapy; and cooperative with/without concomitant radiotherapy. For the improvement of OS, the leading treatments were as follows: (1) ADT + enzalutamide (ENZA) (64.1%)/ADT + abiraterone acetate + prednisone (AAP) (54.3%); (2) ADT + ENZA (41.9%)/ADT + APA (39.2%); (3) ADT + ENZA (39.2%)/ADT + APA (32.1%); (4) ADT + radiotherapy (51%)/ADT + ENZA (76.7%); (5) ADT + AAP (51%)/ADT + AAP (60%). Three endocrine therapy drugs, abiraterone, enzalutamide, and APA, exhibited the best effects in improving the OS and FFS in all patients and subgroups; however, APA had the most prominent treatment effects. Therefore, ADT + APA should be applied as the common treatment for patients with HSPC based on objective and clinical conditions. Trial Registration. This meta-analysis has been registered on the PROSPERO website (Trial number: https://www.crd.york.ac.uk/prospero/CRD42020221062).

Early discontinuation of abiraterone acetate/prednisone (AA/P) in localized prostate cancer.

e17003 Background: Data from STAMPEDE trial supporting systemic therapy intensification with long course AA/P was first presented in 2017. Overall survival benefit was confirmed in 2021. Our institution proceeded with early adoption of addition of 24 months of AA/P to ADT and radiotherapy (RT) in patients with high-risk localized or regional prostate cancer in 2017. In STAMPEDE, only 17% patients discontinued AA/P prior to completion of planned course. Outside of a clinical trial, whether patients adhere to this intense combination therapy that is associated with toxicities and expense is unknown. We hypothesized that adherence to long course AA/P in real-world practice in definitively treated prostate cancer would be poor. Methods: We performed a retrospective study for patients with clinically localized prostate cancer treated with AA/P combined with standard ADT and RT who had at least 6 months of follow-up data. Primary endpoint was rate of early discontinuation (prior to the 24mo) of AA/P. Secondary outcomes included rates of RT completion and disease recurrence and toxicity of intensive therapy. Reasons for early discontinuation were analyzed. Fisher's Exact, Chi-square analysis and Mann-Whitney tests were used to compare variables. SAS 9.4 was used for statistical analysis. Results: We identified 77 patients who met inclusion criteria, including 2 (2%) with high-risk, 30 (39%) with very high-risk, 19 (25%) with regional risk and 26 (34%) with locally recurrent disease after prostatectomy. AA/P was discontinued in 29 (38%) patients prior to completion of 24mo. Among those with early discontinuation, median duration of AA/P was 12.1 mo [0.1-21.7] and median duration of ADT was 17 mo[3.5-32.2]. Common reasons for early AA/P discontinuation included refractory hypokalemia (n = 4), diarrhea (n = 3), heart failure and fluid retention (n = 2 each) and quality of life deterioration (n = 8). Other reasons included hepatotoxicity, arrhythmia, osteoporotic fracture and financial toxicity (n = 1 each). All patients completed definitive RT. Only 1 of 77 patients had disease recurrence and had discontinued AA/P after 14 mo. A statistically significant association between age at diagnosis and treatment completion was noted(p = 0.01); each 1-year increase in age was associated with 9.4% decrease in odds of completing AA/P. Median age at diagnosis in those completing vs not completing AA/P was 65 vs 71 years. Conclusions: Very high rates of early discontinuation of AA/P were observed among patients with localized prostate cancer receiving definitive RT. Patients were less tolerant of toxicity in adjuvant setting compared to in a clinical trial or advanced disease. Shorter durations of AA/P appeared more acceptable but whether similar benefit is derived with a truncated course of AA/P is unknown. Future studies need to explore an optimal duration of AA/P that will reduce toxicity without compromising survival benefit.

Treatment of patients with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) in Belgium: a real world data analysis

ABSTRACT INTRODUCTION Abiraterone acetate + prednisone (AAP) and docetaxel have proven their efficacy in the treatment of patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) in clinical trials. However, real-world data are scarce. The goal of this study is to evaluate real-world data on the efficacy and safety of these therapies in mHSPC patients. PATIENTS AND METHODS Records of 93 patients from 21 different centres were retrospectively reviewed. Primary and secondary endpoints were radiographic and PSA progression-free survival (RPFS – PSA-PFS) and cancer specific and overall survival (CSS – OS), respectively. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Differences in oncological outcome and AEs were evaluated between three treatment groups: ADT only (N=26) – ADT + AAP (N=48) – ADT + docetaxel (N=19). Survival analysis was performed using Kaplan–Meier statistics. RESULTS Median RPFS was 13 months (95% confidence interval [CI]: 9–17) for ADT only, 21 months (95% CI: 19–23) for ADT + AAP and 12 months (95% CI: 11–14) for ADT + docetaxel (p = 0.004). The 1-year PSA-PFS, CSS and OS were 73.5%, 90.7% and 88.7%, respectively, with no significant differences between the three groups. Adverse events of grade 3 or higher were not observed more frequently. CONCLUSION Retrospective real-world data show a significantly longer RPFS for mHSPC patients treated with ADT + AAP compared to ADT only or ADT + docetaxel at short-term follow-up. This can aid in counselling of mHSPC patients in daily clinical practice.

A phase 3 trial with a 2x2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): First results of PEACE-1.

5000 Background: Historically, androgen deprivation therapy (ADT) was the standard of care (SOC) for men with mCSPC. Since 2015, combining ADT with either docetaxel, novel hormonal therapies, or radiotherapy to the primary tumor (RXT) (for those with low burden metastases) was shown to improve overall survival (OS) and thus has become the new SOC. It is unknown whether combining these new treatments on top of ADT further increments outcomes. Methods: Men with de novo mCSPC were randomized to SOC, SOC + abiraterone acetate-prednisone (abiraterone), SOC + RXT, or SOC + abiraterone + RXT. SOC was initially ADT alone, then from Oct 2015 onwards the use of docetaxel was authorized as part of SOC (at the investigator’s discretion until 2017, then, following the publication of the LATITUDE and STAMPEDE trials, accrual was restricted to men receiving ADT+docetaxel). The trial has two co-primary endpoints of radiographic progression-free survival (rPFS) and OS with type I error of 0.1% and 4.9%, respectively. The required number of rPFS events to achieve 80% power has been reached for the abiraterone question (not yet for the RXT question). The interaction between abiraterone and RXT was first tested using a Cox model adjusted for stratification factors (performance status, type of castration, metastatic burden, and when applicable, docetaxel). A hierarchical testing was used to test the effect of abiraterone: overall population, then ADT+docetaxel population. Results: From Nov 2013 to Dec 2018, 1173 men were enrolled (SOC was ADT+docetaxel in 710 pts and ADT alone in 463 pts), median age 67y (IQR: 60-72), high volume 57%, low volume 43%. The median follow-up is 3.5y. No interaction was detected between the effect of abiraterone and that of RXT (p = 0.64), allowing to pool abiraterone arms for comparisons. rPFS was significantly improved in the abiraterone arm in the overall population (HR: 0.54 (0.46-0.64), p &lt; 0.0001; medians: 2.2 vs 4.5 years) and in the ADT+docetaxel population: (HR: 0.50 (0.40-0.62), p &lt; 0.0001; medians: 2.0 vs 4.5 years). bPFS (PFS including PSA progression as an event) also significantly favored abiraterone in the overall population (HR: 0.40 (0.35-0.47), p &lt; 0.0001; medians: 1.5 vs 3.8 years) and in the ADT+docetaxel population (HR: 0.38 (0.31-0.47), p &lt; 0.0001; medians: 1.5 vs 3.2 years). OS is maturing. Grade 3-4 adverse events reported in &gt; 5% of pts within the first 6 months in the ADT+docetaxel population included neutropenic fever (4.5% vs 5.4%), liver toxicity (19.7% vs 13%), and hypertension (12.2% vs 8.6%) in the abiraterone and control arms, respectively. Conclusion: Adding abiraterone to ADT + docetaxel significantly improves rPFS in men with de novo metastatic prostate cancer, with about 2.5 years of absolute benefit in medians, and no meaningful additional short-term toxicity. Clinical trial information: NCT01957436.

Geographic variation in systemic therapy in men age 66 years and older with de novo metastatic castration-sensitive prostate cancer: A population-based study in a single payer health-system.

50 Background: Significant developments in the standard of care for patients with de novo metastatic castration-sensitive prostate cancer (mCSPC) have been reported over the past decade. Treatment intensification with systemic therapies in addition to androgen deprivation therapy (ADT) alone is guideline recommended for most patients. We studied the geographic variation in the use of systemic therapy for de novo mCSPC in Ontario, Canada, a single-payer health system. Methods: We performed a population-based study of men aged 66 years and older diagnosed with de novo mCSPC between 2014-2019. We linked population-based healthcare databases, as administered at the level of Local Health Integration Networks (LHINs) in Ontario, to examine treatment patterns following diagnosis of de novo mCSPC. We categorized initial mCSPC treatments as those begun within 60 days preceding and 6 months following diagnosis and examined the proportion of patients receiving LHRH alone, first generation anti-androgen (AA) alone, combined androgen blockade (CAB; LHRH + 1st gen AA), ADT + abiraterone acetate + prednisone (AAP), and, ADT + docetaxel (D). In aggregate, we considered LHRH alone, AA alone and CAB as “standard ADT”, and ADT + AAP and ADT + D as “ADT-plus”. Multinomial logistic regression analyses were used to examine the association between receiving systemic treatment intensification (“ADT-plus”) or no prostate cancer pharmacotherapy relative to ADT across geographic regions, while adjusting for baseline patient and disease characteristics. Results: We identified 3,556 men over 66 with de novo mCSPC. Overall, 2794 (78.6%) received standard ADT, 311 (8.7%) did not receive prostate cancer-directed pharmacotherapy, and 451 patients (12.7%) of patients received “ADT-plus”. Utilization of AAP increased from 0.5% to 3% following the LATITUDE data release in 2017, while D decreased from 12% to 10%. There was significant variation in treatment strategies between geographic regions in use of “ADT-plus” ranging from 7 to 20% (p &lt; 0.0001), a difference which persisted after accounting for patient demographics, comorbidity, rurality, and disease characteristics (p = 0.036). Conclusions: Despite proven survival benefits in randomized controlled trials, intensified treatment with docetaxel or abiraterone in addition to ADT was infrequently utilized in this population-based study of men age 66 years and over with mCSPC.

Association Between CYP17A1, CYB5A Polymorphisms and Efficacy of Abiraterone Acetate/Prednisone Treatment in Castration-ResistantProstate Cancer Patients.

PurposeThe purpose of this study was to investigate the association between single nucleotide polymorphisms (SNPs) of CYP17A1, CYB5A and the efficacy of abiraterone acetate treatment in patients with castration-resistant prostate cancer (CRPC).Patients and MethodsData were collected from 58 CRPC patients who had been treated with abiraterone acetate/prednisone (AA/P). The SNPs rs743572 and rs10883783 on CYP17A1 and SNPs rs1790834 and rs1790858 on CYB5A were assayed, and their relationship with prostate-specific antigen (PSA) response in patients after AA/P treatment, overall survival (OS) and progression-free survival (PFS) were analyzed by logistic regression, Cox regression, Kaplan–Meier and Log rank analyses.ResultsThe SNP rs1790834 on CYB5A showed significant association with PSA response in CRPC patients treated with AA/P (P < 0.05), but rs743572, rs10883783 and rs1790858 did not. The rs1790834 variant significantly decreased both PFS and OS (P < 0.05).ConclusionThe CYB5A rs790834 genotype is a novel SNP related to CRPC and may be used as a biomarker for CRPC treatment.

PD10-09 INTERIM ANALYSIS OF PHASE 2 RANDOMIZED PROSPECTIVE STUDY ON NEOADJUVANT APALUTAMIDE/ABIRATERONE ACETATE WITH PREDNISONE AND THE FEASIBILITY OF PERFORMING NERVE-SPARING RADICAL PROSTATECTOMY IN MEN WITH HIGH-RISK PROSTATE CANCER (NCT02949284)

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I (PD10)1 Apr 2020PD10-09 INTERIM ANALYSIS OF PHASE 2 RANDOMIZED PROSPECTIVE STUDY ON NEOADJUVANT APALUTAMIDE/ABIRATERONE ACETATE WITH PREDNISONE AND THE FEASIBILITY OF PERFORMING NERVE-SPARING RADICAL PROSTATECTOMY IN MEN WITH HIGH-RISK PROSTATE CANCER (NCT02949284) Joshua Sterling*, Kevin Chua, Hiren Patel, and Isaac Kim Joshua Sterling*Joshua Sterling* More articles by this author , Kevin ChuaKevin Chua More articles by this author , Hiren PatelHiren Patel More articles by this author , and Isaac KimIsaac Kim More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000844.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Neoadjuvant androgen deprivation therapy has been shown to decrease positive surgical margin rates following radical prostatectomy (RP). Here we report early outcomes of a randomized prospective clinical trial evaluating the effect of neoadjuvant apalutamide ± abiraterone acetate (AA)/prednisone (AAP) and gonadotropin-releasing hormone (GnRH) agonist on the feasibility of performing nerve-sparing radical prostatectomy in men with a high-risk prostate cancer (PCa). METHODS: This is a multi-center phase 2 randomized three arm trial (NCT02949284). High-risk PCa was defined as either PSA > 20 ng/ml or Gleason score ≥ 8. Patients were randomized to one of three study arms: I) daily apalutamide for 3 months followed by surgery, II) apalutamide/AAP/GnRH agonist for 3 months followed by surgery, III) immediate surgery. Patients are followed for 2 years post-operatively. Primary outcome is potency at 1 year. Secondary outcomes are change in tumor volume on MRI, biochemical recurrence (BCR), post-operative continence rates, and quality of life. RESULTS: Thirty-two patients have been enrolled to date: 4 patients opted out after randomization, 1 was declared ineligible due to a major vascular event that occurred prior to starting treatment, 3 are still receiving neoadjuvant treatment, and 24 are in the follow up phase. Two patients in the neoadjuvant groups did not complete the prescribed treatment. Overall pathologic outcome is shown in table 1. There were no significant differences in operative times across the groups. There was a median reduction of 32.4% and 55.7% in tumor volume in Arm I and II, respectively. There was no pathologically complete response. Potency was achieved in 50%, 14.2%, and 28.5% in Arm I, II, and III, respectively. Three patients have BCR (1 in Arm I and 2 in Arm II). Surgical margin was positive in 3, 1, and 3 patients in arm I, II, and III respectively. CONCLUSIONS: Early results indicate that neoadjuvant therapy prior to RP resulted in reduction of tumor volume and trends supporting increased potency preservation without an adverse effect on positive surgical margin rates. Collectively, these interim results suggest that neoadjuvant apalutamide ± AAP may be a reasonable strategy for nerve-sparing RP in men with a high-risk PCa. Source of Funding: This work is supported by an Investigator Initiated Study grant from Janssen, LLC and NIH (P30CA072720) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e249-e249 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joshua Sterling* More articles by this author Kevin Chua More articles by this author Hiren Patel More articles by this author Isaac Kim More articles by this author Expand All Advertisement PDF downloadLoading ...

Cost-effectiveness of upfront therapeutic options in low-volume de novo metastatic hormone-sensitive prostate cancer.

211 Background: Low-volume de novo metastatic hormone-sensitive prostate cancer (mHSPC) has historically been treated with lifelong androgen deprivation therapy (ADT). Recently, however, the addition of several advanced therapeutic options – radiation therapy (RT) to the primary, advanced hormonal therapy agents such as abiraterone acetate/prednisone (AAP), and chemotherapy – to ADT have been shown to improve survival in low-volume mHSPC. The objective of this study was to compare the cost-effectiveness of treating low-volume mHSPC patients upfront with RT+ADT, AAP+ADT, or docetaxel+ADT. Methods: A Markov-based cost-effectiveness analysis was constructed comparing three treatment strategies for low-volume mHSPC patients: (1) upfront RT+ADT --&gt; salvage AAP+ADT --&gt; salvage docetaxel+ADT; (2) upfront AAP+ADT --&gt; salvage docetaxel+ADT, and (3) upfront docetaxel+ADT --&gt; salvage AAP+ADT. Transition probabilities were calculated using data from STAMPEDE arms C/G/H, COU-AA-301, COU-AA-302, and TAX-327. RT was delivered via five-fraction stereotactic body radiation therapy. The analysis utilized a 10-year time horizon, and a $100,000/quality adjusted life year (QALY) willingness-to-pay threshold. Utilities were extracted from the literature; costs were taken from Medicare fee schedules and VA oral drug contracts. Results: At 10 years, total cost was $140K, $259K, and $189K, with total QALYs of 4.66, 5.03, and 3.72 for strategies (1) upfront RT+ADT, (2) upfront AAP+ADT, and (3) upfront docetaxel+ADT, respectively. Compared to upfront RT+ADT, upfront AAP+ADT was not cost-effective (ICER: $321K/QALY). This result remained unchanged even after modification of various model inputs in 1-way sensitivity analysis. Upfront docetaxel+ADT was both more costly and less effective than upfront RT+ADT (ICER: -$53K/QALY). Conclusions: At 10 years, RT+ADT is cost-effective compared to other advanced systemic therapy options alone, and should be considered as a viable treatment strategy in all patients with a low-burden of metastatic disease. Additional studies are needed to determine whether any benefit exists in combining RT to the primary with upfront advanced systemic therapy.

Clinical and Biological Characterisation of Localised High-risk Prostate Cancer: Results of a Randomised Preoperative Study of a Luteinising Hormone-releasing Hormone Agonist with or Without Abiraterone Acetate plus Prednisone

Optimal therapeutic strategy remains an unmet need in localised high-risk prostate cancer (LHRPC). Androgen biosynthesis inhibition in the preoperative setting may improve outcomes. In this single-centre randomised trial, we looked at therapy outcomes of preoperative treatment with abiraterone acetate+prednisone (AAP)+luteinising hormone-releasing hormone agonist (LHRHa) or LHRHa alone followed by radical prostatectomy in 65 men. We did not see a significant difference of organ-confined carcinoma (p=0.27). However, tumour volume measures were significantly lower for AAP+LHRHa treatment (p≤0.001). Of note, lower tumour epithelium volume correlated with improved biochemical recurrence-free survival at ≥4-yr follow-up (p=0.0014). Tumours pretreated with AAP+LHRHa had lower proliferation and androgen signalling expression than LHRHa. On multivariate analysis, glucocorticoid receptor (GR) overexpression correlated with persistent tumours in AAP+LHRHa (p=0.018). The presence of nuclear androgen receptor splice variant (nARV7) correlated with persistent tumours in both arms. No new safety signals were observed. This is the first study investigating the role of preoperative AAP+LHRHa versus LHRHa alone in LHRPC. We report significant cytoreduction by tumour volume measures inversely correlating with biochemical relapse. Validation of these proposed tumour volume measures is planned. A potential role of GR in resistance to androgen biosynthesis inhibition warrants further study. Patient summaryThis is the first study of abiraterone acetate plus leuprolide versus leuprolide alone in high-risk localised prostate cancer followed by prostatectomy. Patients in the combination arm had a significantly smaller tumour size.

Evolution of androgen receptor variant (ARV) profiles in serial metastatic solid and liquid biopsies in metastatic castrate resistant prostate cancer (mCRPC) treated with abiraterone acetate/ prednisone (AA/P).

e16559 Background: ARVs that develop early during treatment with abiraterone acetate/ prednisone (AA/P) may play a role in treatment resistance. We evaluated metastatic site and whole blood mRNA expression of full-length AR (AR-FL) and ARVs to characterize treatment-emergent ARVs (TE-ARVs) from men with mCRPC pre- and post- 12 weeks of AA/P collected in a prospective clinical trial (NCT#01953640). Methods: RNAseq performed on paired metastatic site biopsy (n = 40) and whole blood (n = 25) passed quality control. Reads were aligned to the GRCh38 reference genome with the spliced-alignment TopHat2 package. AR-FL or ARVs were detected if ≥ 2 splice reads aligned to unique splice junctions for AR-FL, AR-8, AR-45, AR-23, AR-V3, AR-V5V6, AR-V7, AR-V8, AR-V9, AR-V10, AR-V12, AR-V13, and AR-V14, and normalized to splice reads per million (SRPM). Cox proportional hazard regression analysis was performed on AR-FL and AR-Vs with ≥1 SRPM for association with time to treatment change (TTTC). Results: In metastatic site biopsies post-AA/P, the average number of splice reads was 27,376,541 (range 7,753,998 to 62,456,773). The median number of ARVs detected was 2 (range 0-8), with a total of total of 110 ARVs identified (Table). Dynamic shifts in ARV profiles were observed post-AAP, with 41 TE-ARVs identified in 17 unique patients. The most common TE-ARV was AR-8 (n = 8), followed by AR-45 (n = 5), AR-23 (n = 5), and AR-V7 (n = 4). The presence of AR-V7 post-AAP was adversely associated with TTTC (hazard ratio 2.46, p = 0.013). The identification of early TE- ARV was not associated with TTTC. In whole blood samples, post-AA/P detection of AR-FL was low (n = 3) and no ARVs were detected. Conclusions: No specific patterns were observed in ARV profiles obtained in the metastatic biopsies after 12 weeks of treatment with AA/P. Clinical trial information: 01953640. [Table: see text]