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Prior Endocrine Therapy Impact on Abiraterone Acetate Clinical Efficacy in Metastatic Castration-resistant Prostate Cancer: Post-hoc Analysis of Randomised Phase 3 Studies.

ABSTRACT: The duration of prior hormonal treatment can predict responses to subsequent therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).To determine if prior endocrine therapy duration is an indicator of abiraterone acetate (AA) sensitivity.Post-hoc exploratory analysis of randomised phase 3 studies examining post-docetaxel (COU-AA-301) or chemotherapy-naïve mCRPC (COU-AA-302) patients receiving AA. The treatment effect on overall survival (OS), radiographic progression-free survival (rPFS), and prostate-specific antigen (PSA) response analysed by quartile duration of prior gonadotropin-releasing hormone agonists (GnRHa) or androgen receptor (AR) antagonist.Patients were randomised to AA (1000mg, orally once daily) plus prednisone (5mg, orally twice daily) or placebo plus prednisone. Prior endocrine therapy was GnRHa (COU-AA-301, n=1127 [94%]; COU-AA-302, n=1057 [97%], 45.1 mo or 36.7 mo median duration, respectively) and/or orchiectomy (COU-AA-301, n=78 [7%] COU-AA-302, n=44 [4%]); castrated patients received prior AR antagonists (COU-AA-301, n=1015 [85%]; COU-AA-302, n=1078 [99%], 15.7 mo or 16.1 mo median duration, respectively).Cox model was used to obtain hazard ratio and associated 95% confidence interval with statistical inference by log rank statistic.Clinical benefit with AA was observed for OS, rPFS, and PSA response for nearly all quartiles with GnRHa or AR antagonists in both COU-AA-301 and COU-AA-302. In COU-AA-301, patients with a longer duration of prior endocrine therapy tended to have greater AA OS, rPFS, and PSA response benefit, with lead-time chemotherapy bias potentially impacting COU-AA-301 results. Time to castration resistance was not captured. This analysis is limited as a post-hoc exploratory analysis.In the COU-AA-301 and COU-AA-302 studies, AA produced clinical benefits regardless of prior endocrine therapy duration in patients with mCRPC.Metastatic castration-resistant prostate cancer patients derived clinical benefits with abiraterone acetate regardless of prior endocrine therapy duration.

SUBMITTER: Bellmunt J

PROVIDER: S-EPMC5465643 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Prior Endocrine Therapy Impact on Abiraterone Acetate Clinical Efficacy in Metastatic Castration-resistant Prostate Cancer: Post-hoc Analysis of Randomised Phase 3 Studies.

Bellmunt Joaquim J Kheoh Thian T Yu Margaret K MK Smith Matthew R MR Small Eric J EJ Mulders Peter F A PF Fizazi Karim K Rathkopf Dana E DE Saad Fred F Scher Howard I HI Taplin Mary-Ellen ME Davis Ian D ID Schrijvers Dirk D Protheroe Andrew A Molina Arturo A De Porre Peter P Griffin Thomas W TW de Bono Johann S JS Ryan Charles J CJ Oudard Stéphane S

European urology 20151024 5

<h4>Background</h4>The duration of prior hormonal treatment can predict responses to subsequent therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).<h4>Objective</h4>To determine if prior endocrine therapy duration is an indicator of abiraterone acetate (AA) sensitivity.<h4>Design, setting, and participants</h4>Post-hoc exploratory analysis of randomised phase 3 studies examining post-docetaxel (COU-AA-301) or chemotherapy-naïve mCRPC (COU-AA-302) patients receiving ...[more]

PMID: 26508309

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Project description:PurposeMetastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naïve mCRPC when combined with androgen receptor signaling inhibition.MethodsMAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the BRCA1/2 subgroup and then in the full HRR+ cohort, with secondary end points analyzed for the full HRR+ cohort if rPFS was statistically significant. A futility analysis was preplanned in the HRR- cohort.ResultsMedian rPFS in the BRCA1/2 subgroup was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9 months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001). In the overall HRR+ cohort, rPFS was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.5 v 13.7 months; HR, 0.73; 95% CI, 0.56 to 0.96; P = .022). These findings were supported by improvement in the secondary end points of time to symptomatic progression and time to initiation of cytotoxic chemotherapy. In the HRR- cohort, futility was declared per the prespecified criteria. Treatment with niraparib + AAP was tolerable, with anemia and hypertension as the most reported grade ≥ 3 adverse events.ConclusionCombination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP.[Media: see text].

Project description:Treatment patterns for metastatic castration-resistant prostate cancer (mCRPC) have changed substantially in the last few years. In trial COU-AA-302 (chemotherapy-naïve men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival (OS) when compared to placebo plus prednisone (P).This post hoc analysis investigated clinical responses to docetaxel as first subsequent therapy (FST) among patients who progressed following protocol-specified treatment with AA, and characterized subsequent treatment patterns among older (?75 yr) and younger (<75 yr) patient subgroups.Data were collected at the final OS analysis (96% of expected death events). Subsequent therapy data were prospectively collected, while response and discontinuation data were collected retrospectively following discontinuation of the study drug.At the discretion of the investigator, 67% (365/546) of patients from the AA arm received subsequent treatment with one or more agents approved for mCRPC.Efficacy analysis was performed for patients for whom baseline and at least one post-baseline prostate-specific antigen (PSA) values were available.Baseline and at least one post-baseline PSA values were available for 100 AA patients who received docetaxel as FST. While acknowledging the limitations of post hoc analyses, 40% (40/100) of these patients had an unconfirmed ?50% PSA decline with first subsequent docetaxel therapy, and 27% (27/100) had a confirmed ?50% PSA decline. The median docetaxel treatment duration among these 100 patients was 4.2 mo. Docetaxel was the most common FST among older and younger patients from each treatment arm. However, 43% (79/185) of older patients who progressed on AA received no subsequent therapy for mCRPC, compared with 17% (60/361) of younger patients.Patients with mCRPC who progress with AA treatment may still derive benefit from subsequent docetaxel therapy. These data support further assessment of treatment patterns following AA treatment for mCRPC, particularly among older patients.ClinicalTrials.gov NCT00887198.Treatment patterns for advanced prostate cancer have changed substantially in the last few years. This additional analysis provides evidence of clinical benefit for subsequent chemotherapy in men with advanced prostate cancer whose disease progressed after treatment with abiraterone acetate. Older patients were less likely to be treated with subsequent therapy.

Project description:Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy.Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients.This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial.Patients were grouped by concomitant BTT use or no BTT use.Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models.While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p=0.01) and increased the time to ECOG deterioration (HR 0.75; p<0.001) and time to opiate use for cancer-related pain (HR 0.80; p=0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients.AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT.Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone.ClinicalTrials.gov NCT00887198.

Project description:BACKGROUND:It is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone. OBJECTIVE:To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC). DESIGN, SETTING, AND PARTICIPANTS:This open-label, single-centre interventional study was conducted in bmCRPC patients. INTERVENTION:Enzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and Cmin plasma concentrations were evaluated. RESULTS AND LIMITATIONS:Sixty patients were enrolled. Common AEs independent of grade/causality included fatigue (72%), hyperglycaemia (67%), alkaline phosphatase (ALP) elevation (53%), and hot flush (43%). Grade 3 AEs included hypertension (17%), alanine aminotransferase elevation (12%), ALP elevation (5%), and arthralgia (5%). No treatment-related grade 4 AEs or deaths were reported. Median treatment-discontinuation time was 312d (95% confidence interval [CI] 196.0-483.0). Maximal PSA decline ?50% and ?90% occurred in 46 (77%) and 29 (48%) patients, respectively. Median PFS was 251d (95% CI 147-337). At week 9, median tumour microenvironment androgens, precursors, and nuclear AR expression decreased (p<0.001). The baseline tumour AR C/N terminal ratio of ?80% was associated with treatment benefit. At enzalutamide steady state, abiraterone acetate Cmin was ?23% lower (range 14.05-200.5ng/ml) than when given alone. CONCLUSIONS:Enzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC. PATIENT SUMMARY:This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.

Project description:Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy.Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302.Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1).Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone.Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets ?-spending function was used for OS. Adverse events were summarised descriptively.With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p<0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p=0.0151) but did not reach the prespecified statistical efficacy boundary (?-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p=0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports.The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ?24 mo.Study COU-AA-302, ClinicalTrials.gov number, NCT00887198.The updated results of this ongoing study showed that disease progression was delayed in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone, and there was a continued trend in prolongation of life compared with patients treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well tolerated by patients who were treated for >2 yr.

Project description:BACKGROUND:Abiraterone acetate suppresses adrenal androgens and glucocorticoids through the inhibition of CYP17; however, given the risk of mineralocorticoid excess, it is administered with glucocorticoids. Herein, the authors performed a phase 2, single-arm study that was designed to assess the safety of abiraterone acetate without steroids in patients with castration-resistant prostate cancer. METHODS:Eligible patients had castration-resistant prostate cancer with controlled blood pressure and normal potassium. Patients initially received abiraterone acetate at a dose of 1000 mg daily alone. Those with persistent or severe mineralocorticoid toxicity received treatment with prednisone initiated at a dose of 5 mg twice daily. Therapy was continued until radiographic progression, toxicity, or withdrawal. The primary objective of the current study was to determine the percentage of men requiring prednisone to manage mineralocorticoid toxicity. Toxicity was graded according to Common Terminology Criteria for Adverse Events, version 4.0. RESULTS:A total of 58 patients received at least 1 dose of abiraterone acetate; the majority had metastases (53 patients; 91.4%). Sixteen patients (27.6%) received prior chemotherapy, 6 patients (10.3%) received prior enzalutamide, and 4 patients (7%) received prior ketoconazole. Grade 3 to 4 adverse events of interest included hypertension (9 patients; 15.5%) and hypokalemia (4 patients; 7%). There was no grade ?3 edema. Seven patients (12%) initiated prednisone therapy for mineralocorticoid toxicity, 3 patients for hypertension (5%), and 4 patients for hypokalemia (7%). Two patients initiated prednisone therapy for fatigue (3%). Forty patients (68%) experienced a decline in prostate-specific antigen of ?50% with the use of abiraterone acetate alone. Patients with lower baseline levels of androstenedione (P = .04), androsterone (P = .01), dehydroepiandrosterone (P = .03), and 17-hydroxyprogesterone (P = .03) were found to be more likely to develop mineralocorticoid toxicity. CONCLUSIONS:Treatment with abiraterone acetate without steroids is feasible, although clinically significant adverse events can occur in a minority of patients. The use of abiraterone acetate without prednisone should be balanced with the potential for toxicity and requires close monitoring.

Project description:BackgroundAbiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This study's objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone.Patients and methodsAll patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation.ResultsA confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%-50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis.ConclusionsA composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.

Dataset Information

Prior Endocrine Therapy Impact on Abiraterone Acetate Clinical Efficacy in Metastatic Castration-resistant Prostate Cancer: Post-hoc Analysis of Randomised Phase 3 Studies.

Publications

Prior Endocrine Therapy Impact on Abiraterone Acetate Clinical Efficacy in Metastatic Castration-resistant Prostate Cancer: Post-hoc Analysis of Randomised Phase 3 Studies.

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