[Show abstract][Hide abstract] ABSTRACT: Outcome measurements and statistical analysis: Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets a-spending function was used for OS. Adverse events were summarised descriptively. Results and limitations: With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p < 0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p = 0.0151) but did not reach the prespecified statistical efficacy boundary (a-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p = 0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports.
European Urology 11/2014; 66(5). DOI:10.1016/j.eururo.2014.02.056 · 12.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
We retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel.
The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n=584) or placebo (n=289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (PSA or radiographic) and treatment group. Patients were categorized into risk groups.
Complete data was evaluable in 784 men for construction of a prognostic model. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-LDH (HR 2.86 [95% CI=2.29, 3.56], P<0.001), hemoglobin (0.80 [0.74, 0.85], P<0.001), >1 organ involved by metastatic disease (1.49 [1.21, 1.84], P<0.001), log-alkaline phosphatase (1.13 [0.99, 1.28], P=0.074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P=0.031), progression on docetaxel (1.35 [1.00, 1.81], P=0.049), log-PSA (1.06 [1.00, 1.12], P=0.075) and log-NLR (1.55 [1.32, 1.83], P<0.001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715.
High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation.
Clinical Genitourinary Cancer 10/2014; 12(5). DOI:10.1016/j.clgc.2014.03.005 · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and Methods Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as >= 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. Conclusion The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.
[Show abstract][Hide abstract] ABSTRACT: Abiraterone acetate, an androgen biosynthesis inhibitor, prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the pre- and post-chemotherapy setting as demonstrated by the pivotal phase III studies COU-AA-301 and COU-AA-302. We performed population pharmacokinetic analyses to estimate pharmacokinetic parameters after oral administration of 1,000 mg/day of abiraterone acetate in patients with mCRPC, with or without prior chemotherapy, and after a single 1,000 mg dose in healthy volunteers. The study objectives were to determine consistency between patient populations and to characterize factors that may influence abiraterone pharmacokinetics.
[Show abstract][Hide abstract] ABSTRACT: Context
Androgen-deprivation therapy (ADT) is a key component of treatment for aggressive and advanced prostate cancer, but it has also been associated with adverse effects on bone, metabolic, cardiovascular, sexual, and cognitive health as well as body composition.
To review the current literature on the adverse effects of ADT and strategies for ameliorating harm from ADT.
The Medline database (through PubMed) was searched from inception to August 1, 2013, for studies documenting the side effects of ADT and for randomized and prospective trials of interventions to mitigate those side effects.
Adverse effects of ADT include decreases in bone mineral density; metabolic changes such as weight gain, decreased muscle mass, and increased insulin resistance; decreased libido and sexual dysfunction; hot flashes; gynecomastia; reduced testicle size; anemia; and fatigue. Several observational studies suggest an increased risk of diabetes and cardiovascular events, although most published studies report that ADT is not linked to greater cardiovascular mortality. Randomized trials have found value in treatments for some adverse effects including bone loss (bisphosphonates, denosumab, selective estrogen receptor modulators), markers of metabolic syndrome (exercise, diet, metformin), gynecomastia (tamoxifen, prophylactic radiation), muscle loss (resistance and aerobic exercise), and hot flashes (venlafaxine, medroxyprogesterone, cyproterone acetate, gabapentin).
ADT is often a necessary component of the treatment of aggressive prostate cancer, yet it has known harms that can impair health and quality of life. Clinicians should be aware of interventions that can help mitigate these adverse effects.
Androgen deprivation therapy is a critical component of the management of aggressive and advanced prostate cancer, but it causes adverse effects including bone loss, metabolic changes, gynecomastia, muscle loss, hot flashes, and possibly increased cardiovascular events. Clinicians should be aware of interventions that can help mitigate these adverse effects.
European Urology 08/2014; 67(5). DOI:10.1016/j.eururo.2014.07.010 · 12.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat and currently available therapies have limited efficacy to treat this complication. The anti-myostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice. Objective: The objective was to evaluate safety, pharmacokinetics (PK) and muscle efficacy of AMG 745 in men undergoing ADT for non-metastatic prostate cancer. Methods: This was a randomized, blinded, placebo-controlled multiple dose phase 1 study of AMG 745 given for 28 days. The endpoint of percent change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry (DXA) was pre-specified. Results: Rates of adverse events (AMG 745 versus placebo) were: diarrhea (13% versus 9%), fatigue (13% versus 4%), contusion (10% versus 0%), and injection site bruising (6% versus 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg versus placebo groups on Day 29 by 2.2% (± 0.8% standard error [SE]), p = 0.008; in exploratory fat mass analysis, a decrease - 2.5% (± 1.0% SE), p = 0.021 was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after Day 29. Conclusion: Four weekly SC doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for non-metastatic prostate cancer. Results support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.
[Show abstract][Hide abstract] ABSTRACT: The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer.
This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years, with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had non-castration levels of testosterone and prostate-specific antigen (PSA) of 2 ng/mL or greater at screening, and an Eastern Cooperative Oncology Group score of 0, received oral enzalutamide 160 mg/day. The primary outcome was the proportion of patients with an 80% or greater decline in PSA at week 25. All analyses included all patients who had received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT01302041.
67 men were enrolled into the study. 62 patients (92·5%, 95% CI 86·2-98·8) had a decline in PSA of 80% or greater at week 25. The most commonly reported treatment-emergent adverse events up to week 25 were gynaecomastia (n=24), fatigue (n=23), nipple pain (n=13), and hot flush (n=12), all of which were of mild to moderate severity. Nine patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients). Five patients reported serious adverse events, none of which were deemed to be treatment related.
Our findings suggest that enzalutamide monotherapy in men with hormone-naive prostate cancer of varying severity provides a level of disease suppression, and was generally well tolerated. These findings provide a rationale for further investigation of clinical response and outcomes with enzalutamide in non-castrate men with prostate cancer.
Astellas Pharma Inc, Medivation Inc.
The Lancet Oncology 04/2014; 15(6). DOI:10.1016/S1470-2045(14)70129-9 · 24.73 Impact Factor