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Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer.

ABSTRACT: CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles, 3 months apart, in which they received bicalutamide 150 mg daily days 1-28 and tremelimumab on day 29. The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.

SUBMITTER: McNeel DG

PROVIDER: S-EPMC3349783 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer.

McNeel Douglas G DG Smith Heath A HA Eickhoff Jens C JC Lang Joshua M JM Staab Mary Jane MJ Wilding George G Liu Glenn G

Cancer immunology, immunotherapy : CII 20111231 7

CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response eli ...[more]

PMID: 22210552

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Project description:Based on in vitro studies, it is known that androgen deprivation therapy (ADT) increases prostate-specific membrane antigen (PSMA) expression on prostate cancer (PCa) cells. However, ADT also has cytoreductive effects which can decrease lesion size. The present evaluation was conducted to further analyze the influence of ongoing ADT on [18F]DCFPyL positron emission tomography/computed tomography (PET/CT) performance in the setting of biochemically recurrent PCa. We retrospectively evaluated two groups of PCa patients, previously treated with radical intent, who had undergone [18F]DCFPyL PET/CT because of biochemical relapse with a minimum PSA level of 0.4 ng/mL. One group consisted of 95 patients under ADT at the time of the PET examination, and the other consisted of 445 patients not receiving ADT at the time of PET/CT. The uptake characteristics of the cardiac blood pool, liver, parotid glands, and five most active lesions were measured and compared between these two groups. The overall detection rate of [18F]DCFPyL PET/CT in patients under ADT at the time of imaging was significantly higher than patients not under ADT (91.6% vs. 80.4%, p-value = 0.007). However, the PSA-stratified differences in detection rates between patients with and without ADT did not reach statistical significance. Except for the maximal standardized uptake values corrected for lean body mass (SULmax) in the PSA range of 1 to <2 ng/mL, the intensity and volume of [18F]DCFPyL accumulation were higher in patients with ADT compared to the patients without. Statistical significance was attained for the SULmax in PSA range of 0.5 to <1 ng/mL (p-value = 0.0004) and metabolic tumor volume (MTV) in all PSA ranges (p-values of 0.0005 to 0.03). No significant difference was observed for radiotracer uptake in normal organs between the two groups with and without ADT. In this study population with biochemical recurrence of PCa and measurable PSA, ongoing ADT at the time of [18F]DCFPyL PET/CT imaging was associated with higher radiotracer uptake and overall lesion detection rate. This could be due in part to the more aggressive disease phenotype in patients with ongoing ADT.

Project description:PurposeThis randomized phase 2 study sought to assess the treatment effect of a finite duration of apalutamide with and without androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BCR PC). Materials and Methods. Patients with BCR PC after primary definitive therapy and prostate-specific antigen (PSA) doubling time ≤12 months were randomized to open-label apalutamide (240 mg/d) alone, apalutamide plus ADT, or ADT alone (1 : 1:1 ratio) for 12 months followed by a 12-month observation period (NCT01790126). Mean changes from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) at 12 months (primary endpoint) and other prespecified assessments of health-related quality of life (HRQoL), PSA nadir, time to PSA progression, time to testosterone recovery, recovered testosterone >150 ng/dL without PSA progression at 24 months, and molecular markers were evaluated.ResultsIn 90 enrolled patients (apalutamide plus ADT (n = 31), apalutamide (n = 29), ADT (n = 30)), FACT-P at 12 months was not significantly different between apalutamide, ADT and apalutamide, and ADT groups. Addition of apalutamide to ADT prolonged time to PSA progression but this change did not reach statistical significance (hazard ratio (HR): 0.56, 95% confidence interval (CI): 0.23-1.36, P=0.196); time to testosterone recovery was similar in the ADT-containing groups. In apalutamide plus ADT, apalutamide, and ADT groups, 37.9%, 37.0%, and 19.2% of patients, respectively, had testosterone >150 ng/dL at 24 months without confirmed PSA progression. Of the few biomarkers expressed in blood, EPHA3 was significantly associated with shorter time to PSA progression (P=0.02) in the overall population.ConclusionsHRQoL was similar in patients treated with apalutamide alone, ADT alone, or their combination, although apalutamide plus ADT did not demonstrate statistically significant noninferiority in change from baseline in overall HRQoL. The aggregated efficacy and safety outcomes support further evaluation of apalutamide plus ADT in BCR PC.

Project description:ObjectiveTo compare the tumor control in prostate cancer patients with oligo-metastasis following combined robot-assisted radical prostatectomy and androgen deprivation versus androgen deprivation therapy alone based on total prostate-specific antigen (tPSA) assessment.MethodsMedical data of a total of 18 prostate cancer patients with oligometastasis administered in The First Affiliated Hospital of Nanchang University from March 2017 to March 2018 were prospectively collected. 10 patients received a combined therapy of robot-assisted radical prostatectomy and pharmaceutical androgen deprivation (RARP+ADT group), while 8 patients received pharmaceutical androgen deprivation therapy alone (ADT group). Then demographic characteristics, prostate volume, tumor characteristics and tPSA data were analysised and compared. Statistical analysis was performed using t-test for continuous variables and Pearson chi-square test or Fisher's exact test for categorical variables.ResultsNo significant difference was found in patients' age (p = 0.075), prostate volume (p = 0.134) and number of bone metastasis (p = 0.342). Pre-treatment Gleason score was significantly lower in RA group (p = 0.003). Patients in RARP+ADT group had significantly lower pre-treatment tPSA (p = 0.014), while no statistical difference was noted in reexamined tPSA (p = 0.140) on follow-up. No statistical difference was noted in tPSA decline rates (declined tPSA value per day) in RARP+ADT and ADT group (8.1 ± 4.7 verse 7.5 ± 8.0 ng/ml/d, p = 0.853). However, tPSA percentage decline rate (declined tPSA percentage per day) was significantly higher in RARP+ADT group (11.6 ± 1.5%/d verses 2.9 ± 2.2%/d, p< 0.001). Immediate urinary continence was achieved in 9 patients (90%) upon removal of urethral catheter on post-operative day 7 in RARP+ADT group.ConclusionADT alone and in combination with RARP both provide effective tumor control in patients suffering from prostate cancer with oligometastasis. ADT combined with RARP exhibited significant advantage in PSA percentage decline rate without compromising patients' urinary continence. Long-term tumor control requires further follow-up.

Project description:Androgen deprivation therapy (ADT) is a cornerstone of advanced prostate cancer (PCa) therapy. Its use is associated with a loss of bone mineral density (BMD) and a greater risk of falls and osteoporotic fractures. In this prospective cohort study, we examined the impact of ADT on muscle and bone strength in men initiating ADT for PCa. Participants were evaluated at three time points: immediately before (week 0), and 6 and 24 weeks after ADT initiation. Study measures included fasting blood levels (for markers of muscle and bone metabolic activity), MRI and QCT imaging (for muscle fat content, and bone density and architecture), and validated clinical tests of muscle strength and gait. Sixteen men completed all study visits. At baseline and throughout the study, participants exercised a median of four times/week, but still experienced weight gain (+2.0 kg at week 24 versus week 0, p = 0.004). Biochemically, all men sustained dramatic early and persistent reductions in sex hormones post-ADT, along with a progressive and significant increase in serum C-telopeptide of type I collagen (CTX, +84% at week 24 versus week 0). There was a trend for rise in serum sclerostin (p = 0.09) and interleukin 6 (IL-6) (p = 0.08), but no significant change in serum myostatin (p = 0.99). Volumetric BMD by QCT declined significantly at the femoral neck (-3.7% at week 24 versus week 0), particularly at the trabecular compartment. On MRI, there were no significant changes in thigh muscle fat fraction. On physical testing, men developed weaker grip strength, but experienced no worsening in lower extremity and lumbar spine muscle strength, or on functional tests of gait. In conclusion, in physically active men, ADT for 24 weeks results in a significant increase in bone resorption and reduction in BMD, but nonsignificant changes in thigh muscle quality (on imaging) or strength and gait (on functional testing). © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Project description:PurposeTo evaluate whether quantitative whole-body (WB) PSMA-PET metrics under long-term androgen deprivation therapy (ADT) and/or androgen receptor signaling inhibitors (ARSi) are associated with PSA progression.MethodsPatients who underwent at least 2 68Ga-PSMA-11 PET/CT scans between October 2016 and April 2021 (n = 372) and started a new line of ADT ± ARSi between PET1 and PET2 were retrospectively screened for inclusion. We investigated the association between PCWG3-defined PSA progression status at PET2 and the following PSMA-PET parameters: appearance of new lesions on PET2, ≥ 20% increase in WB-PSMA tumor volume (WB-PSMA-VOL), progression of disease (PD) by RECIP 1.0, and ≥ 30% increase in WB-PSMA-SUVmean from PET1 to PET2. Spearman's rank correlation coefficients and Fisher's exact test were used to evaluate the associations.ResultsThirty-five patients were included: 12/35 (34%) were treated with ADT only and 23/35 (66%) with ARSi ± ADT. The median time between PET1 and PET2 was 539 days. Changes (%) in median PSA levels, WB-PSMA-SUVmean, and WB-PSMA-VOL from PET1 to PET2 were -86%, -23%, and -86%, respectively. WB-PSMA-VOL ≥ 20%, new lesions, RECIP-PD, and WB-PSMA-SUVmean ≥ 30% were observed in 5/35 (14%), 9/35 (26%), 5/35 (14%), and 4/35 (11%) of the whole cohort, in 3/9 (33%), 7/9 (78%), 3/9 (33%), and 2/9 (22%) of patients with PSA progression at PET2, and in 2/26 (8%), 2/26 (8%), 2/26 (8%), and 2/26 (8%) of patients without PSA progression at PET2 (p = 0.058, p < 0.001, p = 0.058, p = 0.238, respectively). Changes in PSA were correlated to percent changes in WB-PSMA-VOL and WB-PSMA-SUVmean (Spearman ρ: 0.765 and 0.633, respectively; p < 0.001).ConclusionChanges in PSA correlated with changes observed on PSMA-PET, although discordance between PSA and PSMA-PET changes was observed. Further research is necessary to evaluate if PSMA-PET parameters can predict progression-free survival and overall survival and serve as novel endpoints in clinical trials.

Dataset Information

Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer.

Publications

Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer.

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