Dataset Information

Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer.

ABSTRACT:

Background

Abiraterone 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 methods

All 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.

Results

A 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.

Conclusions

A 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.

SUBMITTER: Leibowitz-Amit R

PROVIDER: S-EPMC4433513 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Publications

Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer.

Leibowitz-Amit R R Templeton A J AJ Omlin A A Pezaro C C Atenafu E G EG Keizman D D Vera-Badillo F F Seah J-A JA Attard G G Knox J J JJ Sridhar S S SS Tannock I F IF de Bono J S JS Joshua A M AM

Annals of oncology : official journal of the European Society for Medical Oncology 20140123 3

<h4>Background</h4>Abiraterone 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 respons ...[more]

PMID: 24458472

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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: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:BackgroundLoss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer.ObjectiveTo explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression.Design, setting, and participantsWe retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis.Outcome measurements and statistical analysisThe primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses.Results and limitationsA total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio [HR]: 1.75; 95% confidence interval [CI], 1.19-2.55; p=0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12-2.28; p=0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis.ConclusionsOur results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted.Patient summaryPTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate. We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression.

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.

Dataset Information

Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer.

Background

Patients and methods

Results

Conclusions

Publications

Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer.

Similar Datasets

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