Dataset Information

Comparison of Systemic Treatments for Metastatic Castration-Resistant Prostate Cancer After Docetaxel Failure: A Systematic Review and Network Meta-analysis

ABSTRACT: Background: Lacking head-to-head trial, the optimal treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure is unclear. This study is to compare the efficacy and safety of systemic treatments in patients who progressed after docetaxel to aid clinical decision-making. Methods: Databases including MEDLINE, EMBASE, and the Cochrane Library were searched from inception to June 15th, 2021. The outcomes of interest include overall survival (OS), biochemical progression-free survival (bPFS), and serious adverse events (SAEs). The Cochrane risk of bias tools were used to assess study quality. Indirect comparisons of competing treatments were performed via Bayesian network meta-analysis. Results: Five trials with 3,862 patients comparing four treatments (abiraterone, enzalutamide, cabazitaxel, and radium-223) were identified. All the four treatments were associated with improved OS and bPFS relative to best supportive care. Among them, enzalutamide (hazard ratio [HR] = 0.58, 95% credible interval [Crl]: 0.49–0.69) had the highest probability of ranking first in terms of OS, followed by cabazitaxel (HR = 0.70, 95% Crl: 0.59–0.83), radium-223 (HR = 0.71, 95% Crl: 0.56–0.90) and abiraterone (HR = 0.73, 95% Crl: 0.63–0.84). Similarly, enzalutamide (HR = 0.25, 95% Crl: 0.20–0.31) showed the greatest improvement of bPFS, followed by abiraterone (HR = 0.60, 95% Crl: 0.51–0.71) and cabazitaxel (HR = 0.75, 95% Crl: 0.63–0.89). In terms of safety, treatments ranked from the safest to the least safe were radium-223 (OR = 0.58, 95% Crl: 0.20–1.68), enzalutamide (OR = 0.80, 95% Crl: 0.28–2.29), abiraterone (OR = 0.94, 95% Crl: 0.39–2.27) and cabazitaxel (OR = 2.50, 95% Crl: 0.84–7.44). Conclusion: For patients with mCRPC who progressed after docetaxel, enzalutamide may offer the most significant survival benefits and satisfying safety. Cabazitaxel is effective in post-docetaxel settings but associated with a high risk of SAEs. Although network meta-analysis provides indirect comparisons and ranking probabilities, the results should be treated with caution as it cannot replace randomized direct comparison. Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020223040, identifier CRD42020223040.

SUBMITTER: Chen J

PROVIDER: S-EPMC8804311 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ImportanceMultiple systemic treatments are available for metastatic castration-sensitive prostate cancer (mCSPC), with unclear comparative effectiveness and safety and widely varied costs.ObjectiveTo compare the effectiveness and safety determined in randomized clinical trials of systemic treatments for mCSPC.Data sourcesBibliographic databases (MEDLINE, Embase, and Cochrane Central), regulatory documents (US Food and Drug Administration and European Medicines Agency), and trial registries (ClinicalTrials.gov and European Union clinical trials register) were searched from inception through November 5, 2019.Study selection, data extraction, and synthesisEligible studies were randomized clinical trials evaluating the addition of docetaxel, abiraterone acetate, apalutamide, or enzalutamide to androgen-deprivation therapy (ADT) for treatment of mCSPC. Two investigators independently performed screening. Discrepancies were resolved through consensus. A Cochrane risk-of-bias tool was used to assess trial quality. Relative effects of competing treatments were assessed by bayesian network meta-analysis and survival models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used.Main outcomes and measuresOverall survival, radiographic progression-free survival, and serious adverse events (SAEs).ResultsSeven trials with 7287 patients comparing 6 treatments (abiraterone acetate, apalutamide, docetaxel, enzalutamide, standard nonsteroidal antiandrogen, and placebo/no treatment) were identified. Ordered from the most to the least effective determined by results of clinical trials, treatments associated with improved overall survival when added to ADT included abiraterone acetate (hazard ratio [HR], 0.61; 95% credible interval [CI], 0.54-0.70), apalutamide (HR, 0.67; 95% CI, 0.51-0.89), and docetaxel (HR, 0.79; 95% CI, 0.71-0.89); treatments associated with improved radiographic progression-free survival when added to ADT included enzalutamide (HR, 0.39; 95% CI, 0.30-0.50), apalutamide (HR, 0.48; 95% CI, 0.39-0.60), abiraterone acetate (HR, 0.51; 95% CI, 0.45-0.58), and docetaxel (HR, 0.67; 95% CI 0.60-0.74). Docetaxel was associated with substantially increased SAEs (odds ratio, 23.72; 95% CI, 13.37-45.15), abiraterone acetate with slightly increased SAEs (odds ratio, 1.42; 95% CI, 1.10-1.83), and other treatments with no significant increase in SAEs. Risk of bias was noted for 4 trials with open-label design, 3 trials with missing data, and 2 trials with potential unprespecified analyses.Conclusions and relevanceIn this network meta-analysis, as add-on treatments to ADT, abiraterone acetate and apalutamide may provide the largest overall survival benefits with relatively low SAE risks. Although enzalutamide may improve radiographic progression-free survival to the greatest extent, longer follow-up is needed to examine the overall survival benefits associated with enzalutamide.

Project description:Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform an exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR]=1.61, 95% confidence interval [CI]=1.08-2.39, p=0.018), but not PFS (HR=1.04, 95% CI 0.74-1.46, p=0.8) or PSA response (odds ratio=1.14, 95% CI=0.65-1.99, p=0.7). We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 73 chemotherapy-naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC patients receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR=0.16, 95% CI=0.06-0.46, p<0.001) and PFS (HR=0.31, 95% CI=0.12-0.80, p=0.02). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal patients (HR=1.93, 95% CI=1.19-3.12, p=0.008) and a suggestion favoring docetaxel for AR-gained patients (HR=0.53, 95% CI=0.24-1.16, p=0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. This treatment selection merits prospective evaluation in a randomized trial. PATIENT SUMMARY: We investigated whether plasma androgen receptor (AR) predicted outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel, and we performed an exploratory analysis in patients treated with docetaxel or AR-directed drugs as first-line mCRPC therapy. We showed that plasma AR normal favored hormonal treatment, whilst plasma AR-gained patients may have had a longer response to docetaxel, suggesting that plasma AR status could be a useful treatment selection biomarker.

Project description:BackgroundFor nonmetastatic castration-resistant prostate cancer (nmCRPC), 3 drugs under patent protection-apalutamide, enzalutamide, and darolutamide-were approved based on randomized, placebo-controlled trials; 1 drug with generic availability, abiraterone acetate, showed efficacy in a single-arm trial and is commonly prescribed. Lacking head-to-head trials, the optimal treatment for nmCRPC is unknown, despite widely varied treatment costs. We compared the efficacy and safety of nmCRPC treatments.MethodsWe searched bibliographic databases, regulatory documents, and trial registries for nmCRPC trials. We included published results and, when available, original data. We performed matching-adjusted indirect comparison and network meta-analysis and compared treatments regarding metastasis-free survival, overall survival, and serious adverse events.ResultsWe analyzed 5 trials with 4360 participants. Compared with placebo, abiraterone acetate engendered the lowest hazard of metastasis and death (hazard ratio [HR] = 0.22, 95% credible interval [CrI] = 0.12-0.41), followed by apalutamide (HR = 0.28, 95% CrI = 0.23-0.34), enzalutamide (HR = 0.30, 95% CrI = 0.25-0.36), and darolutamide (HR = 0.41, 95% CrI = 0.34-0.49); darolutamide led to the lowest hazard of death (HR = 0.69, 95% CrI = 0.53-0.90), followed by enzalutamide (HR = 0.73, 95% CrI = 0.61-0.87) and apalutamide (HR = 0.75, 95% CrI = 0.59-0.95); darolutamide resulted in the lowest odds of serious adverse events (odds ratio [OR] = 1.32, 95% CrI = 1.02-1.70), followed by enzalutamide (OR =1.43, 95% CrI = 1.08-1.89), apalutamide (OR = 1.58, 95% CrI = 1.23-2.03), and abiraterone acetate (OR = 1.94, 95% CrI = 1.17-3.22).ConclusionsFor nmCRPC, darolutamide offered optimal efficacy and safety among approved drugs, and abiraterone acetate may offer comparable metastasis-free survival benefit with cost savings from generic availability. Future research is needed to more fully examine the benefit of abiraterone acetate.

Project description:Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting.We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (??50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models.One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P?=?0.089). Median TTPP was 7.2 months (95% CI?=?4.5?-?17.2) in the D-naïve group versus 2.6 mo (95% CI?=?1.9?-?3.5) in the D-pretreated group (P?<?0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI?=?2.5?-?4.8) for D-pretreated men (P?<?0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR?=?2.32; 95% CI?=?1.19?-?4.50; P?=?0.013) and marginally significant for PFS (HR?=?1.90; 95% CI?=?0.94?-?3.84; P?=?0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n?=?34), results suggested a trend towards shorter duration of response in D-pretreated patients.The clinical activity of enzalutamide appears to be blunted in patients who have previously received docetaxel chemotherapy. These results support the concept of cross-resistance between these two agents.

Project description:BACKGROUND:Multiple androgens drive prostate cancer progression and higher pre-treatment levels of androgens, even within the castrate range, have been previously shown to be associated with an improved overall survival (OS) in mCRPC. Docetaxel impairs microtubules, has androgen receptor (AR) inhibitory effects and is used in both the castration resistant and sensitive settings, where androgen dynamics may impact outcome. The present analysis evaluates the association of decline in serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA in docetaxel-treated mCRPC patients with OS. METHODS:Data from 1050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were evaluated. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment, 6 week and progression serum assays for T, A and DHEA were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS). Changes in T, A and DHEA levels from baseline to 6 weeks were calculated as the ratio of 6-week over baseline. The proportional hazards model was used to assess the prognostic significance of changes in T, A, and DHEA from baseline to 6 weeks in predicting OS adjusting for known prognostic factors. RESULTS:Median baseline values for T, A, and, DHEA were 1.0, 13.5, and 8.1?ng/dL respectively while 6 week levels were 0.64, 7.0, and 6.8?ng/dL respectively. Median OS for low testosterone decline is 20.9 months vs 26.3 months for high testosterone decline. In multivariable analysis including known prognostic variables, change in testosterone levels was independently associated with greater OS; the hazard ratio for death with each unit increase in the 6-week/baseline ratio is 1.02 (95% CI?=?1.01-1.03, p?=?0.001). Decline in A and DHEA were not significant predictors of OS. In multivariable analysis change in the serum changes did not predict PFS however the ratio of T at 6-weeks over baseline was prognostic of ?50% decline in PSA with an odds ratio of 0.93 (95% CI?=?0.85-0.98, p-value?=?0.039). CONCLUSIONS:Declines in testosterone during docetaxel treatment is associated with a longer survival, consistent with a favorable prognostic significance of higher serum androgens in the CRPC.

Dataset Information

Comparison of Systemic Treatments for Metastatic Castration-Resistant Prostate Cancer After Docetaxel Failure: A Systematic Review and Network Meta-analysis

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets