Statin Use and Survival in Patients with Metastatic Castration-resistant Prostate Cancer Treated with Abiraterone Acetate.

BACKGROUND: Although statin use has been associated with favorable effects in various solid malignancies, no conclusive evidence is available at present. Statins are safe and inexpensive, and may synergize with novel antiandrogen agents abiraterone via pharmacokinetic interactions and decrease substrate availability for de novo androgen biosynthesis. OBJECTIVE: To determine whether statin use affects survival in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone. DESIGN, SETTING, AND PARTICIPANTS: Medical records of patients with documented mCRPC between September 2011 and August 2016 were reviewed at multiple participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. A total of 187 patients receiving abiraterone for mCRPC between September 2011 and August 2016 were eligible for inclusion in this retrospective study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were assessed for overall survival (OS), statin use at the time of treatment initiation, prostate-specific antigen (PSA) variations, and other variables of interest. Univariable and multivariable analysis was used to explore the association of variables of interest with OS and PSA declines. RESULTS AND LIMITATIONS: Statin use was a significant prognostic factor for longer OS in univariable (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.37-0.72; p<0.001) and multivariable analysis (HR 0.40, 95% CI 0.27-0.59; p<0.001) and was significantly associated with PSA declines (>50% decline at 12 wk: 72.1% in statin users vs 38.5% in non-users; p<0.001). CONCLUSIONS: Our study suggests a prognostic impact of statin use in patients receiving abiraterone for mCRPC. The mechanism of this interaction warrants elucidation, but may include enhancement of the antitumor activity of abiraterone as well as cardioprotective effects. PATIENT SUMMARY: We assessed the effects of statin use in patients with advanced prostate cancer receiving abiraterone. Patients treated with a statin plus abiraterone appeared to live longer than those treated with abiraterone only. Since no negative drug-drug interaction is known and statins are widely used and inexpensive, further studies assessing the use of abiraterone plus statins are warranted.

PSA declines and survival in patients with metastatic castration-resistant prostate cancer treated with enzalutamide: A retrospective case-report study.

RATIONALE: PSA responses have been associated with a survival benefit in patients treated with enzalutamide in retrospective analyses. PATIENT CONCERNS: However the prognostic value of PSA declines in highly pretreated patients receiving enzalutamide remains to be defined. DIAGNOSES AND INTERVENTATIONS: Medical records of patients with documented mCRPC treated with enzalutamide between September 2011 and August 2016 were reviewed at multiple participating centers and assessed for overall survival (OS), PSA variations, and other variables of interest. Univariable and multivariable analyses were conducted. OUTCOMES: A total of 129 patients received enzalutamide. PSA response rates (>50% PSA declines) were 58/119 (48.7%), 58/115 (50.4%), 54/110 (49.1%), and 47/91 (51.7%) at weeks 4, 8, 12, and 16, respectively. Having a PSA response was a statistically significant prognostic factor of improved OS at 8 and 12 weeks in univariable analysis, whereas it was significant at 12 weeks in the multivariable analysis. Patients treated with enzalutamide had a median OS of 7.8 months. LESSONS: Our study supports the prognostic value of PSA declines in heavily treated patients receiving enzalutamide.

Third-Line Chemotherapy for Metastatic Urothelial Cancer: A Retrospective Observational Study.

The prognosis of locally advanced (T3/T4 or N1) and metastatic disease urothelial carcinoma is poor. In this retrospective study, we reviewed data about patients receiving third-line chemotherapy for metastatic disease, in view of the lack of data in this setting.We retrospectively analyzed medical records of patients with a pathologic diagnosis of urothelial carcinoma treated with systemic chemotherapy for metastatic disease at 4 participating Institutions between January, 2010, and January, 2015. Cox proportional hazards regression was used to evaluate the association of the chemotherapy agent used versus others with overall survival, adjusted for 5 externally validated prognostic factors in advanced urothelial carcinoma.Of 182 patients that received first-line chemotherapy/adjuvant chemotherapy as defined above, 116 patients (63.73%) received second-line salvage treatment. Fifty-two patients were finally included in this analysis, whereas 9 were excluded due to missing data. Third-line chemotherapy was based on cyclophosphamide, platinum, vinflunine, taxanes, and gemcitabine in 16, 12, 11, 10, and 3 patients, respectively. Median PFS (progression-free survival) and OS (overall survival) of the population were 13 (10-17) and 31 (28-36) weeks. Single-agent cyclophosphamide was associated with a PFS of 18 (13-22) and an OS of 38 (33-41) weeks, whereas platinum-based combinations were associated with a PFS of 5 weeks and an OS of 8 weeks. Multivariate analysis showed improved survival in patients treated with cyclophosphamide (hazard ratio (HR) = 0.42; 95% CI: 0.20-0.89; P = 0.025) and a worse survival in those treated with platinum-based regimens (HR: 4.37; 95% CI = 1.95-9.77; P < 0.01).We observed a significantly longer overall survival in patients receiving single-agent cyclophosphamide, with few grade 3 to 4 toxicities. Further studies should assess the efficacy of metronomic single-agent cyclophosphamide in advanced lines of treatment, as it may yield a survival benefit with low costs and no detrimental effects on quality of life.

Phase 1/2 study of intravenous paclitaxel and oral cyclophosphamide in pretreated metastatic urothelial bladder cancer patients.

BACKGROUND: To the authors' knowledge, no previous studies have been reported with the combination of paclitaxel and oral cyclophosphamide in patients with metastatic bladder cancer. A phase 1/2 study was conducted of paclitaxel in combination with oral cyclophosphamide for patients with advanced urothelial bladder cancer who had been previously treated with gemcitabine/cisplatin chemotherapy as first-line metastatic treatment. METHODS: This was a single-arm phase 1/2 study. Patients were treated with paclitaxel and oral cyclophosphamide at 3-week intervals until disease progression or irreversible toxicity occurred. Primary endpoints were to determine the maximum tolerated doses (MTD) and objective response rate; secondary endpoints were safety, time to disease progression (TTP), and overall survival (OS). RESULTS: Forty-four patients were enrolled. Dose levels of paclitaxel of 175 mg/m(2) (Day 1) and cyclophosphamide of 50 mg (Days 1-7 orally) (dose level I) of a 21-day cycle were tolerated without dose-limiting toxicities (DLTs). At a cyclophosphamide dose of 100 mg (dose level II) the MTD was exceeded; 3 of 6 patients experienced a DLT (grade 3 constipation and grade 4 neutropenia and thrombocytopenia [toxicities were graded using National Cancer Institute Common Toxicity Criteria (version 3.0)]). Dose level I was expanded and determined to be the MTD. A total of 32 patients were treated at dose level I in the phase 2 portion. Partial responses were observed in 31% of patients (10 of 32 patients; 95% confidence interval [95% CI], 17%-45%). Grade 1/2 vomiting, peripheral neuropathy, and neutropenia were the most common side effects, noted in 11 (34%), 8 (25%), and 10 (31%) patients, respectively. The median TTP was 5 months (95% CI, 2 months-7.5 months) and the median OS was 8 months (95% CI, 4 months-14 months). CONCLUSIONS: The combination of paclitaxel and cyclophosphamide is well tolerated and associated with promising efficacy. Further trials are needed to confirm these preliminary results.