Juan Morote

Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial.

BACKGROUND Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. METHODS In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov, number NCT00286091. FINDINGS 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4-33·3] vs 25·2 [22·2-29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73-0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5-38·0] vs 29·5 [22·4-33·1] months; HR 0·84, 95% CI 0·71-0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1-not estimable] months vs placebo, 44·8 [40·1-not estimable] months; HR 1·01, 95% CI 0·85-1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. INTERPRETATION This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. FUNDING Amgen Inc.

Denosumab and Bone Metastasis–Free Survival in Men With Nonmetastatic Castration-Resistant Prostate Cancer: Exploratory Analyses by Baseline Prostate-Specific Antigen Doubling Time

PURPOSE Denosumab, an anti-RANK ligand monoclonal antibody, significantly increases bone metastasis-free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months. PATIENTS AND METHODS A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died. RESULTS In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets. CONCLUSION Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.

Effect of inflammation and benign prostatic enlargement on total and percent free serum prostatic specific antigen.

Objective: To analyze the influence of inflammation and benign prostatic enlargement on total and percent free serum prostatic specific antigen (PSA).Patients and Methods: Total and free PSA serum levels were determined in 284 patients with no evidence of cancer in the sextant ultrasound–guided biopsy. Double antibody immunoradiometric assay Tandem and Tandem free PSA were used. Benign tissue without inflammation was found in 23.2% of the patients (group 1), while in 68.3%, it was associated with chronic prostatitis (group 2) and with acute prostatitis in 8.4% (group 3).Results: Median serum PSA was 7.8 ng/ml in group 1, 6.7 ng/ml in group 2 and 6.4 ng/ml in group 3, p>0.05. Median percent free PSA was 14.1, 15.6 and 16.4%, respectively, p>0.05. Multiple linear regression analysis showed that prostatic size was the only significant contributor to serum PSA concentration. Moreover, total PSA and prostatic size contributed significantly to the percent free serum PSA. Inflammation had no significant influence on total or percent free serum PSA.Conclusion: Inflammation has an important prevalence in cancer–free prostatic biopsy specimens. It seems to have no significant influence on total and percent free serum PSA. However, prostatic size seems to be the major contributor.

PTOV1 Enables the Nuclear Translocation and Mitogenic Activity of Flotillin-1, a Major Protein of Lipid Rafts

ABSTRACT PTOV1 is a mitogenic protein that shuttles between the nucleus and the cytoplasm in a cell cycle-dependent manner. It consists of two homologous domains arranged in tandem that constitute a new class of protein modules. We show here that PTOV1 interacts with the lipid raft protein flotillin-1, with which it copurifies in detergent-insoluble floating fractions. Flotillin-1 colocalized with PTOV1 not only at the plasma membrane but, unexpectedly, also in the nucleus, as demonstrated by immunocytochemistry and subcellular fractionation of endogenous and exogenous flotillin-1. Flotillin-1 entered the nucleus concomitant with PTOV1, shortly before the initiation of the S phase. Protein levels of PTOV1 and flotillin-1 oscillated during the cell cycle, with a peak in S. Depletion of PTOV1 significantly inhibited nuclear localization of flotillin-1, whereas depletion of flotillin-1 did not affect nuclear localization of PTOV1. Depletion of either protein markedly inhibited cell proliferation under basal conditions. Overexpression of PTOV1 or flotillin-1 strongly induced proliferation, which required their localization to the nucleus, and was dependent on the reciprocal protein. These observations suggest that PTOV1 assists flotillin-1 in its translocation to the nucleus and that both proteins are required for cell proliferation.

Comparison of Percent Free Prostate Specific Antigen and Prostate Specific Antigen Density as Methods to Enhance Prostate Specific Antigen Specificity in Early Prostate Cancer Detection in Men With Normal Rectal Examination and Prostate Specific Antigen Between 4.1 and 10 ng./ml.

PURPOSE We analyzed the behavior of prostate specific antigen (PSA) density and percent free PSA to enhance the specificity of PSA in the early diagnosis of prostate cancer in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. MATERIALS AND METHODS PSA serum level, PSA density and percent free PSA were analyzed in 74 men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. All men underwent systematic prostate biopsy, and the diagnosis was benign prostate hyperplasia in 52 and prostate cancer in 22. Furthermore, we determined the decrease in unnecessary biopsies and the cancer detection rate using 0.10 versus 0.15 as cut points for PSA density, and 20 versus 25 as cut points for percent free PSA. RESULTS In patients with benign prostatic hyperplasia and prostate cancer, respectively, the median PSA level was 6.7 and 7.0 ng./ml. (p > 0.05), median prostate volume was 50 and 37 cc (p < 0.04), median PSA density was 0.14 and 0.19 (p < 0.007) and median percent free PSA was 18.9 and 10.1 (p < 0.005). Using PSA density cut points of 0.15 and 0.10, the decrease in negative biopsies was 53.8 and 36.5% with a sensitivity of 86.4 and 90.9%, respectively. However, using percent free PSA cut points of 20 and 25, the decrease in negative biopsies was 36.5 and 26.9% with a sensitivity of 77.3 and 95.5%, respectively. CONCLUSIONS Although both methods could minimize unnecessary biopsies in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml., the percent free PSA was more cost-effective since transrectal ultrasound was not required. In this small series of symptomatic patients a percent free PSA cut point of 25 could detect at least 95% of prostate cancers and decrease 26.9% of negative biopsies.

Bone Mineral Density Changes in Patients With Prostate Cancer During the First 2 Years of Androgen Suppression

PURPOSE We characterized bone mineral density changes in patients with prostate cancer on androgen deprivation therapy during the first 2 years of uninterrupted therapy, and identified which location most reflects bone mass loss. MATERIALS AND METHODS Using dual energy x-ray absorptiometry, bone mineral density was prospectively assessed in patients with nonmetastatic prostate cancer at the lumbar spine and femoral neck, Wards triangle, trochanter and total hip. Measurements were performed at baseline and yearly thereafter in patients on ADT, and at baseline and 1 year in controls (age matched patients with prostate cancer, free of biochemical progression after radical prostatectomy). RESULTS A total of 62 patients were included in the study, 31 in each group. Median age (70 and 69 years, respectively), mean Gleason score and mean baseline serum testosterone did not significantly differ. Patients receiving ADT experienced a significant bone mass loss at 12 months in all locations, ranging from 2.29% to 5.55% (p <0.001). In contrast, bone mineral density did not change significantly (0.64% to 1.68%) in patients not receiving ADT. In the 20 patients on ADT after 24 months, the second year decrease was not as severe, nor was it significant compared to first year values. The major bone mass loss occurred in Wards triangle, with decreases of 5.55% at 12 months and 7.05% at 24 months. CONCLUSIONS Bone mineral density decreases during the first 24 months of androgen suppression with the most relevant effect occurring in the first year. Wards triangle is the axial skeletal site that reflects the major bone mass loss. Because the deleterious impact of long-term androgen suppression on bone mineral density is inversely related to fracture risk and indirectly related to survival in patients with prostate cancer, early diagnosis and prevention of bone mass loss are warranted in these patients.

Osteoporosis during continuous androgen deprivation: influence of the modality and length of treatment.

OBJECTIVE To analyze the prevalence of osteoporosis in patients with prostate cancer with and without androgen ablation. To know the influence of the modality and the length of androgen ablation on the prevalence of osteoporosis. To analyze the relative risk of hip fracture. MATERIAL AND METHODS In a cross-sectional study, we assessed bone densitometry at the Wards triangle of the femoral neck in 110 patients with non-metastatic prostate cancer and without biochemical relapse. A cohort of 53 patients under continuous androgen suppression during a median period of 41 months (12-191) formed the study group and 57 age-matched patients that had been submitted to a radical prostatectomy formed a control group. RESULTS Both subsets of patients had similar mean age (70.4 vs. 69.2, p=0.07). Mean bone mass was 0.70 g/cm2 in patients under androgen suppression and 0.76 g/cm2 in the control group, p=0.06. The rate of osteoporosis was 41.5% (22/53) and 28.1% (16/57) respectively, p=0.16 and the odds ratio was 1.82 (95% CI 0,82-4.03). The rate of osteoporosis was 41.4% (12/29) in patients under maximal androgen blockade and 41.7% (10/24) in patients under chemical castration, p=0.735. According to the length of the androgen suppression the rate of osteoporosis was 36.4% when it was between 12 and 36 months, 42.1% from 36 to 60 months and 50% when it was longer than 60 months. While the overall relative risk of hip fracture in the control group was 2.0, it was 2.4 when the length of androgen suppression was between 12 and 36 months, 2.9 between 36 and 60 months and 3.9 when it was longer than 60 months. CONCLUSIONS Androgen suppression increases the prevalence of osteoporosis in patients with prostate cancer. The modality of continues androgen suppression seems not to affect its prevalence. However the length of androgen suppression would be related to its development. The relative risk of hip fracture is also increasing during the androgen suppression.

Clinical Efficacy of Bone Alkaline Phosphatase and Prostate Specific Antigen in the Diagnosis of Bone Metastasis in Prostate Cancer

PURPOSE We investigated the usefulness of bone alkaline phosphatase isoenzyme and prostate specific antigen (PSA) determined by radioimmunoassay to predict bone scan evidence of metastasis in newly diagnosed untreated and treated prostate cancer. MATERIALS AND METHODS We analyzed bone alkaline enzyme concentrations in 350 men, including 150 controls, 100 with benign prostatic hyperplasia and 100 with prostate cancer (52 with stages T1 to 4, M0 and 48 with stages T1 to 4, M1 to 4). We also analyzed bone alkaline phosphatase enzyme concentrations in 61 stages T1 to 4, M0 prostate cancer cases during followup after radical prostatectomy or hormonal therapy, and 17 had clinical progression (9 with local, 5 with lymph node and 3 with bone metastases). Simultaneously, we analyzed PSA concentrations. RESULTS Average bone alkaline phosphatase enzyme levels were 12, 11.1 and 10.0 ng./ml. in the control, benign prostatic hyperplasia and stage M0 prostate cancer groups, respectively (p not significant), and 83.2 ng./ml. in patients with stage M1 to 4 disease (p<0.001). Considering that to diagnose bone metastasis the cutoff for bone alkaline phosphatase enzyme and PSA is 30 ng./ml. and 100 ng./ml., respectively, clinical effectiveness was 93.7% and 81.8%, respectively. Finally, measurement of both substances at the same time increased clinical effectiveness to 97.9%. During followup a bone alkaline phosphatase enzyme level that becomes greater than 30 ng./ml. (0% in the local and lymphatic progression groups, and 100% in the bone metastasis group) indicates the need to perform a bone scan. CONCLUSIONS We recommend the clinical use of bone alkaline phosphatase enzyme determined by radioimmunoassay and PSA measurement for the diagnosis of bone metastases and progression of prostate cancer because of the good sensitivity and specificity.

Failure to Maintain a Suppressed Level of Serum Testosterone during Long-Acting Depot Luteinizing Hormone-Releasing Hormone Agonist Therapy in Patients with Advanced Prostate Cancer

Objectives: It was the aim of this study to analyze the failure rates in achieving or maintaining castrate levels of serum testosterone in patients with advanced prostate cancer treated with the 3-month luteinizing hormone-releasing hormone agonist (LH-RH) therapy. Methods:Total serum testosterone was determined in 234 patients with prostate cancer in a cross-sectional study. A subset of 90 patients submitted to radical prostatectomy was used as the control group (group 1), and 144 patients with advanced prostate cancer under androgen suppression therapy were included in the study group (groups 2 and 3). The study group was divided into 93 patients (group 2) treated with 50 mg daily bicalutamide and LH-RH agonist (maximal androgen blockade, MAB) and 51 patients treated with the LH-RH agonist alone (group 3). Median follow-up after androgen suppression was 42 months. The castrate testosterone level was defined below 50 ng/dl. Results: The mean serum testosterone level was 29.1 ng/dl in patients undergoing MAB (group 2) and 29.5 ng/dl in patients treated with the LH-RH agonist (group 3; p > 0.05). In group 1, the mean serum testosterone was 445.2 ng/dl (p < 0.0001). The rate of patients with a serum testosterone level higher than 50 ng/dl was 10.9% in patients undergoing androgen suppression, 10% in patients with MAB treatment and 12.5% in those with LH-RH agonist therapy (p > 0.05). In group 1, 98.9% of the patients had a serum testosterone level higher than 50 ng/dl. Conclusions: A small but clinically significant rate of patients under 3-month LH-RH agonist therapy fail to achieve or maintain castrate testosterone serum levels. This finding supports the need of monitoring testicular response during LH-RH agonist therapy.

Value of Routine Transition Zone Biopsies in Patients Undergoing Ultrasound-Guided Sextant Biopsies for the First Time

Objective: To analyze the efficacy of routine transition zone biopsies in patients undergoing ultrasound-guided sextant biopsies for the first time because of a suspicious digital rectal examination (DRE) or an elevated serum prostate-specific antigen (PSA) level. Patients and Methods: During sextant prostatic biopsy two additional transition zone biopsies were performed in 164 consecutive patients: in 98 because of a serum PSA of >4.0 ng/ml, and in 66 because of a suspicious DRE. Results: The overall cancer detection rate was 46.9% (77/164). In 28 patients (36.4%) cancer was only detected in the peripheral zone, in 2 (2.6%) only in the transition zone and in 47 (61%) in both zones. Conclusion: Routine transition zone biopsies performed at the time of a first sextant biopsy seem to have low efficacy.