Third-line Life-prolonging Drug Treatment in a Real-world Metastatic Castration-resistant Prostate Cancer Population: Results from the Dutch Castration-resistant Prostate Cancer Registry.

BACKGROUND: Evidence concerning third-line life-prolonging drugs (LPDs) in the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients is incomplete. OBJECTIVE: To evaluate third-line LPD outcomes in a real-world cohort of mCRPC patients, identify variables associated with overall survival (OS), and establish a prognostic model. DESIGN, SETTING, AND PARTICIPANTS: Patients with mCRPC who were progressive on second-line LPD before July 1, 2017 were retrospectively identified from the Dutch Castration-resistant Prostate Cancer Registry (CAPRI) and followed until December 31, 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association of potential risk factors with OS was tested by Cox proportional hazard models after multiple imputation of missing baseline characteristics. A predictive score was computed from the regression coefficient and used to classify patients into risk groups. RESULTS AND LIMITATIONS: Of 1011 mCRPC patients progressive on second-line LPD, 602 (60%) received third-line LPD. Patients receiving third-line LPD had a more favorable prognostic profile at baseline and longer median OS than patients with best supportive care (10.4 vs 2.4 mo, p < 0.001). Eastern Cooperative Oncology Group performance status 1 and ≥2 (hazard ratio [HR] 1.51, p < 0.007 and HR 3.08, p < 0.001, respectively), opioid use (HR 1.55, p = 0.019), visceral metastases (HR 2.09, p < 0.001), hemoglobin <7 mmol/l (HR 1.44, p < 0.002), prostate-specific antigen ≥130 µg/l (HR 1.48, p = 0.001), alkaline phosphatase ≥170 U/l (HR 1.52, p < 0.001), and lactate dehydrogenase ≥250 U/l (HR 1.44; p = 0.015) were associated with shorter survival. Harrell's C-index was 0.74. The median OS values for low-, low-intermediate-, high-intermediate-, and high-risk groups were 14, 7.7, 4.7, and 1.8 mo, respectively. Limitations include the retrospective design. CONCLUSIONS: We developed a prognostic model and identified a subgroup of patients in whom third-line LPD treatment has no meaningful benefit. Our results need to be confirmed by prospective clinical trials. PATIENT SUMMARY: We reported outcomes from third-line life-prolonging drugs in metastatic prostate cancer patients and developed a prognostic model that could be used to guide treatment decisions.

Differences in Trial and Real-world Populations in the Dutch Castration-resistant Prostate Cancer Registry.

BACKGROUND: Trials in castration-resistant prostate cancer (CRPC) treatment have shown improved outcomes, including survival. However, as trial populations are selected, results may not be representative for the real-world population. The aim of this study was to assess the differences between patients treated in a clinical trial versus standard care during the course of CRPC in a real-world CRPC population. DESIGN, SETTING, AND PARTICIPANTS: Castration-resistant Prostate Cancer Registry is a population-based, observational, retrospective registry. CRPC patients from 20 hospitals in the Netherlands have been included from 2010 to 2013. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics, systemic treatment, and overall survival were the main outcomes. Descriptive statistics, multivariate Cox regression, and multiple imputations with the Monte Carlo Markov Chain method were used. RESULTS AND LIMITATIONS: In total, 1524 patients were enrolled of which 203 patients had participated in trials at any time. The median follow-up period was 23 mo. Patients in the trial group were significantly younger and had less comorbidities. Docetaxel treatment was more frequently used in trial patients (85% vs 40%). Despite an observed unadjusted median overall survival difference of 35 mo versus 24 mo between the trial and standard care group, this difference was not retained after adjustment for baseline characteristics and treatment effect. CONCLUSIONS: At CRPC diagnosis, the baseline characteristics of the patients who had been enrolled in trials notably differed from patients who received standard treatment options only. The survival difference between the trial and standard care group could be explained by baseline differences and treatment effects. These results indicate that trial results cannot easily be translated to real-world practice. PATIENT SUMMARY: We observed that patients treated in clinical trials differed from patients who were not. We concluded that this may lead to differential treatment and survival. Caution is warranted when real-world outcomes are compared with trial results.

Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment.

PURPOSE: Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. METHODS: In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. RESULTS: A strong and highly significant correlation (r = -0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. CONCLUSION: Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies.