Abiraterone Acetate Plus Prednisone Research Articles

Serum Androgens as Predictive Biomarkers: Results From a Randomized Clinical Trial Comparing Enzalutamide and Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer

IntroductionThe purpose of this study was to investigate the association between baseline androgen concentrations and outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line enzalutamide or abiraterone acetate plus prednisone (AAP). Materials and MethodsWe previously randomized men with mCRPC to enzalutamide or AAP to compare side-effects and measured androgen concentrations. In this post-hoc analysis, patients were grouped in quartiles (Q) based on their serum androgen values. Kaplan-Meier and Cox regression were used to analyze progression-free and overall survival for baseline androgen groups, treatment subgroups and their interaction. The trial was registered at clinicaltrialsregister.eu (2017-000099-27). ResultsEighty-four patients received enzalutamide and 85 AAP. Overall, higher (Q4) compared with lower (Q1) baseline serum testosterone was associated with longer progression-free survival (24.8 vs. 10.7 months, hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.33; 0.84) and overall survival (52.8 vs. 31.5 months, HR 0.49, 95% CI 0.28; 0.85). The risk reduction in death seemed to be treatment dependent (treatment subgroup interaction P = .04). For men in the AAP subgroup, the Q4 compared with Q1 group had a significant lower risk of death (HR 0.30, 95% CI 0.13; 0.73), while no difference was found for enzalutamide (HR 0.77, 95% CI 0.35; 1.69). Similar results were found for the other androgens. ConclusionPre-treatment serum testosterone levels may be a clinically useful biomarker for predicting mCRPC treatment responses and guiding treatment selection.

Survival outcome and prognostic factors in patients with chemotherapy-naive metastatic castration-resistant prostate cancer treated with abiraterone acetate – real-world experience in Vietnam

Introduction and aim. In real life, metastatic castration-resistant prostate cancer patients (mCRPC) had more complex clinical presentation than patients in the COU-AA-302 trial. This study primarily aimed to describe the overall survival of chemotherapy-naive mCRPC treated with abiraterone acetate plus prednisone (AAP). Other relevant outcomes and baseline characteristics of these patients were also evaluated. Material and methods. This retrospective, observational study collected data from chemotherapy-naive mCRPC patients treated with AAP in Vietnam. Kaplan-Meier curves were used to estimate time to treatment failure (TTF), and overall survival (OS). The impact of baseline characteristics on OS was explored using univariate and multivariate Cox proportional hazard models. Results. Data from 65 eligible patients were analyzed. The rate of PSA response was 73.8%, median PSA PFS was 10.5 months (95% CI: 7.4–13.6), median TTF was 15 months (95% CI: 11.1–18.9), and median OS was 24.9 months (95% CI: 18.9–30.9). Shorter OS was significantly associated with a higher Gleason score (≥8), shorter time from ADT start to mCRPC (<12 months), visceral metastases, and <50% PSA decline (p<0.05). Conclusion. Abiraterone acetate plus prednisone is well tolerated and effective for chemotherapy-naive mCRPC patients in clinical practice. Moreover, Gleason score, visceral metastasis, time from ADT start to mCRPC, and PSA response are the independent indicators for predicting the OS of mCRPC patientsin both univariate and multivariate analyses.

Combination of Abiraterone Acetate, Prostate Bed Radiotherapy, and Luteinizing Hormone-releasing Hormone Agonists in Biochemically Relapsing Patients After Prostatectomy (CARLHA): A Phase 2 Clinical Trial

BackgroundThe relevance of next-generation hormone therapies and circulating tumor cells (CTCs) are not elucidated in biochemical recurrence after prostatectomy. ObjectiveTo evaluate the combination of abiraterone acetate plus prednisone (AAP), prostate bed radiotherapy (PBRT), and goserelin in biochemically relapsing men after prostatectomy, and to investigate the utility of CTCs. Design, setting, and participantsIn this single-arm multicenter phase 2 trial, 46 biochemically relapsing men were enrolled between December 2012 and January 2019. The median follow-up was 47 mo. InterventionAll patients received AAP 1000 mg daily (but 750 mg during PBRT), salvage PBRT, and goserelin. Outcome measurements and statistical analysisThe primary outcome was 3-yr biochemical recurrence-free survival (bRFS) when prostate-specific antigen (PSA) levels were ≥0.2 ng/ml. The secondary outcomes included alternative bRFS (alt-bRFS) when PSA levels were ≥0.5 ng/ml and safety assessment. CTC count was assessed. Results and limitationsThe 3-yr bRFS and alt-bRFS were 81.5% (95% confidence interval or CI [66.4–90.3%]) and 95.6% (95% CI [83.5-98.9%]), respectively. The most common acute radiotherapy-related adverse effect (AE; all grades was pollakiuria (41.3%). The most common late AE (all grades) was urinary incontinence (15.2%). Grade 3-4 acute or late radiotherapy-related AEs were scarce. Most frequent AEs nonrelated to radiotherapy were hot flashes (76%), hypertension (63%), and hepatic cytolysis (50%, of which 20% were of grades 3-4). Of the patients, 11% had a CTC count of ≥5, which was correlated with poorer bRFS (p = 0.042) and alt-bRFS (p = 0.008). The association between CTC count and higher rates of relapse was independent of the baseline PSA level and PSA doubling time (p = 0.42 and p = 0.09, respectively). This study was nonrandomized with a limited number of patients, and few clinical events were reported. ConclusionsAdding AAP to salvage radiation therapy and goserelin resulted in high bRFS and alt-bRFS. AEs remained manageable, although a close liver surveillance is advised. CTC count appears as a promising biomarker for prognosis and predicting response to treatment. Patient summaryOur study was a phase 2 clinical trial that exhibited the efficacy and tolerance of a novel androgen-receptor targeting agent (abiraterone acetate plus prednisone) in patients with prostate cancer who experienced rising prostate-specific antigen after radical prostatectomy, in combination with prostate bed radiotherapy. The results also indicated the feasibility and potential value of circulating tumor cell detection, which constitutes a possible advance in managing prostate cancers.

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.

Patient-reported health-related quality of life (HRQoL) in the randomized FORMULA-509 trial of salvage radiotherapy and 6 months of GnRH agonist with either bicalutamide or abiraterone acetate plus prednisone (AAP) and apalutamide (Apa) after radical prostatectomy (RP).

260 Background: The randomized FORMULA-509 trial demonstrated that for patients with a PSA >0.5 after RP receiving salvage radiation and 6 months of GnRH Agonist, the addition of AAP and Apa improved metastasis-free survival compared to bicalutamide. Here we present the patient-reported health-related quality of life (HRQoL) results. Methods: Validated questionnaires were administered at baseline, end of treatment, and 1 year after completion of treatment. Patients completed EPIC-26, PROMIS Fatigue, and Saint Louis University Mental Status Exam (SLUMS). EPIC-26 is scored from 0 to 100 with 100 indicating higher function. PROMIS Fatigue is scored using a standardized T score with higher score indicating greater fatigue. SLUMS is scored from 0 to 30 with 27 to 30 interpreted as normal, 21 to 26 as mild neurocognitive disorder and 20 or less as dementia. Scores between treatment arms were compared using the t-test. Results were interpreted using established thresholds for clinically meaningful differences (4-6 for EPIC-26 hormonal domain, 5-10 for PROMIS Fatigue). Results: 345 patients were randomized (172 bicalutamide; 173 AAP/Apa). Completion rates at baseline, end of treatment, and 1 year, were 96%, 80%, and 70% for EPIC-26, 95%, 79%, and 67% for PROMIS Fatigue, and 96%, 80%, and 70% for SLUMS. From baseline to end of treatment, both arms demonstrated clinically meaningful declines in EPIC-26 hormonal domain (median change -15 bicalutamide; -15 AAP/Apa) and increase in PROMIS Fatigue (median change 6 bicalutamide; 7.4 AAP/Apa). From end of treatment to 1 year after treatment patient-reported HRQoL improved to near baseline for both EPIC-26 hormonal function (bicalutamide median score baseline: 95, end: 75, 1 year: 90; AAP/Apa baseline: 95, end: 75, 1 year: 90) and fatigue (bicalutamide median score baseline: 43.1, end: 48.6, 1 year: 46.0; AAP/Apa baseline: 43.1, end: 51.0, 1 year: 46.0). Median SLUMS score was within normal range at baseline (27 bicalutamide; 27 AAP/Apa), end of treatment (28, 28) and 1 year after treatment (27, 27). There was no difference in patient-reported hormonal function, fatigue, or mental status between treatment arms, at end of treatment (p=0.40; 0.78; 0.41 respectively) and 1 year after treatment (p=0.78; 0.89; 0.76 respectively). Conclusions: The addition of AAP/Apa improved oncologic outcomes without causing a detectable difference in patient-reported hormonal function, fatigue, or mental status compared to bicalutamide. Clinical trial information: NCT03141671 .

Evaluating Policies of Expanding Versus Restricting First-Line Treatment Choices: A Cost-Effectiveness Analysis Framework

ObjectivesHealthcare payers often implement coverage policies that restrict the utilization of costly new first-line treatments. Cost-effectiveness analysis can be conducted to inform these decisions by comparing the new treatment with an existing one. However, this approach may overlook important factors such as treatment effect heterogeneity and endogenous treatment selection, policy implementation costs, and diverse patient preferences across multiple treatment options. We aimed to develop a cost-effectiveness analysis framework that considers these real-world factors, facilitating the evaluation of alternative policies related to expanding or restricting first-line treatment choices. MethodsWe introduced a metric of incremental cost-effectiveness ratio (ICER) that compares an expanded choice set (CS) including the new first-line treatment with a restricted CS excluding the new treatment. ICER(CS) accounts for treatment selection influenced by heterogeneous treatment effects and policy implementation costs. We examined a basic scenario with 2 standard first-line treatment choices and a more realistic scenario involving diverse preferences toward multiple choices. To illustrate the framework, we conducted a retrospective evaluation of including versus excluding abiraterone acetate plus prednisone (AAP) (androgen deprivation therapy [ADT] + AAP) as a first-line treatment for metastatic hormone-sensitive prostate cancer. ResultsThe traditional ICERs for ADT + AAP versus ADT alone and ADT+ docetaxel were $104 269 and $206 324/quality-adjusted life-year, respectively. The ICER(CS) for comparing an expanded CS with ADT + AAP with a restricted CS without ADT + AAP was $123 179/quality-adjusted life-year. ConclusionsThe proposed framework provides decision makers with policy-relevant tools, enabling them to assess the cost-effectiveness of alternative policies of expanding versus restricting patients’ and physicians’ first-line treatment choices.

Tolerability of Metastasis-Directed Stereotactic Body Radiotherapy with Short-Course Triple-Agent Androgen Annihilation Therapy in Recurrent Oligometastatic Prostate Cancer: Secondary Analysis of a Phase II Study.

A majority of patients with oligometastatic prostate cancer experience relapse within 12 months of metastasis-directed therapy. Intense, triple-agent androgen annihilation therapy (AAT) with leuprolide, abiraterone acetate plus prednisone (AAP), and apalutamide may improve efficacy, but long courses of AAT have been shown to be associated with increased rates of grade≥3 toxicity. The purpose of this secondary analysis of this study is to characterize the tolerability of a short, six-month course of AAT added to metastasis-directed therapy. All 28 patients enrolled on this phase II study were included in this analysis. All patients had oligometastatic prostate cancer after initial radical prostatectomy, defined by the presence of 1-5 extrapelvic metastases on prostate-specific membrane antigen (PSMA) PET/CT. Patients were started on six months of AAT. After the first month, patients received stereotactic body radiotherapy (SBRT) in 1, 3, or 5 fractions to metastases with or without radiotherapy to the prostate bed and pelvic lymph nodes. Physician-scored toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Median follow-up time was 11.4 months. Twenty patients (71.4%) completed AAT with all three agents. Six patients (21.4%) completed six months of therapy but discontinued at least one agent [4 patients (14.3%) discontinued apalutamide, 1 patient (3.6%) discontinued AAP, and 1 patient (3.6%) discontinued both apalutamide and AAP]. Two patients (7.1%) withdrew from the trial due to adverse events and did not complete therapy. Grade 2 and grade 3 toxicity rates from AAT were each 21.4%. Of the 6 cases of grade 3 toxicity, 3 were skin rashes, 2 were hypertension, and 1 was hepatic toxicity. At the time of SBRT, 1 patient had withdrawn from the study and 1 patient declined radiation therapy. All 26 remaining patients completed SBRT. Grade 2 and grade 3 toxicity rates from SBRT were 7.7% and 0%, respectively. A majority of patients were able to tolerate and complete AAT in combination with metastasis-directed SBRT. Some patients experienced acute grade 3 toxicities, the most common being drug-related skin rashes and hypertension. While efficacy data are needed to evaluate the oncologic benefit, these data suggest a short course of AAT is considerably better tolerated than longer courses of AAT, with grade 3 toxicity rates similar to long courses of single-agent androgen deprivation therapy alone.

LBA85 Niraparib (NIRA) with abiraterone acetate plus prednisone (AAP) as first-line (1L) therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations: Three-year update and final analysis (FA) of MAGNITUDE

LBA85 Niraparib (NIRA) with abiraterone acetate plus prednisone (AAP) as first-line (1L) therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations: Three-year update and final analysis (FA) of MAGNITUDE

Association between concomitant proton pump inhibitor use and survival of patients with metastatic prostate cancer receiving abiraterone acetate: a post-hoc analysis of pooled data from three randomized controlled trials.

Evidence suggests proton pump inhibitor (PPI) use may attenuate the effect of abiraterone acetate plus prednisone (AAP) in metastatic prostate cancer via the modification of gut microbiota. This study aimed to examine whether concomitant PPI use is associated with survival in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT) and AAP. Post-hoc analysis was conducted in patients with metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) treated in the LATITUDE, COU-AA-301, and COU-AA-302 trials (ADT vs. ADT plus AAP). PPI users and non-users were compared for restricted mean overall survival time (RMOST) and restricted mean progression-free survival time (RMPFST) based on inverse probability of treatment weight (IPTW)-adjusted Kaplan-Meier curves. IPTW-adjusted Cox regression models were used to assess heterogeneity of treatment effect. In patients treated with AAP, PPI use was associated with inferior RMOST [difference (95% confidence interval): -4.2 (-7.0 to -1.4)] and RMPFST [-3.5 (-6.6 to -0.4)] compared with non-users. However, RMOST and RMPFST were similar between PPI users and non-users in patients treated with ADT alone [RMOST, -2.6 (-5.8 to 0.6); RMPFST, -1.7 (-4.8 to 1.4)]. Interaction term analyses did not show evidence of heterogeneity in treatment effect between AAP and ADT, despite the prominent treatment effect shown in mCSPC vs. mCRPC. PPI use may be associated with inferior survival in patients with metastatic prostate cancer who receive ADT plus AAP. Discontinuing unnecessary PPI use might improve those outcomes.

Prostate irradiation in men with de novo, low-volume, metastatic, castration-sensitive prostate cancer (mCSPC): Results of PEACE-1, a phase 3 randomized trial with a 2x2 design.

LBA5000 Background: PEACE-1 demonstrated that combining ADT and docetaxel with abiraterone acetate plus prednisone (AAP) improves both overall survival (OS) and radiographic progression-free-survival (rPFS) in men with de novo mCSPC. The present analysis examines the second pre-planned primary endpoint of PEACE-1 in the low-volume population: the impact of prostate irradiation (RT) in men receiving intensified systemic treatment. Methods: PEACE-1 is an academic, multicentre, international, 2x2 design, phase 3 trial. The co-primary endpoints for each question were rPFS and OS. The standard of care (SOC) was ADT alone or ADT plus docetaxel (Doce) at investigator’s discretion until 2017, then accrual was restricted to men receiving ADT+Doce. RT (74 Gy/37 fractions) was delivered after Doce completion when applicable. SOC included continuous ADT, with or without Doce at 75 mg/m² every 3 weeks for 6 cycles. AAP, 1000 mg/day with prednisone 10 mg/day was given to men randomized to the AAP arms until disease progression or intolerance. The overall type I error testing the RT effect was 5% (4.9% for OS, 0.1% for rPFS). In the low-volume population, 299 and 213 events were required to detect an HR of 0.62 for rPFS and 0.68 for OS with 80% power, respectively. Results: Between 11/2013 and 12/2018, 1172 men were randomized to receive either SOC (+/- AAP) plus RT (n=584) or SOC (+/- AAP) without RT (n=588). 505 patients had low-volume disease (0-3 bone metastases +/- lymph nodes), 252 in the RT arms, 253 in the non-RT arms. Baseline characteristics were similar across arms. With a median follow-up of 6.1 years, 303 rPFS and 214 OS events were recorded for the low-volume population. A qualitative interaction between RT and AAP was observed for rPFS (p=0.026) and therefore, each experimental arm was assessed individually. RT did not improve rPFS with a median of 3 years (99.9%CI 2.3-4.8) for SOC vs 2.6 (1.7-4.6) for SOC+RT; HR=1.12 (0.68-1.85). When compared individually to SOC, rPFS was improved by SOC+AAP+RT (median 7.5 years (99.9%CI: 4.0-NR); HR=0.49, [0.28-0.87], p<0.0001) and borderline improved by SOC+AAP (median 4.4 years (95% CI: 2.5-7.6); HR=0.74, [0.44-1.26], p=0.066). The HR between AAP arms was 0.66 [0.36-1.19]. For OS the predefined threshold for a statistical interaction was not reached (p=0.11). OS was not improved by RT: median OS was 6.9 years (95.1%CI: 5.9-7.5) without RT vs 7.5 (6.0-NR) with RT (HR=0.97 [0.74-1.27], p=0.81). Median OS was 7.1 years in the SOC arm and not yet reached in the SOC+AAP+RT arm. Data on the RT prevention effect on severe urinary symptoms are pending. Conclusions: Combining prostate RT to systemic treatment did not improve OS in men with de novo mCSPC and low metastatic burden. However, best outcomes (rPFS and OS) were observed in men receiving SOC+AAP+RT. The impact of RT on severe urinary symptom prevention will be presented. Clinical trial information: NCT01957436 .

Depth of PSA nadir and subsequent PSA progression-free survival in patients (pts) with high-risk biochemically relapsed prostate cancer: Results from the phase 3 PRESTO study (AFT-19).

5077 Background: In the phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (Apa) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated the association between PSA nadir within 3 months of treatment initiation with subsequent PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months, without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + Apa, or ADT + Apa + AAP, stratified by PSADT (< 3 vs 3–9 months), with post-treatment follow-up. The association between PSA nadir within the first three months on treatment with subsequent PSA PFS was analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + Apa (N = 168) or ADT + Apa + AAP (N = 169). 463 pts were evaluable for PSA nadir at 3 months. Across the three treatment arms, a PSA nadir of less than 0.1, between 0.1 – 0.2, and ≥ 0.2 ng/mL within the first three months of treatment was observed in 86.3%, 4.4%, and 9.3% of patients, respectively. A PSA nadir of < 0.2 ng/mL was reached within 3 months of treatment initiation in 79.8%, 96.9%, and 95.0% of pts randomized to the ADT, ADT + Apa, and ADT + Apa + AAP arms, respectively. The association between time to PSA nadir and subsequent PSA PFS was -0.30 (standard error = 0.03, Kendall’s tau modified for bivariate censoring), and median time to PSA nadir was 2.0 months (interquartile range 1.12 – 4.76 months). Failure to reach a PSA nadir < 0.2 ng/mL within the first three months of treatment was associated with a significantly shorter PSA PFS compared to pts with a PSA nadir ≤ 0.1 ng/mL (median PSA PFS of 13.9 vs. 22.8 months from 3 months post-treatment initiation; hazard ratio = 5.60, 95% CI: 3.58 – 8.75, p < 0.0001). There was also a significant difference in PSA PFS in those with a three-month PSA nadir between 0.1 – 0.2 vs ≤ 0.1 ng/mL (median PSA PFS 17.4 vs 22.8 months, HR = 2.63, 95:CI: 1.49 – 4.63, p = 0.0008). Conclusions: Using a landmark analysis at 3 months, a failure to reach PSA nadir less than 0.1 ng/mL within three months following initiation of ADT in BRPC is associated with shorter time to subsequent progression following treatment discontinuation. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissues and whole blood RNA in pts with suboptimal PSA nadir to identify potential markers of relative androgen pathway inhibitor resistance. Clinical trial information: NCT03009981 .

A prospective trial of apalutamide and abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer.

5015 Background: Abi Race was the first prospective parallel cohort study of abiraterone acetate plus prednisone (AAP) in Black and White men with metastatic castrate-resistant prostate cancer (mCRPC) and demonstrated greater prostate-specific antigen (PSA) response, time to PSA progression (TTP) and toxicity rates among Black patients (pts). We designed the PANTHER trial to estimate clinical outcomes among Black and White pts with mCRPC treated with apalutamide, abiraterone, plus prednisone. Methods: This parallel cohort multicenter study treated androgen receptor pathway inhibitor naïve mCRPC pts with oral apalutamide (240 mg/d), abiraterone (1000 mg/d) and prednisone (10 mg/d) (AAAP) continuously until disease progression, unacceptable toxicity or 2 years. The primary endpoint was radiographic progression free survival (rPFS); secondary endpoints were to estimate TTP, overall survival (OS) and best PSA response, among Black and White pts, separately. Exploratory endpoints included safety and correlative biomarkers of outcome by race and ancestry. Results: Between July 2017 and January 2021, we enrolled 43 Black and 50 White pts from 8 sites. Baseline prognostic characteristics were largely similar with some differences. We report an interim analysis as the pts are still followed for OS. At the time of the abstract submission, there were 18 and 36 rPFS events and 15 and 30 deaths in Black and White pts, respectively. We present the time to event endpoint rates at 12 and 24 mos and PSA declines for Black and White pts. Conclusions: We hypothesize that treatment with the combination of AAAP may result in clinical efficacy in Black men with mCRPC. Black pts were underrepresented in the phase III ACIS trial which compared AAP to AAAP and demonstrated longer rPFS but not OS. Further studies of AAAP combination therapy among Black men with advanced prostate cancer are needed to determine potential clinical benefits in this understudied population. Clinical trial information: NCT03098836 . [Table: see text]

Baseline characteristics associated with PSA progression-free survival in patients (pts) with high-risk biochemically relapsed prostate cancer: Results from the phase 3 PRESTO study (AFT-19).

208 Background: In the Phase 3 PRESTO study, intensified androgen deprivation therapy (ADT) with apalutamide (APA) with or without abiraterone acetate plus prednisone (AAP), administered for a finite treatment period of 52 weeks, prolonged prostate-specific antigen progression-free survival (PSA PFS) in pts with high-risk biochemically relapsed prostate cancer (BRPC). We evaluated baseline factors associated with PSA PFS in this study. Methods: PRESTO is a randomized phase 3, open-label trial in pts with BRPC following radical prostatectomy (RP) and PSA doubling time (PSADT) ≤ 9 months (mo), without distant metastases on conventional imaging (NCT03009981). Pts were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + APA, or ADT + APA + AAP, stratified by PSADT (< 3 vs 3–9 mo), with post-treatment follow-up. Baseline factors associated with PSA PFS including Gleason sum at RP (6-7, 8, ≥ 9) were analyzed in a post hoc fashion. Results: 504 pts were randomized to ADT alone (N = 167), ADT + APA (N = 168) or ADT + APA + AAP (N = 169). Baseline patient characteristics including Gleason sum at diagnosis, serum PSA and PSADT at study entry, time interval from radical prostatectomy, and receipt of prior radiation (none, adjuvant, salvage) were well balanced across the three treatment arms. At the first planned interim analysis, both experimental arms significantly prolonged PSA PFS compared to the control arm (median 24.9 mo for ADT + APA vs 20.3 mo for ADT, HR = 0.52 (95% CI: 0.35–0.77); median 26.0 mo for ADT + APA + AAP vs 20.0 mo for ADT, HR = 0.48 (95% CI: 0.32–0.71)). Across the study cohort, Gleason sum ≥ 9 at diagnosis was associated with shorter PSA PFS (median 21.9 mo for Gleason ≥ 9 vs. 31.1 mo for Gleason 8 vs. 25.2 mo for Gleason 6-7, log-rank p-value = 0.0409). In addition, within each treatment arm, a shorter observed median PSA PFS was detected for patients with Gleason ≥ 9 prostate cancer. Serum PSA and PSADT at study entry, time from prior radical prostatectomy, and prior radiation were not associated with PSA PFS in the overall study cohort or in individual study arms. Conclusions: Gleason sum ≥ 9 prostate cancer at diagnosis was associated with shorter time to PSA progression following subsequent intensified ADT administered for a finite treatment interval in BRPC. Follow-up is ongoing to integrate genomic profiling of primary prostate cancer tissue with these results and validate with longer term endpoints including metastasis-free survival. Clinical trial information: NCT03009981 .

Efficacy of subsequent treatments in patients who progressed to mCRPC following treatment with apalutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC): A post-hoc analysis of the SPARTAN phase III trial.

157 Background: Apalutamide (Apa) delays the onset of metastases and extends survival in nmCRPC. However, the benefit of subsequent therapy for metastatic castration resistant prostate cancer (mCRPC) following progression on Apa remains inadequately explored. Methods: A post-hoc analysis of SPARTAN, a randomized phase III (NCT01946204), double-blind, placebo-controlled trial with Apa for the treatment of men with nmCRPC was undertaken in order to assess the impact of post-protocol treatment. Patients included in this analysis were SPARTAN patients who developed mCRPC while on Apa and received a first subsequent therapy for mCRPC (the “Next Cohort”). The index date of the analysis was the initiation of first subsequent treatment for mCRPC. The baseline characteristics of the Next Cohort (reported from the time of initial randomization because updated characteristics at the index date could not be derived) were compared to those of the ITT Apa arm in SPARTAN. Subsequent overall survival (sOS) and subsequent progression-free survival per physician assessment (sPFS) were calculated from the index date using Kaplan-Meier method. Results: At study completion, 237 patients remained on Apa without progression, while 311 were included in the Next Cohort. Of these, 241 (77.5%) received abiraterone acetate plus prednisone (AAP) provided by the sponsor as an option as first subsequent treatment, 29 (9.3%) received docetaxel; 20 (6.4%) enzalutamide and 21 other treatments (6.8%). Compared to the ITT Apa arm in SPARTAN, a higher proportion of the Next Cohort had PSA doubling time ≤6 months (79.1% vs 71.5%) and a PSA value above median at baseline, and experienced poorer PSA response (51% PSA90 overall response rate vs 62%) whilst on apalutamide treatment. The median sPFS and sOS were 6.8 months (95% confidence interval, CI, 5.8-7.9) and 20.0 months (95% CI, 17.0-22.6), respectively. Choice of subsequent next treatment did not appear to have an impact on sPFS and sOS. Conclusions: Limitations of this analysis include its retrospective nature and the lack of randomization to first line mCRPC therapy and related potential confounding, and the inclusion of patients who had progressed at SPARTAN study completion with associated poorer prognosis. Nevertheless, the analysis suggests comparable efficacy of selected first line mCRPC therapies, following progression on Apa for nmCRPC. Clinical trial information: NCT01946204 . [Table: see text]

The safety of radium-223 combined with new-generation hormonal agents in bone metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis.

Patients with bone metastatic castration-resistant prostate cancer (mCRPC) might benefit from radium-223 (223Ra) combined with new-generation hormonal agents (NHAs) in terms of survival and quality of life (QoL). However, the safety of combination therapies remains unclear. Therefore, we aimed to perform a network meta-analysis by reviewing the literature about the combination of 223Ra with abiraterone acetate plus prednisone (AAP) or enzalutamide and to evaluate the safety of combination therapy in bone mCRPC patients. Ultimately, ten studies (2835 patients) were selected, including four randomized controlled trials (RCTs), five retrospective cohort studies, and one single-arm study. Overall, there was no difference in the incidence of fracture between the 223Ra+NHA combination group and the 223Ra monotherapy group (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 0.91-2.34, P = 0.66), but the incidences in both the 223Ra+NHA combination group (OR: 3.22, 95% CI: 2.24-4.63, P < 0.01) and the 223Ra monotherapy group (OR: 2.24, 95% CI: 1.23-4.08, P < 0.01) were higher than that in the NHA monotherapy group. However, in the meta-analysis involving only RCTs, there was no difference between the 223Ra monotherapy group and the NHA monotherapy group (OR: 1.14, 95% CI: 0.22-5.95, P = 0.88), while the difference between the 223Ra+NHA combination group and the NHA monotherapy group remained significant (OR: 3.22, 95% CI: 2.24-4.63, P < 0.01). Symptomatic skeletal events (SSEs), SSE-free survival (SSE-FS), all grades of common adverse events (AEs), and ≥grade 3 AEs among all groups did not show any significant difference. Our results indicate that the combination of 223Ra with NHAs was well tolerated in bone mCRPC patients compared to 223Ra monotherapy, even though the incidence of fracture was higher in patients who received 223Ra than that among those who received NHA monotherapy. More evidence is needed to explore the safety and efficiency of 223Ra combination therapies.

A phase II randomised trial of abiraterone acetate plus prednisone in combination with docetaxel or docetaxel plus prednisone after disease progression to abiraterone acetate plus prednisone in patients with metastatic castration-resistant prostate cancer: The ABIDO-SOGUG trial

BackgroundWe aimed to compare the efficacy and safety of maintaining or withdrawing abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer who had experienced cancer progression to this treatment and were beginning a docetaxel-based therapy. Patients and methodsPhase II, randomised, open-label study conducted in patients with metastatic castration-resistant prostate cancer who were asymptomatic or mildly symptomatic. After open-label treatment with AAP, patients who had experienced cancer progression to AAP were randomised to 75 mg/m2 of docetaxel plus AAP or to receive 75 mg/m2 of docetaxel plus 10 mg of prednisone orally daily. The primary outcome was the radiographic progression-free survival rate at 12 months as evaluated by the investigators in all randomised patients. ResultsA total of 148 patients were included in open-label treatment with AAP, and of them, 94 patients were randomised to receive either docetaxel plus AAP (intervention group; n = 47) or docetaxel plus prednisone (control group; n = 47). The 12-month radiographic progression-free survival rates did not differ between the intervention group (34.9%; 95% CI 20.7–49.2) and the control group (33.9%; 95% CI 19.5–48.3). There were no significant differences in the time to radiographic progression and the overall survival between the intervention and control groups. Grade 3–5 neutropenia with the combination of docetaxel plus prednisone and AA was more frequent than with docetaxel plus prednisone (59.6% versus 27.7%). ConclusionOur results indicate that the therapeutic strategy of maintaining AAP added to docetaxel in chemotherapy-naïve patients who have experienced cancer progression to AAP treatment should not be further evaluated and should be avoided in clinical practice. Clinical trialsNCT02036060 https://clinicaltrials.gov/ct2/show/NCT02036060.

LBA63 PRESTO: A phase III, open-label study of androgen annihilation in patients (pts) with high-risk biochemically relapsed prostate cancer (AFT-19)

Pts with biochemically relapsed prostate cancer (BRPC) following radical prostatectomy (RP) and a short PSA doubling time (PSADT) are at risk for distant metastases. Apalutamide (APA), an androgen receptor (AR) antagonist, and abiraterone acetate plus prednisone (AAP), prolong survival in the metastatic setting. We evaluated if intensification of androgen deprivation therapy (ADT) prolongs biochemical progression-free survival (bPFS) in BRPC.

Abstract 52: Analytical validation of the Resolution HRD plasma assay used to identify mCRPC patients with mutations, including homozygous deletions, in DNA repair genes as a companion diagnostic for niraparib

Abstract Tumor cells of metastatic castration-resistant prostate cancer (mCRPC) patients with homologous recombination deficiency (HRD) are highly sensitive to the blockade of DNA single-strand break repair via the inhibition of the poly(adenosine diphosphate-ribose) polymerase (PARP) family of nuclear proteins. Niraparib is a highly selective PARP inhibitor, with activity against PARP-1/2 DNA-repair polymerases, and the Resolution HRD assay is being developed as a companion diagnostic for niraparib. Detection of HRD in cell free DNA (cfDNA) isolated from blood is minimally invasive and is of special benefit to mCRPC patients, many without accessible lesions. The Resolution HRD assay identifies patients with substitutions, insertions, deletions, and homozygous deletions of the ATM, BRCA1, BRCA2, BRIP1, CDK12 (except homozygous deletions), CHEK2, FANCA, HDAC2, and PALB2 genes by targeted NGS sequencing of cfDNA isolated from plasma. Analytical performance of the Resolution HRD assay was validated using cfDNA from mCRPC patient plasma, cfDNA from healthy donor plasma, and contrived samples with a wide spectrum of technically challenging genetic aberrations along with CRISPR-engineered human cell lines with ATM and BRCA2 gene deletions. The LOD95 was established for substitutions, insertions, deletions, and homozygous deletions for genes represented in the HRD panel with variant types including complex indels, long indels, and challenging genomic settings including homopolymeric and GC-rich regions. mCRPC specimens were used to confirm an acceptable level of precision near 1X LOD and 2-3X LOD concentrations for all 4 variant types. No false-positives were detected in any samples from healthy donors. Resolution HRD has been validated to give consistent results across the 15-30 ng input range. Studies to confirm accuracy of the Resolution HRD test results using a validated orthogonal method will be presented. The Resolution HRD assay offers highly sensitive, specific, and robust test results, and meets analytical requirements for clinical applications. It is intended as a companion diagnostic to niraparib in combination with abiraterone acetate plus prednisone (AAP) for the treatment of mCRPC patients. Citation Format: Julia Pollak, Kristy Potts, PuiYee Chan, Chen-Hsun Tsai, Angela Liao, Carly Garrison, Taylor Brown, Paul Stull, Zhen Li, Christine Baker, Kavita Garg, Ira Pekker, Michael Farabaugh, Michael Gormley, Lesley Farrington, Katherine Bell, Usha Singh. Analytical validation of the Resolution HRD plasma assay used to identify mCRPC patients with mutations, including homozygous deletions, in DNA repair genes as a companion diagnostic for niraparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 52.

Fatigue, health-related quality-of-life and metabolic changes in men treated with enzalutamide or abiraterone acetate plus prednisone for metastatic castration-resistant prostate cancer: A randomised clinical trial (HEAT)

IntroductionEnzalutamide and abiraterone acetate plus prednisone (AAP) have similar efficacy in metastatic castration-resistant prostate cancer (mCRPC). Herein, we compare fatigue, health-related quality-of-life (HRQoL) and metabolic changes in men with mCRPC treated with enzalutamide and AAP. Materials and methodsIn this single-centre, open-labelled, phase IV trial, patients with metastatic prostate cancer progressing on androgen deprivation therapy were randomly assigned to enzalutamide (160 mg daily) or AAP (1000 mg abiraterone acetate and 10 mg prednisone daily) as first-line mCRPC treatment. The primary outcome was the difference in changed fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire). The secondary outcomes were differences in changed HRQoL (Functional Assessment of Cancer Therapy-Prostate questionnaire), body composition, weight, glucose homeostasis, lipid profile and blood pressure. All outcomes were assessed at baseline and at 12-week follow-up. Trial registration: clinicaltrialsregister.eu (2017-000099-27). Results170 patients were randomised (1:1) to enzalutamide or AAP. The primary outcome was positive with a clinically meaningful difference in fatigue, favouring AAP (3.4 points, 95% CI 1.2; 5.6, P = 0.003). The group difference in changed HRQoL did not reach clinical significance. The most important metabolic finding was a higher increase in glycated haemoglobin (HbA1c) for AAP than enzalutamide (3.4 mmol/mol, 95% CI 2.1; 4.8, P = 0.001). Eight patients developed type 2 diabetes (T2D) in the AAP group and none in the enzalutamide group. No treatment-related serious adverse event was observed. ConclusionsAAP resulted in less fatigue than enzalutamide in a randomised setting. This was at the expense of a higher HbA1c increase and incidence of T2D.

MP48-05 CHANGES IN PITUITARY–GONADAL HORMONES AFTER ENZALUTAMIDE OR ABIRATERONE PLUS PREDNISONE IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER (HEAT): RESULTS FROM A RANDOMISED CLINICAL TRIAL

You have accessJournal of UrologyCME1 May 2022MP48-05 CHANGES IN PITUITARY–GONADAL HORMONES AFTER ENZALUTAMIDE OR ABIRATERONE PLUS PREDNISONE IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER (HEAT): RESULTS FROM A RANDOMISED CLINICAL TRIAL Klara Ternov, Jens Sønksen, Mikkel Fode, Henriette Lindberg, Caroline Kistorp, Rasmus Bisbjerg, Jens Faber, Ganesh Palapattu, and Peter Busch Østergren Klara TernovKlara Ternov More articles by this author , Jens SønksenJens Sønksen More articles by this author , Mikkel FodeMikkel Fode More articles by this author , Henriette LindbergHenriette Lindberg More articles by this author , Caroline KistorpCaroline Kistorp More articles by this author , Rasmus BisbjergRasmus Bisbjerg More articles by this author , Jens FaberJens Faber More articles by this author , Ganesh PalapattuGanesh Palapattu More articles by this author , and Peter Busch ØstergrenPeter Busch Østergren More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002619.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Enzalutamide (ENZ) and abiraterone acetate plus prednisone (AAP) are both androgen receptor targeting treatments for metastatic castration-resistant prostate cancer (mCRPC). AAP inhibits the androgen production, whereas ENZ blocks the androgen receptor signalling. Herein, we compare treatment changes between ENZ and AAP in hormones of the pituitary–gonadal axis. METHODS: First-line ENZ (160 mg/day) and AAP (1000 mg abiraterone acetate and 10 mg prednisone/day) for mCRPC were compared in this randomised (1:1) phase IV trial. Eligible patients had progressive metastatic prostate cancer castrate levels of testosterone (<1.7 nmol/L). Fasting serum hormones, including testosterone, free-testosterone, sexual hormone binding globulin (SHGB), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), were measured by the gold standard assay liquid chromatography – tandem mass spectrometry before 11 am at baseline and at 12-week post-intervention. The treatment difference in changed hormones was compared with logarithmic mixed models analysis, and the within-subject change for each treatment group was analysed with logarithmic paired samples t-test. RESULTS: From June 2017 to September 2019, 170 participants were randomized to receive ENZ (n=84 analysed) or AAP (n=85 analysed). A 19.9% higher increase in FSH was found for ENZ than AAP. A larger decline in testosterone and SHGB was found for AAP than ENZ. More patients had lower than detectable levels of free-testosterone in the AAP group (83/85) than the ENZ group (6/84) (chi-square test p <0.001). CONCLUSIONS: In men with castrate-levels of testosterone, ENZ and AAP both inhibit the androgen stimulation of prostate cancer, but by different mechanism of action resulting in different pituitary–gonadal hormonal profiles. Source of Funding: Herlev and Gentofte University Hospital © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e821 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Klara Ternov More articles by this author Jens Sønksen More articles by this author Mikkel Fode More articles by this author Henriette Lindberg More articles by this author Caroline Kistorp More articles by this author Rasmus Bisbjerg More articles by this author Jens Faber More articles by this author Ganesh Palapattu More articles by this author Peter Busch Østergren More articles by this author Expand All Advertisement PDF DownloadLoading ...