Relative risk of HTN and major cardiovascular events associated with use of androgen receptor antagonists for nonmetastatic, castration-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17605-e17605
Author(s):  
Nusrat Jahan ◽  
Francis Mogollon-Duffo ◽  
Shabnam Rehman ◽  
Sakshi Singal ◽  
Fred L. Hardwicke
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Relative Risk ◽  
Meta Analysis ◽  
Castration Resistant Prostate Cancer ◽  
Phase 3 ◽  
Castration Resistant ◽  
Increased Risk ◽  
Myocardial Infraction ◽  
Grade 3

e17605 Background: Metastatic, castration-resistant prostate cancer (mCRPC) is a lethal disease, often preceded by nonmetastatic, castration-resistant phase. Recently, three androgen receptor (AR) antagonists — apalutamide, enzalutamide, and darolutamide — have been approved for nonmetastatic, castration-resistant prostate cancer (nmCRPC). AR-antagonists have been associated with increased risk of hypertension (HTN) and major cardiovascular (CV) events. We conducted a systematic review and meta-analysis of the published phase 3 randomized controlled trials (RCTs) to determine the relative risk of HTN and major CV events associated with use of AR-antagonists for nmCRPC. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts from inception until November 2019. Published phase 3 RCTs using AR-antagonists in the study arm for nmCRPC and reporting the number of events of HTN and major CV events were included in the analyses. We used Mantel-Haenszel (MH) method and random effects model to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) randomizing 2687 patients in the AR-antagonist arms and 1417 patients in the control arms were included in the final analysis for HTN. SPARTAN did not include data for major CV events; hence, other two studies comprising 2903 patients were analyzed for major CV events. Major CV events included myocardial infraction/coronary artery disease, ischemic/hemorrhagic cerebrovascular events, and heart failure. AR-antagonists used in the study arms were — ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy. Randomization was 2:1 in all studies. The pooled RR of any-grade HTN is 1.5 (95% CI: 1.03 – 2.18, p = 0.03, I2 = 70%); and, the pooled RR of grade ≥3 HTN is 1.39 (95% CI: 1.03 – 1.88, p = 0.03, I2 = 13%). The pooled RR of any-grade major CV events is 1.49 (95% CI: 1.05 – 2.13, p = 0.03, I2 = 0%); and, the pooled RR of grade ≥3 major CV events is 1.80 (95% CI: 1.11 – 2.92, p = 0.02, I2 = 0%). Conclusions: Our meta-analysis demonstrated use of AR-antagonists for nmCRPC is associated with increased risk of HTN and major CV events. A careful selection of patients and aggressive management of the CV risk factors are crucial to enhance safety and proper utilization of these promising drugs.

Safety and tolerance of androgen receptor antagonists in nonmetastatic, castration-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17607-e17607
Author(s):  
Sariya Wongsaengsak ◽  
Nusrat Jahan ◽  
Fred L. Hardwicke
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Final Analysis ◽  
Treatment Discontinuation ◽  
Castration Resistant Prostate Cancer ◽  
Phase 3 ◽  
Risk Of Death ◽  
Castration Resistant ◽  
Increased Risk ◽  
Grade 3

e17607 Background: Metastatic castration resistant prostate cancer (mCRPC) is a fatal disease. Nonmetastatic, castration-resistant prostate cancer (nmCRPC) often predates mCRPC. Recently, three androgen receptor (AR) antagonists i.e. apalutamide, enzalutamide, and darolutamide have been approved for nmCRPC. Nonetheless, any new therapeutic approach poses new safety concerns. We conducted a systematic review and meta-analysis of the published phase 3 randomized controlled trials (RCTs) to determine the safety and tolerance of AR-antagonists in nmCRPC patients. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until November 2019. Published phase 3 RCTs using AR-antagonists in the study arm for nmCRPC were included in the analyses. We used Mantel-Haenszel (MH) method and random effects model to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) comprising 2687 patients in the AR-antagonist arm and 1417 patients in the control arm were included in the final analysis. AR-antagonists used in the study arms were following— ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy (ADT). Randomization was 2:1 in all studies. No publication bias was appreciated all three studies. The pooled RR of any-grade adverse events (AEs) is 1.08 (95% CI: 1.02 – 1.14, p = 0.01, I2 = 79%) which was statistically significant. The pooled RR of grade ≥ 3 AEs was also significant at 1.32 (95% CI: 1.19 – 1.46, p < 0.00001, I2 = 0%). The pooled RR of grade 5 event is 2.67 (95% CI: 0.79 – 9.02, p = 0.11, I2 = 70%) which was not statistically significant. The pooled RR for discontinuation of treatment regimen was also statistically significant at 1.31 (95% CI: 1.00 – 1.72, p = 0.05, I2 = 35%). Conclusions: In nmCRPC patients, AR-antagonists in combination with ADT is associated with a mild increase risk of any-grade AEs, grade ≥3 AEs, and treatment discontinuation secondary AEs. However, AR-antagonists were not associated with a significantly increased risk of death due to AEs. Careful clinical vigilance and timely intervention with appropriate supportive care are critical to prevent AEs related morbidities and prevent treatment discontinuation.

Efficacy of androgen receptor antagonists in combination with androgen deprivation therapy in nonmetastatic, castration-resistant prostate cancer: A systematic review and meta-analysis of published phase III randomized controlled trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17606-e17606
Author(s):  
Nusrat Jahan ◽  
Shabnam Rehman ◽  
Francis Mogollon-Duffo ◽  
Somedeb Ball ◽  
Sariya Wongsaengsak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Doubling Time ◽  
Meta Analysis ◽  
Final Analysis ◽  
Castration Resistant Prostate Cancer ◽  
Phase 3 ◽  
Free Survival ◽  
Castration Resistant ◽  
Psa Doubling Time

e17606 Background: Nonmetastatic, castration-resistant prostate cancer (nmCRPC) often heralds metastatic disease which is responsible for majority of the morbidity and mortality associated with prostate cancer. Hence, delaying metastasis is an expedient therapeutic goal for the patients with nmCRPC. Three androgen receptor (AR) antagonists — apalutamide, enzalutamide, and darolutamide — have been approved recently for nmCRPC on the basis of prolongation of metastasis-free survival. The purpose of our meta-analysis is to consolidate the efficacy data of AR-antagonists prolonging metastasis-free survival in nmCRPC. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until November 2019. Phase 3 RCTs using AR-antagonists for nmCRPC were included in the final analysis. We used generic inverse variance method and random effects model to calculate the pooled hazard ratio (HR) for distant metastasis or death with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) randomizing 2694 patients in the AR-antagonist arms and 1423 patients in the control arms are included in the final analysis. All studies enrolled only patients with prostate specific antigen (PSA) doubling time of 10 months or less. AR-antagonists used in the study arms were — ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy (ADT). Randomization was 2:1 in all studies. The pooled HR for distant metastasis or death was highly significant at 0.32 (95% CI: 0.25 - 0.41; P < 0.00001, I2 = 79%) in the favor of AR-antagonist arm in overall population. The pooled HR remained significant when patients were stratified according to PSA doubling time. For patients with PSA doubling time > 6months, the pooled HR was 0.34 (95% CI: 0.27 - 0.43; P < 0.00001, I2 = 0%); for patients with PSA doubling time ≤6 months, the pooled HR was 0.32 (95% CI: 0.25 - 0.41; P < 0.00001, I2 = 73%). Conclusions: Our meta-analysis demonstrated addition of AR-antagonists to ADT significantly prolongs the metastasis-free survival in patients with nmCRPC — an exciting new development in the management of prostate cancer.

scholarly journals Novel Androgen Receptor Inhibitors in Non-Metastatic, Castration-Resistant Prostate Cancer: A Systematic Review and Network Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Yelin Mulati ◽  
Yu Fan ◽  
Wei Yu ◽  
Qian Zhang ◽  
Zhisong He
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
High Risk ◽  
Subgroup Analysis ◽  
Meta Analysis ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Grade 3

IntroductionEnzalutamide, apalutamide, and darolutamide have all been approved by Food and Drug Administration to treat high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) since 2018 based on interim results of several phase III clinical trials. Final analyses of long-term overall survival (OS) and adverse events (AEs) results of these trials have been successively published recently. To help clinical practice to precisely select optimal treatment for high-risk nmCRPC patients, we performed a network meta-analysis to indirectly compare the final long-term results among these medications.MethodsPubMed, EMBASE, and Cochrane Libraries were searched for phase III clinical trial that reports OS and AEs results in nmCRPC patients published before January 30, 2021. Primary outcome was OS; secondary outcomes were Time to first chemotherapy, Subsequent antineoplastic therapy rate, and AEs. Firstly, class-level effect was assessed as the second-generation androgen receptor antagonists (SGARAs) were regarded as one whole class compared with placebo through traditional meta-analysis by using Revman 5.4, then a Bayesian network meta-analysis was conducted to give indirect comparison among SGARAs by using R 3.5.3 software. Subgroup analysis of OS was only conducted in the certain subgroups which were available in all included studies.ResultsThree eligible studies including 4,104 participants were finally selected. OS was significantly improved by the SGARAs as a class compared with placebo (HR, 0.74; 95% CI, 0.66–0.84). Darolutamide had the highest likelihood of providing best OS (p-score=0.802). SGARAs also significantly delayed the first time to chemotherapy (HR, 0.58; 95% CI, 0.50–0.66). Patients who received darolutamide experienced similar toxicity compared with placebo regarding AEs of grade 3 or higher (OR, 1.3; 95% CI, 1.0–1.7) and serious AEs (OR, 1.3; 95% CI, 0.99–1.6). When compared with darolutamide, enzalutamide caused significantly higher toxicity in terms of any AEs (OR, 2.3; 95% CI,1.5–3.7) and AEs of grade 3 or higher (OR, 1.6; 95% CI, 1.1–2.2), apalutamide caused significantly more AEs of grade 3 or higher (OR, 1.9; 95% CI, 1.4–2.7) and serious AEs (OR, 1.9; 95% CI, 1.3–2.8). Subgroup analysis showed that SGARAs as a group significantly improved OS in ECOG=1 population, although insignificant results were found in these patients from included studies.ConclusionsSGARAs combined with ADT significantly improved OS when compared with ADT alone in high-risk nmCRPC patients. Darolutamide may not only provide best OS but also have the most favorable safety profile among the included SGARAs in high-risk nmCRPC patients.

scholarly journals Abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: a systematic review of ‘real-life’ studies

2018 ◽  
Vol 10 (10) ◽  
pp. 305-315 ◽  
Author(s):  
Michele Marchioni ◽  
Petros Sountoulides ◽  
Maida Bada ◽  
Sebastiano Rapisarda ◽  
Cosimo De Nunzio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Meta Analysis ◽  
Real Life ◽  
Castration Resistant Prostate Cancer ◽  
The Real ◽  
Castration Resistant ◽  
Real Life Setting ◽  
Grade 3 ◽  
Baseline Psa

Background: To assess the efficacy and safety of treatment with abiraterone acetate (AA) in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC) in the ‘real-life’ setting. Methods: Data acquisition on the outcomes of the use of AA in chemotherapy-naive patients with mCRPC was performed by a MEDLINE comprehensive systematic literature search using combinations of the following key words: ‘prostate cancer’, ‘metastatic’, ‘castration resistant’, ‘abiraterone’, ‘real life’, and excluding controlled clinical trials (phase II and III studies). Identification and selection of the studies was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria. Outcomes of interest were overall survival (OS), progression-free survival (PFS), 12-week 50% reduction in prostate-specific antigen (PSA), and grade 3 and higher adverse events. Data were narratively synthesized in light of methodological and clinical heterogeneity. Results: Within the eight identified studies that fulfilled the criteria, a total of 801 patients were included in the meta-analysis. Baseline PSA ranged between 9.5 and 212.0 ng/ml. Most of the patients had bone metastases. Duration of treatment with AA was longer in the studies with lower baseline PSA levels. The median OS ranged between 14 and 36.4 months. The PFS, assessed according to different definitions, ranged from 3.9 to 18.5 months. A 50% PSA reduction at 12 weeks was reached by a variable percentage of patients ranging from 36.0% to 62.1%. Finally, the rate of grade 3 and higher adverse events was reported in three studies and ranged from 4.4% to 15.5%. Conclusions: Despite the high grade of heterogeneity among studies, treatment with AA seems to ensure good survival outcomes in the ‘real-life’ setting. However, prospective studies based on patients’ characteristics being more similar to ‘real-life’ patients are necessary.

YB-1 variant and androgen receptor axis-targeted agents in metastatic castration-resistant prostate cancer patients

2020 ◽  
Vol 21 (13) ◽  
pp. 919-928
Author(s):  
Ana Afonso ◽  
Jani Silva ◽  
Ana Rita Lopes ◽  
Sara Coelho ◽  
Ana Sofia Patrão ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Patients ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Allelic Discrimination ◽  
Cox Regression Analysis ◽  
Castration Resistant ◽  
Increased Risk

Aim: To evaluate the influence of YB-1 rs10493112 variant as a genetic marker for response to second-generation androgen receptor axis-target agents. Methods: A hospital-based cohort study of 78 patients with metastatic castration-resistant prostate cancer was conducted. Genotyping was performed by TaqMan® allelic discrimination technology. Main results: In abiraterone-treated and high-risk patients, YB-1 rs10493112 AA genotype carriers showed lower progression-free survival than C allele genotype patients (4 vs 17 months; p = 0.009). For carriers of AA genotype, multivariate Cox regression analysis revealed a fivefold increased risk of progression (p = 0.035). Conclusion: The study findings suggest that, for metastatic and castration-resistant prostate cancer patients, this polymorphism might be a putative marker for the clinical outcome.

scholarly journals Sipuleucel-T and Androgen Receptor-Directed Therapy for Castration-Resistant Prostate Cancer: A Meta-Analysis

2016 ◽  
Vol 2016 ◽  
pp. 1-10
Author(s):  
Renliang Yi ◽  
Baoxin Chen ◽  
Peng Duan ◽  
Chanjiao Zheng ◽  
Huanyu Shen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Adverse Event ◽  
Placebo Group ◽  
Treatment Group ◽  
Meta Analysis ◽  
Castration Resistant Prostate Cancer ◽  
Time To Progression ◽  
Castration Resistant ◽  
Grade 3

New treatments, such as sipuleucel-T and androgen receptor- (AR-) directed therapies (enzalutamide (Enz) and abiraterone acetate (AA)), have emerged and been approved for the management of castration-resistant prostate cancer (CRPC). There are still debates over their efficacy and clinical benefits. This meta-analysis aimed to investigate the efficacy and safety of sipuleucel-T and AR-directed therapies in patients with CRPC. RevMan 5.1 was used for pooled analysis and analysis of publication bias. Seven studies were included in the meta-analysis, with three studies in sipuleucel-T (totally 737 patients, 488 patients in treatment group, and 249 patients in placebo group) and four in AR-directed therapies (totally 5,199 patients, 3,015 patients in treatment group, and 2,184 patients in placebo group). Treatment with sipuleucel-T significantly improved overall survival in patients with CRPC and was not associated with increased risk of adverse event of grade ≥3 (p>0.05). However, treatment with sipuleucel-T did not improve time-to-progression and reduction of prostate-specific antigen (PSA) level ≥50% was not significantly different from that with placebo. AR-directed therapies significantly improved overall survival in patients with CRPC and improved time-to-progression and reduction of PSA level ≥50%. AR-directed therapies did not increase risk of adverse event of grade ≥3 (p>0.05).

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