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Tolerability and efficacy of docetaxel in older men with metastatic castrate-resistant prostate cancer (mCRPC) in the TAX 327 trial.

ABSTRACT: Prostate cancer is a disease of older men. Weekly docetaxel (DPq1w) is often favored over the standard three-weekly regimen (DPq3w) due to concerns about safety and tolerability in this population.Two subgroup analyses of TAX 327 were conducted. Among patients receiving DPq3w, tolerability and efficacy were compared between three age groups: <65, 65-74 and ?75 years. For men ?75 years, these outcomes were compared between DPq3w, DPq1w, and mitoxantrone (MP) arms. Tolerability outcomes included dose delivery, grade 3/4 adverse events and quality of life. Efficacy outcomes included overall survival and tumor response.Of 1006 men with metastatic castrate-resistant prostate cancer (mCRPC) in the trial, 335 received DPq3w. Among these, 20% were age ?75 years. For DPq3w, there were non-significant associations of worse tolerability and efficacy with advancing age. Twenty-eight percent of men age ?75 years had an objective pain response, compared to 38% and 34% of patients 65-74 and <65 years, respectively. There were no significant differences in prostate-specific antigen (PSA) response (43-48%, p = 0.74) or measurable tumor response (7-17%, p = 0.30) according to age. Among men ?75 years, DPq3w resulted in more dose reductions than DPq1w (22% versus 8%, p = 0.007), but tolerability was otherwise comparable. Both were associated with more favorable efficacy than mitoxantrone.Tolerability and efficacy of DPq3w appear less favorable with advancing age. Compared to DPq1w, DPq3w is associated with better survival outcomes, but similar tolerability, and remains the standard first-line chemotherapy option in mCRPC. Toxicity is substantial, therefore careful patient selection, close monitoring and early management of toxicities is advised.

SUBMITTER: Horgan AM

PROVIDER: S-EPMC4352315 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

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Tolerability and efficacy of docetaxel in older men with metastatic castrate-resistant prostate cancer (mCRPC) in the TAX 327 trial.

Horgan Anne M AM Seruga Bostjan B Pond Greg R GR Alibhai Shabbir M SM Amir Eitan E De Wit Ronald R Eisenberger Mario A MA Tannock Ian F IF

Journal of geriatric oncology 20140102 2

<h4>Objective</h4>Prostate cancer is a disease of older men. Weekly docetaxel (DPq1w) is often favored over the standard three-weekly regimen (DPq3w) due to concerns about safety and tolerability in this population.<h4>Materials and methods</h4>Two subgroup analyses of TAX 327 were conducted. Among patients receiving DPq3w, tolerability and efficacy were compared between three age groups: <65, 65-74 and ≥75 years. For men ≥75 years, these outcomes were compared between DPq3w, DPq1w, and mitoxant ...[more]

PMID: 24495703

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Project description:Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on mCRPC, results from additional phase 3 studies with novel antiandrogens which are directed at inhibition of the AR (e.g., MDV3100), as well as other agents, are awaited with interest and may further expand the treatment choices for this difficult-to-manage population of patients.

Project description:Lessons learnedThe negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC).The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge.BackgroundInhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC).MethodsThis multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events.ResultsThe 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm).ConclusionCombining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

Project description:BackgroundMost men who die of prostate cancer are older than 70 years. The ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) randomized men of all ages with metastatic hormone-sensitive prostate cancer (mHSPC) to receive androgen deprivation therapy (ADT) with or without docetaxel demonstrating an overall survival (OS) benefit for docetaxel.MethodsIn a post-hoc analysis of this trial, we assessed patient characteristics and OS in patients ≥70 years ("older men") versus <70 years ("younger men") with Cox proportional hazards models. In addition, we compared adverse events, therapy completion rate, and subsequent treatment patterns between these two groups using Chi-squared tests.Results177 (22.4%) patients were ≥70 years. Docetaxel + ADT resulted in improved OS in both older and younger men (Hazard Ratio [HR] 0.45, 95%CI: 0.25-0.80 for older men; HR 0.71, 95%CI: 0.53-0.95 for younger men). This treatment benefit was seen for subgroups of older men with high volume disease (HR 0.43, 95%CI 0.23-0.79) and de novo metastatic disease (HR 0.36, 95%CI 0.19-0.69). A similar proportion of older and younger men completed six cycles of docetaxel (82.6% vs. 87.1%, p = 0.28). Rates of grade 3-5 adverse events were similar between older and younger men (36.8% vs. 26.8%, respectively, p = 0.069). The rate of any Grades 4-5 adverse events did not differ significantly between older and younger men (14.9% vs. 11.9%, respectively, p = 0.46). In the control arm, a smaller proportion of older men received subsequent cancer treatments (34.4% vs. 51.5%, p = 0.017) or subsequent docetaxel (25.6% vs. 37.6%, p = 0.035) compared to younger men.ConclusionsOlder men with mHSPC had similar OS benefit and clinical outcomes compared to younger men when receiving docetaxel + ADT. Oncologists should consider docetaxel chemotherapy as a favorable treatment option for older men with mHSPC who are fit for chemotherapy.

Project description:Background:Men with metastatic castrate-resistant prostate cancer can experience an array of treatment-related side effects. Accumulating evidence suggests exercise may alleviate some of these adversities and assist in disease management. However, empirical evidence in advanced prostate cancer patients remains limited. The purpose of this study is to determine whether men with metastatic prostate cancer, who are ineligible for high-intensity exercise, can partake in a home-based, moderate-intensity exercise program and the impact of doing so on quality of life and physical fitness parameters. Methods:Thirty men with adenocarcinoma of the prostate and progressive systemic, metastatic disease will be recruited. Clinicians will screen patients against inclusion criteria to determine eligibility. All men enrolled will be prescribed a tailored, home-based, moderate-intensity exercise intervention consisting of aerobic and strengthening components for 12?weeks. Patients will receive supplementary education materials and weekly behavioural change consultations throughout the intervention. The primary outcome will be the feasibility of delivering such an intervention in men with metastatic disease. Secondary endpoints including skeletal events will be monitored for safety, as will the feasibility of patient-reported outcome measures and the sampling time points, generating data pertaining to completion rates and potential effect in future trials. General physical fitness will be assessed during these visits, using timed sit-to-stand testing and a 6-min walking test. Prior to each visit, objective physical activity levels will be captured for 7?days using an accelerometer, to determine the feasibility of this technology and the quality of data obtained. In parallel with the feasibility aspects of the trial, changes compared to baseline will be reported. Direct regular contact will also serve as a feedback loop, should any issues arise. This study has received ethical approval from the Office for Research Ethics Committees Northern Ireland. Conclusions:This study aims to determine the potential utility of a home-based exercise intervention in managing side effects associated with advanced prostate cancer and its treatment. This feasibility trial will inform the design and implementation of a larger randomised control trial to determine the efficacy of moderate aerobic and strengthening exercise as an adjuvant therapy in men with metastatic prostate cancer. Collecting such evidence provides further support for exercise in this paradigm and potential for its inclusion as a low-toxicity therapy in standard cancer care, in the longer term. Trial registration:ClinicalTrials.gov, NCT03658486Trial sponsor: Queen's University Belfast (Reference: B18/15). Contact: Dr. Paula Tighe, Research and Enterprise, Queen's University Belfast. Telephone: 02890 973,296. Email: p.tighe@qub.ac.uk. The sponsor reviewed the protocol and ethical application prior to submission.Protocol issue: Version 1 (18th May 2018). Authors: MB, MM, SJ and GP.

Dataset Information

Tolerability and efficacy of docetaxel in older men with metastatic castrate-resistant prostate cancer (mCRPC) in the TAX 327 trial.

Publications

Tolerability and efficacy of docetaxel in older men with metastatic castrate-resistant prostate cancer (mCRPC) in the TAX 327 trial.

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