Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer

Background Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D. Objective To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT]). Design, setting, and participants Data were accessed from two independent phase III trials of ADT alone or ADT + D—GETUG-AFU15 ( N = 385) and CHAARTED ( N = 790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized. Outcome measurements and statistical analysis The primary end point was OS. Results and limitations Meta-analysis results of the aggregate data showed significant heterogeneity in ADT + D versus ADT effect sizes between HV and LV subgroups ( p = 0.017), and failed to detect heterogeneity in ADT + D versus ADT effect sizes between upfront and PRLT subgroups ( p = 0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT + D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p < 0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT + D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials. Conclusions There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients. Patient summary Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits.

This article considers some of the practical problems inherent in interim analyses and stopping rules for randomized clinical trials. Topics covered include group sequential designs, trials with unplanned interim analyses, estimation problems in clinical trials with planned interim analyses, and the balance between individual and collective ethics. Particular attention is paid to the fact that clinical trials that stop early are prone to exaggerate the magnitude of treatment effect. Accordingly, a Bayesian "shrinkage" method of analysis is proposed to help quantify the extent to which surprisingly large point and interval estimates of treatment difference in clinical trials that stop early should be moderated.

The TAX 327 study compared 3-weekly docetaxel, weekly docetaxel or 3-weekly mitoxantrone, each with prednisone, for 1006 patients with metastatic hormone-refractory prostate cancer. Survival and symptom control were superior following 3-weekly docetaxel as compared with mitoxantrone. At progression, many patients were treated with the other drug. Here, we provide a retrospective report of survival and prostate-specific antigen (PSA) response after second-line therapy. The TAX 327 database provided information about treatment after progression on first-line therapy, and survival has been updated. Investigators were asked to provide information about crossover treatment and serial PSA values. We identified 232 crossover patients. Median survival after crossover was 10 months and did not depend on direction of crossover. Data on PSA response are available for 96 patients: PSA response (> or =50% reduction) occurred in 15% of 71 men receiving mitoxantrone after docetaxel and in 28% of 25 men receiving docetaxel after mitoxantrone. Median PSA progression-free survival was 3.4 months for mitoxantrone after docetaxel and 5.9 months for docetaxel after mitoxantrone. One quarter of men received crossover therapy and survival was similar in the crossover groups. The PSA response rate to docetaxel after mitoxantrone was higher than that for mitoxantrone after docetaxel.