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Serial [18F]-FDHT-PET to predict bicalutamide efficacy in patients with androgen receptor positive metastatic breast cancer.
Boers, J, Venema, CM, de Vries, EFJ, Hospers, GAP, Boersma, HH, Rikhof, B, Dorbritz, C, Glaudemans, AWJM, Schröder, CP
European journal of cancer (Oxford, England : 1990). 2021;:151-161
Abstract
BACKGROUND The androgen receptor (AR) is a potential target in metastatic breast cancer (MBC), and 16β-[18F]-fluoro-5α-dihydrotestosterone positron emission tomography ([18F]-FDHT-PET) can be used for noninvasive visualisation of AR. [18F]-FDHT uptake reduction during AR-targeting therapy reflects AR occupancy and might be predictive for treatment response. We assessed the feasibility of [18F]-FDHT-PET to detect changes in AR availability during bicalutamide treatment and correlated these changes with treatment response. PATIENTS AND METHODS Patients with AR + MBC, regardless of oestrogen receptor status, received an [18F]-FDHT-PET at baseline and after 4-6 weeks bicalutamide treatment. Baseline [18F]-FDHT uptake was expressed as maximum standardised uptake value. Percentage change in tracer uptake, corrected for background activity (SUVcor), between baseline and follow-up PET scan (% reduction), was assessed per-patient and lesion. Clinical benefit was determined in accordance with Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 or clinical evaluation (absence of disease progression for ≥24 weeks). RESULTS Baseline [18F]-FDHT-PET in 21 patients detected 341 of 515 lesions found with standard imaging and 21 new lesions. Follow-up [18F]-FDHT-PET was evaluable in 17 patients with 349 lesions, showing a decrease in median SUVcor from 1.3 to 0.7 per-patient and lesion (P < 0.001). Median % reduction per-patient was -45% and per-lesion -39%. In patients with progressive disease (n = 11), median % reduction was -30% versus -53% for patients who showed clinical benefit (in accordance with RECIST (n = 3) or clinical evaluation (n = 3); P = 0.338). CONCLUSION In this feasibility study, a bicalutamide-induced reduction in [18F]-FDHT uptake could be detected by follow-up [18F]-FDHT-PET in patients with AR + MBC. However, this change could not predict bicalutamide response. CLINICAL TRIAL INFORMATION NCT02697032.
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A Randomized Phase II Study of Androgen Deprivation Therapy with or without Palbociclib in RB-positive Metastatic Hormone-Sensitive Prostate Cancer.
Palmbos, PL, Daignault-Newton, S, Tomlins, SA, Agarwal, N, Twardowski, P, Morgans, AK, Kelly, WK, Arora, VK, Antonarakis, ES, Siddiqui, J, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(11):3017-3027
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PURPOSE Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, blocks proliferation in a RB and cyclin D-dependent manner in preclinical prostate cancer models. We hypothesized that cotargeting androgen receptor and cell cycle with palbociclib would improve outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC). PATIENTS AND METHODS A total of 60 patients with RB-intact mHSPC were randomized (1:2) to Arm 1: androgen deprivation (AD) or Arm 2: AD + palbociclib. Primary endpoint was PSA response rate (RR) after 28 weeks of therapy. Secondary endpoints included safety, PSA, and clinical progression-free survival (PFS), as well as PSA and radiographic RR. Tumors underwent exome sequencing when available. Circulating tumor cells (CTC) were enumerated at various timepoints. RESULTS A total of 72 patients with mHSPC underwent metastatic disease biopsy and 64 had adequate tissue for RB assessment. A total of 62 of 64 (97%) retained RB expression. A total of 60 patients initiated therapy (Arm 1: 20; Arm 2: 40). Neutropenia was the most common grade 3/4 adverse event in Arm 2. Eighty percent of patients (Arm 1: 16/20, Arm 2: 32/40; P = 0.87) met primary PSA endpoint ≤4 ng/mL at 28 weeks. PSA undetectable rate at 28 weeks was 50% and 43% in Arms 1 and 2, respectively (P = 0.5). Radiographic RR was 89% in both arms. Twelve-month biochemical PFS was 69% and 74% in Arms 1 and 2, respectively (P = 0.72). TP53 and PIK3 pathway mutations, 8q gains, and pretreatment CTCs were associated with reduced PSA PFS. CONCLUSIONS Palbociclib did not impact outcome in RB-intact mHSPC. Pretreatment CTC, TP53 and PIK3 pathway mutations, and 8q gain were associated with poor outcome.
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Metabolomic effects of androgen deprivation therapy treatment for prostate cancer.
Chi, JT, Lin, PH, Tolstikov, V, Oyekunle, T, Chen, EY, Bussberg, V, Greenwood, B, Sarangarajan, R, Narain, NR, Kiebish, MA, et al
Cancer medicine. 2020;(11):3691-3702
Abstract
Androgen deprivation therapy (ADT) is the main treatment strategy for men with metastatic prostate cancer (PC). However, ADT is associated with various metabolic disturbances, including impaired glucose tolerance, insulin resistance and weight gain, increasing risk of diabetes and cardiovascular death. Much remains unknown about the metabolic pathways and disturbances altered by ADT and the mechanisms. We assessed the metabolomic effects of ADT in the serum of 20 men receiving ADT. Sera collected before (baseline), 3 and 6 months after initiation of ADT was used for the metabolomics and lipidomics analyses. The ADT-associated metabolic changes were identified by univariable and multivariable statistical analysis, ANOVA, and Pearson correlation. We found multiple key changes. First, ADT treatments reduced the steroid synthesis as reflected by the lower androgen sulfate and other steroid hormones. Greater androgen reduction was correlated with higher serum glucose levels, supporting the diabetogenic role of ADT. Second, ADT consistently decreased the 3-hydroxybutyric acid and ketogenesis. Third, many acyl-carnitines were reduced, indicating the effects on the fatty acid metabolism. Fourth, ADT was associated with a corresponding reduction in 3-formyl indole (a.k.a. indole-3-carboxaldehyde), a microbiota-derived metabolite from the dietary tryptophan. Indole-3-carboxaldehyde is an agonist for the aryl hydrocarbon receptor and regulates the mucosal reactivity and inflammation. Together, these ADT-associated metabolomic analyses identified reduction in steroid synthesis and ketogenesis as prominent features, suggesting therapeutic potential of restricted ketogenic diets, though this requires formal testing. ADT may also impact the microbial production of indoles related to the immune pathways. Future research is needed to determine the functional impact and underlying mechanisms to prevent ADT-linked comorbidities and diabetes risk.
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Exercise Mode Specificity for Preserving Spine and Hip Bone Mineral Density in Prostate Cancer Patients.
Newton, RU, Galvão, DA, Spry, N, Joseph, D, Chambers, SK, Gardiner, RA, Wall, BA, Bolam, KA, Taaffe, DR
Medicine and science in sports and exercise. 2019;(4):607-614
Abstract
PURPOSE Androgen deprivation therapy (ADT) in men with prostate cancer (PCa) is associated with an array of adverse effects, including reduced bone mineral density (BMD) predisposing patients to increased fracture risk. Our purpose was to examine the effects of targeted exercise modes on BMD in men with PCa undergoing ADT. METHODS Between 2009 and 2012, 154 PCa patients 43-90 yr old on ADT were randomized to exercise targeting the musculoskeletal system (impact loading + resistance training [ImpRes], n = 57) supervised for 12 months, cardiovascular and muscular systems (aerobic + resistance training, n = 50) supervised for 6 months followed by a 6-month home-based program, or delayed aerobic exercise (DelAer, n = 47) received exercise information for 6 months followed by 6 months of supervised aerobic exercise (stationary cycling). End points were lumbar spine, hip and whole-body BMD measured by dual-energy x-ray absorptiometry with secondary end points of lean and fat mass, appendicular skeletal muscle mass, and neuromuscular strength. ANOVA was used to compare the exercise groups with DelAer at 6 and 12 months. RESULTS There was a between-group difference in BMD for ImpRes and DelAer at the spine (6 months, P = 0.039; 12 months, P = 0.035) and femoral neck (6 months, P = 0.050), with decline attenuated in ImpRes (~-1.0% vs ~-2.0%). Compared with DelAer, ImpRes increased appendicular skeletal muscle at 6 months (0.3 kg, P = 0.045) and improved muscle strength at 6 and 12 months (P ≤ 0.012) by 9%-34%. A limitation was inclusion of well-functioning patients. CONCLUSION Combined impact loading and resistance exercise attenuates bone loss at the spine and enhances overall musculoskeletal function in PCa patients undergoing ADT.
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Impact of resistance training on body composition and metabolic syndrome variables during androgen deprivation therapy for prostate cancer: a pilot randomized controlled trial.
Dawson, JK, Dorff, TB, Todd Schroeder, E, Lane, CJ, Gross, ME, Dieli-Conwright, CM
BMC cancer. 2018;(1):368
Abstract
BACKGROUND Prostate cancer patients on androgen deprivation therapy (ADT) experience adverse effects such as lean mass loss, known as sarcopenia, fat gain, and changes in cardiometabolic factors that increase risk of metabolic syndrome (MetS). Resistance training can increase lean mass, reduce body fat, and improve physical function and quality of life, but no exercise interventions in prostate cancer patients on ADT have concomitantly improved body composition and MetS. This pilot trial investigated 12 weeks of resistance training on body composition and MetS changes in prostate cancer patients on ADT. An exploratory aim examined if a combined approach of training and protein supplementation would elicit greater changes in body composition. METHODS Prostate cancer patients on ADT were randomized to resistance training and protein supplementation (TRAINPRO), resistance training (TRAIN), protein supplementation (PRO), or control stretching (STRETCH). Exercise groups (EXE = TRAINPRO, TRAIN) performed supervised exercise 3 days per week for 12 weeks, while non-exercise groups (NoEXE = PRO, STRETCH) performed a home-based stretching program. TRAINPRO and PRO received 50 g⋅day- 1 of whey protein. The primary outcome was change in lean mass assessed through dual energy x-ray absorptiometry. Secondary outcomes examined changes in sarcopenia, assessed through appendicular skeletal mass (ASM) index (kg/m2), body fat %, strength, physical function, quality of life, MetS score and the MetS components of waist circumference, blood pressure, glucose, high-density lipoprotein-cholesterol, and triglyceride levels. RESULTS A total of 37 participants were randomized; 32 participated in the intervention (EXE n = 13; NoEXE n = 19). At baseline, 43.8% of participants were sarcopenic and 40.6% met the criteria for MetS. Post-intervention, EXE significantly improved lean mass (d = 0.9), sarcopenia prevalence (d = 0.8), body fat % (d = 1.1), strength (d = 0.8-3.0), and prostate cancer-specific quality of life (d = 0.9) compared to NoEXE (p < 0.05). No significant differences were observed between groups for physical function or MetS-related variables except waist circumference (d = 0.8). CONCLUSIONS A 12-week resistance training intervention effectively improved sarcopenia, body fat %, strength and quality of life in hypogonadal prostate cancer patients, but did not change MetS or physical function. PRO did not offer additional benefit in improving body composition. TRIAL REGISTRATION ClinicalTrials.gov: NCT01909440 . Registered 24 July 2013.
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An Intraprostatic Modified Release Formulation of Antiandrogen 2-Hydroxyflutamide for Localized Prostate Cancer.
Tammela, TL, Häggman, M, Ladjevardi, S, Taari, K, Isotalo, T, Lennernäs, H, Weis, J, von Below, C, Wassberg, C, Lennernäs, B, et al
The Journal of urology. 2017;(6):1333-1339
Abstract
PURPOSE We investigated the tolerability, safety and antitumor effects of a novel intraprostatic depot formulation of antiandrogen 2-hydroxyflutamide (in NanoZolid®) in men with localized prostate cancer. MATERIALS AND METHODS Two clinical trials, LPC-002 and LPC-003, were performed in a total of 47 men. The formulation was injected transrectally into the prostate under ultrasound guidance. In LPC-002 the effects on prostate specific antigen and prostate volume were measured for 6 months in 24 patients. In LPC-003 antitumor effects were evaluated by histopathology and magnetic resonance imaging including spectroscopy during 6 or 8 weeks in 23 patients. In each study testosterone and 2-hydroxyflutamide in plasma were measured as well as quality of life parameters. RESULTS In LPC-002 (mean dose 690 mg) a reduction was observed in prostate specific antigen and prostate volume. Average nadir prostate specific antigen and prostate volume were 24.9% and 14.0% below baseline, respectively. When increasing the dose in LPC-003 to 920 and 1,740 mg, average prostate specific antigen decreased 16% and 23% after 6 and 8 weeks, respectively. Magnetic resonance imaging and magnetic resonance spectroscopy showed morphological changes and a global reduction in metabolite concentrations following treatment, indicating an antitumor response. Injections did not result in hormone related side effects. Three serious adverse events were reported and all resolved with oral antibiotic treatment. CONCLUSIONS Intraprostatic injections of 2-hydroxyflutamide depot formulations showed antitumor effects, and proved to be safe and tolerable. However, for better anticancer effects higher doses and better dose distribution are suggested.
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Failure to suppress markers of bone turnover on first-line hormone therapy for metastatic prostate cancer is associated with shorter time to skeletal-related event.
Hahn, NM, Yiannoutsos, CT, Kirkpatrick, K, Sharma, J, Sweeney, CJ
Clinical genitourinary cancer. 2014;(1):33-40.e4
Abstract
BACKGROUND Elevated markers of bone turnover are prognostic for shorter survival in castration-resistant prostate cancer. We aimed to determine the prognostic value of bone turnover markers in metastatic hormone-sensitive prostate cancer. PATIENTS AND METHODS Markers of bone turnover (urine deoxypyridinoline [DPD] and N-telopeptide, serum bone alkaline phosphatase (AP), and osteocalcin [OC]) from baseline and after 6 months of study were assessed in men enrolled in a prospective metastatic prostate cancer trial with androgen deprivation therapy (ADT) with or without risedronate (ClinicalTrials.gov, NCT00216060). RESULTS Serum samples were collected from 63 patients with bone involvement and a median follow-up of 39.7 months. A multivariate model using Cox regression-which included prostate-specific antigen (PSA) nadir, bisphosphonate treatment, and extent of metastases-showed that suppression of bone turnover markers after 6 months of therapy compared with baseline was significantly associated with longer skeletal-related event (SRE)-free survival. ADT without bisphosphonate therapy was also associated with a decline in markers of bone turnover, presumably resulting from direct anticancer activity. Elevated baseline bone turnover markers were not prognostic. CONCLUSION Failure to suppress bone turnover while receiving ADT, even when otherwise responding to therapy, may identify patients with hormone-sensitive metastatic prostate cancer who are destined for a shorter time to SREs and progression.
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Randomized trial to assess the impact of venlafaxine and soy protein on hot flashes and quality of life in men with prostate cancer.
Vitolins, MZ, Griffin, L, Tomlinson, WV, Vuky, J, Adams, PT, Moose, D, Frizzell, B, Lesser, GJ, Naughton, M, Radford, JE, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;(32):4092-8
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PURPOSE Hot flashes occur in approximately 80% of androgen-deprived men. Few intervention studies have been conducted to relieve hot flashes in men. PATIENTS AND METHODS Eligible androgen-deprived men were randomly assigned to one of four daily regimens (2 × 2 factorial design) for 12 weeks: milk protein powder and placebo pill, venlafaxine and milk protein powder, soy protein powder and placebo pill, or venlafaxine and soy protein powder. The primary end point was hot flash symptom severity score (HFSSS), defined as number of hot flashes times severity. The secondary end point was quality of life (QoL), assessed by using the Functional Assessment of Cancer Therapy-Prostate. RESULTS In all, 120 men age 46 to 91 years participated. Most were white (78%) and overweight or obese (83%). Toxicity was minimal. Neither venlafaxine nor soy protein alone or in combination had a significant effect on HFSSS. Soy protein, but not venlafaxine, improved measures of QoL. CONCLUSION In androgen-deprived men, neither venlafaxine nor soy proved effective in reducing hot flashes. Interventions that appear effective for decreasing hot flashes in women may not always turn out to be effective in men.
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The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance).
Aggarwal, R, Halabi, S, Kelly, WK, George, D, Mahoney, JF, Millard, F, Stadler, WM, Morris, MJ, Kantoff, P, Monk, JP, et al
Cancer. 2013;(20):3636-43
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BACKGROUND Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. METHODS In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. RESULTS Baseline characteristics between patients who did (N=277) and did not (N=728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P=.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P=.342), the proportion achieving a decline ≥ 50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P=.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P=.366). CONCLUSIONS As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC.
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Responder analysis of the effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer.
Egerdie, RB, Saad, F, Smith, MR, Tammela, TL, Heracek, J, Sieber, P, Ke, C, Leder, B, Dansey, R, Goessl, C
Prostate cancer and prostatic diseases. 2012;(3):308-12
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BACKGROUND Denosumab, a fully human monoclonal antibody against RANK ligand, increased bone mineral density (BMD) and reduced fracture risk vs placebo in a phase 3 trial in men with prostate cancer on androgen deprivation therapy (ADT). The present analysis of this study evaluated BMD changes after 36 months in responder subgroups and in individual patients for three key skeletal sites (lumbar spine (LS), femoral neck (FN) and total hip (TH)) and the distal radius. METHODS Men with nonmetastatic prostate cancer receiving ADT were treated with subcutaneous denosumab 60 mg (n=734) or placebo (n=734) every 6 months for up to 36 months in a phase 3, randomized, double-blind study. Patients were instructed to take supplemental calcium and vitamin D. For this BMD responder analysis, the primary outcome measure was the percentage change in BMD from baseline to month 36 at the LS, FN and TH as measured by dual-energy X-ray absorptiometry. BMD at the distal 1/3 radius at 36 months was measured in a substudy of 309 patients. RESULTS At 36 months, significantly more patients in the denosumab arm had increases of >3% BMD from baseline at each site studied compared with placebo (LS, 78 vs 17%; FN, 48 vs 13%; TH, 48 vs 6%; distal 1/3 radius, 40 vs 7% (P<0.0001 for all)). BMD loss at the LS, FN and TH occurred in 1% of denosumab-treated patients vs 42% of placebo patients, and BMD gain at all three sites occurred in 69% of denosumab patients vs 8% of placebo patients. Lower baseline BMD was associated with higher-magnitude BMD responses to denosumab at the LS, FN and TH. CONCLUSIONS In men with prostate cancer receiving ADT, significantly higher BMD response rates were observed with denosumab vs placebo. Patients with lower baseline T-scores benefited the most from denosumab treatment.