[Show abstract][Hide abstract] ABSTRACT: Background:
The duration of prior hormonal treatment can predict responses to subsequent therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).
To determine if prior endocrine therapy duration is an indicator of abiraterone acetate (AA) sensitivity.
Design, setting, and participants:
Post-hoc exploratory analysis of randomised phase 3 studies examining post-docetaxel (COU-AA-301) or chemotherapy-naïve mCRPC (COU-AA-302) patients receiving AA. The treatment effect on overall survival (OS), radiographic progression-free survival (rPFS), and prostate-specific antigen (PSA) response analysed by quartile duration of prior gonadotropin-releasing hormone agonists (GnRHa) or androgen receptor (AR) antagonist.
Patients were randomised to AA (1000mg, orally once daily) plus prednisone (5mg, orally twice daily) or placebo plus prednisone. Prior endocrine therapy was GnRHa (COU-AA-301, n=1127 [94%]; COU-AA-302, n=1057 [97%], 45.1 mo or 36.7 mo median duration, respectively) and/or orchiectomy (COU-AA-301, n=78 [7%] COU-AA-302, n=44 [4%]); castrated patients received prior AR antagonists (COU-AA-301, n=1015 [85%]; COU-AA-302, n=1078 [99%], 15.7 mo or 16.1 mo median duration, respectively).
Outcome measurements and statistical analysis:
Cox model was used to obtain hazard ratio and associated 95% confidence interval with statistical inference by log rank statistic.
Results and limitations:
Clinical benefit with AA was observed for OS, rPFS, and PSA response for nearly all quartiles with GnRHa or AR antagonists in both COU-AA-301 and COU-AA-302. In COU-AA-301, patients with a longer duration of prior endocrine therapy tended to have greater AA OS, rPFS, and PSA response benefit, with lead-time chemotherapy bias potentially impacting COU-AA-301 results. Time to castration resistance was not captured. This analysis is limited as a post-hoc exploratory analysis.
In the COU-AA-301 and COU-AA-302 studies, AA produced clinical benefits regardless of prior endocrine therapy duration in patients with mCRPC.
Metastatic castration-resistant prostate cancer patients derived clinical benefits with abiraterone acetate regardless of prior endocrine therapy duration.
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors
in recurrent disease is variable. Biopsy of bone metastases is challenging; hence, sampling circulating tumor cells (CTCs)
may reveal drug-resistance mechanisms. We established single-cell RNA-sequencing (RNA-Seq) profiles of 77 intact CTCs isolated
from 13 patients (mean six CTCs per patient), by using microfluidic enrichment. Single CTCs from each individual display considerable
heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR
inhibitor, compared with untreated cases, indicates activation of noncanonical Wnt signaling (P = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition,
whereas its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established
mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute
to treatment failure.
[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.
[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.
No preview · Article · Oct 2014 · Clinical Genitourinary Cancer
[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.
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.
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.
No preview · Article · Sep 2014 · Journal of Clinical Oncology
[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.
Studies in this analysis included COU-AA-302 (chemotherapy na < ve); COU-AA-301 and COU-AA-006 (chemotherapy pretreated); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 359 subjects (62 healthy volunteers, 297 patients) were analyzed using non-linear mixed-effects modeling.
An Erlang-type absorption model with first-order elimination and three-transit compartments following sequential zero- and first-order processes was used to characterize abiraterone pharmacokinetics. Absorption-related parameters were affected by food intake. Abiraterone pharmacokinetics were characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1,550 L/h) versus healthy subjects (2,240 L/h), and by large apparent central (5,620 L) and peripheral (17,400 L) volumes of distribution. Abiraterone pharmacokinetics were similar in chemotherapy-pretreated and -na < ve patients and were characterized by a high between- and within-subject variability [e.g., between-subject coefficient of variation (CV%) for relative bioavailability for the modified fasting state was 61.1 % and the CV% for within-subject variability was 71.3 %]. The fat content of food taken with abiraterone acetate affected the bioavailability of abiraterone. No factors beyond food intake and health status (healthy vs. mCRPC) impacted abiraterone pharmacokinetics.
Based on the pharmacokinetics model, the recommended 1,000 mg/day of abiraterone acetate resulted in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy. The fat content of food affected relative bioavailability of abiraterone, though the extent of this effect is dependent on health status.
[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.
No preview · Article · Aug 2014 · European Urology
[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.
No preview · Article · Jun 2014 · Journal of Clinical Endocrinology & Metabolism