Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.

Background: Prognostic models are needed that reflect contemporary practice for men with metastatic castration-resistant prostate cancer (mCRPC). We sought to identify predictive and prognostic variables for overall survival (OS) in chemotherapy-naïve men with mCRPC treated with enzalutamide. Patients and methods: Patients from the PREVAIL trial database (enzalutamide versus placebo) were randomly split 2 : 1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined variables were analyzed and a multivariable model predicting OS was developed and validated in an independent testing set. Results: Patient characteristics and outcomes were well balanced between training and testing sets; median OS was 32.7 months in each. The final validated multivariable model included 11 independent prognostic variables. Median OS for low-, intermediate-, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached (NYR) (95% CI NYR-NYR), 34.2 months (31.5-NYR), and 21.1 months (17.5-25.0), respectively. Hazard ratios (95% CI) for OS in the low- and intermediate-risk groups versus high-risk group were 0.20 (0.14-0.29) and 0.40 (0.30-0.53), respectively. Secondary outcomes of response and progression differed widely in model-defined risk groups. Enzalutamide improved outcomes in all prognostic risk groups. Conclusions: Our validated prognostic model incorporates variables routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide, identifying subsets of patients with widely differing survival outcomes that provide useful information for external validation, patient care, and clinical trial design. Trial registration: ClinicalTrials.gov: NCT01212991.

Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL.

BACKGROUND: Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged ≥75 years who received enzalutamide, an androgen receptor inhibitor, in the phase III PREVAIL trial. PATIENTS AND METHODS: PREVAIL was a randomised, double-blind, multinational study of oral enzalutamide 160 mg/day (N = 872) versus placebo (N = 845) in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Overall survival (OS) and radiographic progression-free survival (rPFS) were coprimary end points. Subgroup analysis of men aged ≥75 years (elderly) and men aged <75 years was pre-specified for the coprimary end points and adverse events (AEs). RESULTS: Among 609 elderly patients (35%) who participated in PREVAIL, median treatment duration was 16.6 and 5.0 months in the enzalutamide and placebo arms, respectively. In the elderly subgroup, OS was greater with enzalutamide than with placebo [32.4 months (95% confidence interval (CI) 27.7-not yet reached] versus 25.1 months (95% CI 22.6-28.0); hazard ratio (HR) = 0.61 (95% CI 0.47-0.79); P = 0.0001], as was rPFS [not yet reached (95% CI 12.3-not yet reached) versus 3.7 months (95% CI 3.6-5.3); HR = 0.17 (95% CI 0.12-0.24); P < 0.0001]. Irrespective of treatment assignment, incidence of AEs was similar between the two age groups, except for an overall higher incidence of falls among elderly patients than younger patients [84/609 (13.8%) versus 62/1106 (5.6%)] and among elderly patients receiving enzalutamide than those receiving placebo [61/317 (19.2%) versus 23/292 (7.9%)]. CONCLUSIONS: Elderly men benefited from treatment with enzalutamide in terms of OS and rPFS. Enzalutamide was well tolerated in the elderly subgroup and those aged <75 years. Age and enzalutamide treatment were associated with a higher incidence of falls. CLINICAL TRIAL IDENTIFIER: NCT01212991, ClinicalTrials.gov.

Perpetuating effects of androgen deficiency on insulin resistance.

BACKGROUND/OBJECTIVES: Androgen deprivation therapy (ADT) is commonly used for treatment of prostate cancer but is associated with side effects, such as sarcopenia and insulin resistance. The role of lifestyle factors such as diet and exercise on insulin sensitivity and body composition in testosterone-deficient males is poorly understood. The aim of the present study was to examine the relationships between androgen status, diet and insulin sensitivity. SUBJECTS/METHODS: Middle-aged (11-12 years old) intact and orchidectomized male rhesus macaques were maintained for 2 months on a standard chow diet and then exposed for 6 months to a Western-style, high-fat/calorie-dense diet (WSD) followed by 4 months of caloric restriction (CR). Body composition, insulin sensitivity, physical activity, serum cytokine levels and adipose biopsies were evaluated before and after each dietary intervention. RESULTS: Both intact and orchidectomized animals gained similar proportions of body fat, developed visceral and subcutaneous adipocyte hypertrophy and became insulin resistant in response to the WSD. CR reduced body fat in both groups but reversed insulin resistance only in intact animals. Orchidectomized animals displayed progressive sarcopenia, which persisted after the switch to CR. Androgen deficiency was associated with increased levels of interleukin-6 and macrophage-derived chemokine (C-C motif chemokine ligand 22), both of which were elevated during CR. Physical activity levels showed a negative correlation with body fat and insulin sensitivity. CONCLUSIONS: Androgen deficiency exacerbated the negative metabolic side effects of the WSD such that CR alone was not sufficient to improve altered insulin sensitivity, suggesting that ADT patients will require additional interventions to reverse insulin resistance and sarcopenia.

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study.

BACKGROUND: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy. PATIENTS AND METHODS: In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response. RESULTS: Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3-13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8-6.1 months). CONCLUSIONS: In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882.

Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium.

BACKGROUND: Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC). METHODS: Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m(-2) intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (≥50% PSA reduction confirmed ≥28 days apart). According to the Simon two-stage design, ≥3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available. RESULTS: In all, 53 patients received ≥2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m(-2) during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity. CONCLUSION: This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.

Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer.

PURPOSE: To determine the safety and efficacy of weekly high-dose oral calcitriol and docetaxel, given to patients with non-resectable, incurable pancreatic cancer. PATIENTS AND METHODS: Twenty-five patients were enrolled onto this phase II study. Patients were treated with oral calcitriol 0.5 microg/kg on day 1, followed by docetaxel 36 mg/m(2) IV on day 2, administered weekly for three consecutive weeks, followed by 1 week without treatment. Patients followed a low-calcium diet and increased their hydration. The primary end-point of the trial was time-to-progression. RESULTS: Three of 25 patients attained a partial response (12%, 95% CI 3 to 31) and seven (28%) achieved stable disease. Median time-to-progression was 15 weeks, and median overall survival was 24 weeks. Toxicities observed (hyperglycemia, fatigue) were mostly attributable to the docetaxel or its pre-treatment. CONCLUSIONS: This regimen of high-dose calcitriol with docetaxel may have activity in incurable pancreatic cancer, with a modest increase in TTP when compared to historical findings using single-agent docetaxel. However, results do not appear superior to those seen with gemcitabine, with or without erlotinib.

Skeletal-related events significantly impact health-related quality of life in metastatic castration-resistant prostate cancer: data from PREVAIL and AFFIRM trials.

BACKGROUND: We investigated the impact of skeletal-related events (SREs) on health-related quality of life (HRQoL) in patients with metastatic castration-resistant prostate cancer (mCRPC) in phase III trials of enzalutamide versus placebo. METHODS: Patients with mCRPC experiencing at least one SRE during AFFIRM and PREVAIL were assessed for trajectory-adjusted mean change in HRQoL by first SRE using Functional Assessment of Cancer Therapy-Prostate (FACT-P; AFFIRM, three domains, and PREVAIL, nine domains) and EQ-5D (PREVAIL) instruments. RESULTS: First SREs caused HRQoL deterioration in both trials. Spinal cord compression had the largest impact, with clinically meaningful reductions in seven of nine FACT-P domains in PREVAIL and all three in AFFIRM (mean (95% confidence interval (CI)) change in FACT-P total score -16.95 (-26.47, -7.44) and -9.69 (-16.10, -3.27), respectively). In PREVAIL, first SREs caused clinically meaningful declines in EQ-5D utility index, irrespective of category; spinal cord compression had the largest impact (mean (95% CI) change -0.24 (-0.39, -0.08)). In AFFIRM, FACT-P and FACT-General total scores showed clinically meaningful declines after radiation/surgery to bone. CONCLUSIONS: SREs were associated with clinically meaningful functional declines in the daily lives of patients with mCRPC. Spinal cord compression had the largest impact on HRQoL.

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL.

BACKGROUND: Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested. METHODS: Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. RESULTS: Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26-2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar. CONCLUSIONS: Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.

Weekly high-dose calcitriol and docetaxel in advanced prostate cancer.

Novel treatment regimens for androgen-independent prostate cancer (AIPC) are needed because currently available approaches have not been shown to improve survival. Docetaxel provides a good foundation for new therapeutic combinations because of its promising single-agent activity against prostate cancer and its favorable tolerability profile, particularly when administered weekly. In both tissue culture and animal models of prostate cancer, calcitriol (the biologically active form of vitamin D) enhanced the activity of docetaxel, paclitaxel, and platinum compounds. These effects were particularly notable at supraphysiologic calcitriol concentrations. Weekly calcitriol dosing is associated with minimal toxicity and permits substantial dose escalation over the daily schedule. A weekly calcitriol dose of 0.5 microg/kg produces plasma calcitriol levels 25-fold higher than the physiologic range. In a preclinical study at the Oregon Health Sciences University, calcitriol 5 micromol/L plus docetaxel 0.15 nmol/L was at least additive in inhibiting PC-3 colony formation. A phase II study is evaluating weekly administration of 0.5 microg/kg calcitriol orally on day 1 followed by 36 mg/m(2) docetaxel intravenously on day 2 in patients with AIPC (repeated for 6 consecutive weeks of each 8-week cycle). At the time of a preliminary analysis, 11 patients had been enrolled and were actively being treated. All 5 patients who had completed 8 weeks of calcitriol/docetaxel treatment achieved prostate-specific antigen (PSA) reductions of > or =50%. Two of these patients had confirmatory assessments, both meeting the formal PSA response criteria. Treatment has been well tolerated, with 1 patient experiencing a self-limited grade 3 toxicity and no patients experiencing grade 4 or 5 toxicities.

Polymorphisms of GSTP1 and related genes and prostate cancer risk.

Glutathione S-transferase P1 (GSTP1) is markedly downregulated in prostate cancer and prostatic intraepithelial neoplasia compared to normal prostate tissue. Downregulation of GSTP1 may, therefore, be an early event in prostate carcinogenesis. An A-->G polymorphism at nucleotide 313 results in an amino acid substitution (Ile105Val) in the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. In a study of 36 prostate cancer patients, Harries et al. reported that the Ile/Ile genotype is associated with a decreased risk of prostate cancer (odds ratio 0.4 (0.17-0.82)). We sought to confirm this finding and to examine the impact of this polymorphism together with several related polymorphisms implicated as risk factors for carcinogen-associated malignancies. One hundred and seventeen patients with prostate adenocarcinoma and 183 population-based controls were recruited to this case-control study. Genotyping of the GSTP1 (Ile105Val), GSTM1 (null), GSTT1 (null) and CYP1A1 (Ile462Val) genes was performed using polymerase chain reaction (PCR) based techniques on DNA prepared from peripheral blood. A questionnaire was used to collect demographic information from each subject. Cases were significantly older (P<0.0001) and had significantly greater family history of prostate cancer (P<0.0001), confirming known risk factors for this disease. By chi(2) analysis, none of the genotype distributions varied among cases and controls. Using a logistic regression model to control for known risk factors we were also unable to demonstrate a significant association with prostate cancer for any of the polymorphisms tested. This population fails to identify a relationship between the above polymorphisms and prostate adenocarcinoma.

Complications of chemotherapy for prostate cancer.

To date, all available therapies for prostate cancer are plagued by adverse effects. Chemotherapy is no exception. The mechanisms of activity of chemotherapy agents are not cancer-specific. Normal tissues, particularly those that require rapid cell proliferation, are vulnerable to the effects of growth inhibition by these cytotoxic agents. Furthermore, both predictable as well as idiosyncratic toxicities unrelated to the antineoplastic activity of these agents can occur. In some cases, the cause of adverse events may be linked to the vehicle required to suspend water-insoluble chemotherapy drugs. Patient-specific factors can also significantly contribute to the risk of chemotherapy side-effects. However, with optimal clinical care the toxicity of antineoplastic agents can be substantially reduced. Long before chemotherapy is contemplated, it is imperative to limit treatments that reduce patients' capacity to tolerate subsequent chemotherapy. Moreover, offering treatment before patients' performance status declines can significantly improve tolerance of treatment. Once chemotherapy is initiated, the incidence and severity of adverse effects can be reduced through individualized selection of chemotherapy regimens and appropriate use of adjunct medications. Finally, aggressive management of toxicities after they occur lessens their duration and severity. The common toxicities of current chemotherapy regimens for prostate cancer, as well as strategies to limit and manage these toxicities are reviewed.

A Phase I trial of pulse calcitriol in patients with refractory malignancies: pulse dosing permits substantial dose escalation.

BACKGROUND: Calcitriol is the principal biologically active metabolite of vitamin D. Calcitriol's activity against many neoplasms is well documented, but calcitriol's therapeutic application has been hampered by predictable hypercalcemia when it is given daily. Because laboratory data has suggested that intermittent exposure to high levels of calcitriol may be sufficient to produce antiproliferative effects, the authors developed a Phase I trial to determine the maximal tolerated dose, dose-limiting toxicity, and the pharmacokinetic profile of calcitriol given weekly by mouth. METHODS: Patients with refractory malignancies were enrolled for 4 weeks of treatment followed by 4 weeks of observation. Reenrollment at a higher dose level was permitted for patients who had evidence of response or stable disease and no Grade 3 or greater toxicity. The starting dose was 0.06 microg/kg. RESULTS: Fifteen patients received 20 cycles of therapy. Doses up to 2.8 microg/kg of calcitriol weekly produced no dose-limiting toxicity. While peak levels and the area under the serum concentration-time curve of calcitriol increased in a linear fashion at lower doses, saturable absorption was observed at doses above 0.48 microg/kg. Doses of 0.48 microg/kg and above produced mean peak calcitriol levels of 1625 pg/mL, approximately 25-fold greater than top normal levels and well within the therapeutic range suggested by in vitro experiments. Eight patients experienced self-limiting Grade 1 hypercalcemia. CONCLUSIONS: Weekly dosing of oral calcitriol permitted substantial dose escalation with minimal toxicity. Peak serum calcitriol levels were in the predicted therapeutic range. A dose of 0.5 microg/kg was selected for evaluation in Phase II studies.

Imatinib mesylate and zoledronic acid in androgen-independent prostate cancer.

OBJECTIVES: To determine the safety and efficacy of zoledronic acid (Zometa) combined with imatinib mesylate (Gleevec) in patients with bone pain due to androgen-independent prostate cancer. METHODS: Fifteen patients were treated with zoledronic acid 4 mg intravenously every 28 days and imatinib mesylate 400 mg/day. The pain response, defined as a 2-point reduction in the Present Pain Intensity Scale or normalization if the initial score was 1, was the primary endpoint. Secondary endpoints included palliative response, prostate-specific antigen response, measurable disease response, time to progression, impact on quality of life, decrease in markers of bone turnover, and tolerability of the drug combination. RESULTS: The study was stopped early because of a lack of activity. No palliative or clinical activity was detected for the combination, and no prostate-specific antigen responses were observed. The median time to progression was 4 weeks (95% confidence interval 3 to 5), and the median duration of treatment was 8 weeks (range 1.6 to 16.7). The median overall survival was 54 weeks (95% confidence interval 18 to 90). Therapy was associated with a reduction in urine N-telopeptides and a trend toward a reduction in serum osteocalcin, but no change occurred in bone-specific alkaline phosphatase. CONCLUSIONS: In this patient population, imatinib mesylate and zoledronic acid produced no prostate-specific antigen responses and had no palliative or clinical activity.

Multiple cycles of intermittent chemotherapy in metastatic androgen-independent prostate cancer.

Recently, completed phase III studies demonstrated a survival benefit for a fixed number of cycles of docetaxel-containing chemotherapy treatment of androgen-independent prostate cancer (AIPC). Management of patients who respond well to initial chemotherapy for AIPC remains ill-defined. We previously reported that in a select group of such patients, retreatment with the same regimen was feasible and was associated with quality of life gains. Here, we report that multiple cycles of such intermittent chemotherapy are feasible. We prospectively tested intermittent chemotherapy in eight AIPC patients responding to calcitriol plus docetaxel who reached a serum prostate-specific antigen (PSA) <4 ng ml(-1) (22% of the 37 patients who were initially treated with this regimen). Chemotherapy was suspended until a rise in PSA > or =50% and 1 ng ml(-1). The median duration of the first treatment holiday was 20 weeks (13-74 weeks) and all patients retained sensitivity to retreatment. Four patients were eligible for a second chemotherapy holiday, and the median duration was 21 weeks (17-28 weeks). Two patients elected to take a third chemotherapy holiday, which lasted 10 and 28 weeks. The median time to treatment failure was 26.5 months (95% CI 23.6-29.4 months), and the median survival is 41 months (95% CI 33.7-48.3 months). Multiple cycles of intermittent chemotherapy interrupted by clinically meaningful treatment holidays are feasible in a subset of AIPC patients treated with this docetaxel-containing regimen. Intermittent chemotherapy for AIPC is feasible and deserves further study.

Intermittent chemotherapy in metastatic androgen-independent prostate cancer.

Intermittent use of chemotherapy for androgen-independent prostate cancer (AIPC) instead of treatment until disease progression may reduce toxicity. We prospectively tested this approach in eight AIPC patients responding to calcitriol plus docetaxel who reached a serum prostate-specific antigen (PSA) <4 ng ml(-1). Chemotherapy was suspended until a rise in PSA>/=50% and 1 ng ml(-1). The median duration of treatment holiday was 20 weeks (13-43+weeks) and all patients retained sensitivity to re-treatment. Chemotherapy holiday was associated with an improvement of fatigue (P=0.05). Intermittent chemotherapy for AIPC is feasible and deserves further study.

Allogeneic stem-cell transplantation in renal-cell carcinoma.

Metastatic renal-cell carcinoma (RCC) remains resistant to nearly all standard cytotoxic therapies, but immune-based cytokine therapies benefit a small minority of patients with advanced RCC. Nonmyeloablative allogeneic stem-cell transplantation is a novel approach to harnessing the immune system to combat this cancer. The strategy relies on a T-cell graft-versus-malignancy effect mediated by donor T cells. Preliminary work in using nonmyeloablative allogeneic stem-cell transplant in RCC has identified a graft-versus-RCC effect and yielded encouraging clinical responses.