Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy.

The authors' affiliations are listed in the Appendix.
New England Journal of Medicine (Impact Factor: 54.42). 12/2012; DOI: 10.1056/NEJMoa1209096
Source: PubMed

ABSTRACT Background Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy. Methods In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival. Results The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone. Conclusions Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer. (Funded by Janssen Research and Development, formerly Cougar Biotechnology; number, NCT00887198 .).


Available from: Josep Maria Piulats, Jun 03, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone metastases cause significant morbidity to patients with prostate cancer, the most commonly diagnosed solid cancer in men. In the last decade, the approach to metastatic castrate-resistant prostate cancer has evolved remarkably, with approval of multiple new medications with survival benefit. We review the radiobiology and phases of development of 223Ra (radium), an α-emitter radiopharmaceutical, and discuss the clinical implications of its use and its future role in the treatment of prostate cancer. A review of the literature was performed through searches of PubMed and Medline databases and related links in these databases, along with recently published abstracts from major medical meetings. 223Ra is an α-emitter, with high affinity to areas of bone metastases. α-Particles have high energy and short range, causing cytotoxicity to targeted cancer cells without affecting surrounding normal tissues. It has been proven to prolong overall survival, delay symptomatic skeletal events, and improve quality of life, while having a minimal toxicity profile. 223Ra is effective and safe in the treatment of bone metastatic castration-resistant prostate cancer. Additional studies are planned to assess the efficacy of 223Ra in combination with other agents known to be active in advanced prostate cancer.
    01/2015; DOI:10.1007/s40336-015-0103-5
  • [Show abstract] [Hide abstract]
    ABSTRACT: Observationally, testosterone is negatively associated with systemic inflammation, but this association is open to both residual confounding and reverse causality. Large-scale randomized controlled trials (RCTs), assessing exogenous effects, are presently unavailable. We examined the association of endogenous testosterone with well-established systemic inflammatory markers (white blood cell, granulocyte, lymphocyte and high-sensitivity C-reactive protein (hsCRP)) using a separate-sample Mendelian randomization analysis to minimize reverse causality. A genetic prediction rule for serum testosterone was developed in 289 young Chinese men with mean age of 21.0, using selected testosterone-related SNPs (rs10046, rs1008805 and rs1256031). Multivariable linear regression was used to examine the association of genetically predicted serum testosterone with inflammatory markers among 4,212 older Chinese men from the Guangzhou Biobank Cohort Study. Genetically predicted testosterone was unrelated to white blood cell count (-0.01 109/L per nmol/L testosterone, 95% confidence interval (CI) -0.05 to 0.04), granulocyte count (-0.02 109/L, 95% CI -0.06 to 0.02), lymphocyte count (0.005 109/L, 95% CI -0.01 to 0.02) and hsCRP (-0.05 mg/L, 95% CI -0.15 to 0.06). Our findings did not corroborate any anti-inflammatory effects of testosterone or corresponding potentially protective effects of testosterone on chronic diseases resulting from reduced low-grade systemic inflammation.
    PLoS ONE 05/2015; 10(5):e0126442. DOI:10.1371/journal.pone.0126442 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure. Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level. A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively. A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 03/2015; 33(12). DOI:10.1200/JCO.2014.55.3487 · 17.88 Impact Factor