Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness

BACKGROUND: Results from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources OBJECTIVE: To assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting. DESIGN, SETTING AND PARTICIPANTS: We modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy. INTERVENTION: SOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75 mg/m2) was administered alongside SOC for six three-weekly cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS AND LIMITATIONS: The model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled. CONCLUSIONS: Docetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available. PATIENT SUMMARY: Starting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body

Addition of docetaxel to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Long-term survival, quality-adjusted survival, and cost-effectiveness analysis

Background: Results from large randomised controlled trials have shown that adding docetaxel to standard of care (SOC) in men initiating hormone therapy for prostate cancer prolongs survival for those with metastatic disease and prolongs time to treatment failure for those without metastatic disease. We report on the impact of docetaxel on health related quality of life (HRQoL), resource use and cost-effectiveness for men treated in the STAMPEDE trial. Methods: Health outcomes and costs in the UK NHS were modelled using EuroQol (EQ-5D)and resource use data collected within the STAMPEDE trial (STAMPEDE enrolled men advanced prostate cancer starting first line hormone therapy. SOC was hormone therapy for ≥2 years and radiotherapy in some patients. Docetaxel (75 mg/m2) was administered alongside SOC for six 3-weekly cycles with prednisolone 10 mg daily. Lifetime predictions of costs, changes in predicted survival duration, quality adjusted life years (QALYs), and incremental cost effectiveness ratios (ICERs) were calculated. Results: Compared to patients allocated SOC, docetaxel was estimated to extend predicted survival by an average of 0.89 years for M1 patients and 0.78 years for M0 patients. Docetaxel was estimated to extend discounted QALYs by 0.51 years in M1 patients and 0.39 years in M0 patients. QALY gains in M0 patients were driven by the beneficial effect of delayed and reduced relapse. Docetaxel was cost-effective both in M1 patients (ICER = £5,514/QALY vs. SOC) and M0 patients (higher QALYs, lower costs vs. SOC). The probabilistic sensitivity analysis indicated a very high probability ( > 99%) that docetaxel is cost-effective in both M0 and M1 patients. Docetaxel remained cost effective in M0 patients even when no survival advantage was assumed due to reductions and delays in relapse. Conclusions: Docetaxel improves overall HRQoL, delays time to, and reduces the need for, subsequent therapy, and is cost-effective, amongst patients with both non-metastatic and metastatic disease. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in non-metastatic patients

Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: The availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an intermediate endpoint for overall survival (OS). OBJECTIVE: To evaluate the association between early PSA decline and OS following abiraterone acetate (AA) treatment. DESIGN, SETTING, AND PARTICIPANTS: We identified mCRPC patients treated with AA before or after docetaxel at the Royal Marsden NHS Foundation Trust between 2006 and 2014. Early PSA decline was defined as a 30% decrease in PSA at 4 wk relative to baseline, and early PSA rise as a 25% increase. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association with OS was analyzed using multivariate Cox regression and log-rank analyses. Spearman's rho correlation coefficient (r) was calculated to evaluate the association between PSA changes at 4 wk and 12 wk. RESULTS AND LIMITATIONS: There were 274 patients eligible for this analysis. A 30% PSA decline at 4 wk was associated with longer OS (25.8 vs 15.1 mo; hazard ratio [HR] 0.47, p<0.001), and a 25% PSA rise at 4 wk with shorter OS (15.1 vs 23.8 mo; HR 1.7, p=0.001) in both univariate and multivariable models. The percentage PSA decline at 4 wk was significantly correlated with the percentage PSA change at 12 wk (r=0.82; p<0.001). Patients achieving a 30% PSA decline at 4 wk were 11.7 times more likely to achieve a 50% PSA decrease at 12 wk (sensitivity 90.9%, specificity 79.4%). Limitations include the retrospective design of this analysis. CONCLUSIONS: Patients not achieving 30% PSA decline after 4 wk of AA have a lower likelihood of achieving PSA response at 12 wk and significantly inferior OS. Prospective multicentre validation studies are needed to confirm these findings. PATIENT SUMMARY: Prostate-specific antigen (PSA) is commonly used to evaluate response to treatment in metastatic castration-resistant prostate cancer. Expert recommendations discourage reliance on PSA changes earlier than 12 wk after treatment initiation. Our data suggest that early PSA changes are associated with survival in patients receiving abiraterone acetate

Mia40-dependent oxidation of cysteines in domain I of Ccs1 controls its distribution between mitochondria and the cytosol

Sod1 is an important antioxidant enzyme that becomes activated by its chaperone, Ccs1. The localization of Ccs1 to mitochondria is controlled by the oxidoreductase Mia40. The formation of a disulfide bond between Cys-27 and Cys-64 in Ccs1 is critical for import and stability but not for Ccs1 activity in the maturation of Sod1

In vivo evidence for cooperation of Mia40 and Erv1 in the oxidation of mitochondrial proteins

The intermembrane space of mitochondria accommodates the essential mitochondrial intermembrane space assembly (MIA) machinery that catalyzes oxidative folding of proteins. The disulfide bond formation pathway is based on a relay of reactions involving disulfide transfer from the sulfhydryl oxidase Erv1 to Mia40 and from Mia40 to substrate proteins. However, the substrates of the MIA typically contain two disulfide bonds. It was unclear what the mechanisms are that ensure that proteins are released from Mia40 in a fully oxidized form. In this work, we dissect the stage of the oxidative folding relay, in which Mia40 binds to its substrate. We identify dynamics of the Mia40–substrate intermediate complex. Our experiments performed in a native environment, both in organello and in vivo, show that Erv1 directly participates in Mia40–substrate complex dynamics by forming a ternary complex. Thus Mia40 in cooperation with Erv1 promotes the formation of two disulfide bonds in the substrate protein, ensuring the efficiency of oxidative folding in the intermembrane space of mitochondria

A discrete pathway for the transfer of intermembrane space proteins across the outer membrane of mitochondria

Mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria with the help of protein translocases. For the majority of precursor proteins, the role of the translocase of the outer membrane (TOM) and mechanisms of their transport across the outer mitochondrial membrane are well recognized. However, little is known about the mode of membrane translocation for proteins that are targeted to the intermembrane space via the redox-driven mitochondrial intermembrane space import and assembly (MIA) pathway. On the basis of the results obtained from an in organello competition import assay, we hypothesized that MIA-dependent precursor proteins use an alternative pathway to cross the outer mitochondrial membrane. Here we demonstrate that this alternative pathway involves the protein channel formed by Tom40. We sought a translocation intermediate by expressing tagged versions of MIA-dependent proteins in vivo. We identified a transient interaction between our model substrates and Tom40. Of interest, outer membrane translocation did not directly involve other core components of the TOM complex, including Tom22. Thus MIA-dependent proteins take another route across the outer mitochondrial membrane that involves Tom40 in a form that is different from the canonical TOM complex