TAXOMET: A French Prospective Multicentric Randomized Phase II Study of Docetaxel Plus Metformin Versus Docetaxel Plus Placebo in Metastatic Castration-Resistant Prostate Cancer

Martin, Marc Pujalte; Borchiellini, Delphine; Thamphya, Brice; Guillot, Aline; Paoli, J; Besson, Dominique; Hilgers, Werner; Priou, Frank; Kouri, Claude El; Hoch, Benjamin; Deville, Jean‐Laurent; Schiappa, Renaud; Cheli, Sandrine; Milano, G.; Tanti, Jean‐François; Bost, Fréd́eric; Ferrero, Jean-­Marc

doi:10.1016/j.clgc.2021.08.008

Cited by 25 publications

(25 citation statements)

References 42 publications

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“…In studies of metformin and chemotherapy, metformin use for shorter periods of time did not show benefit in mCRPC, indicating a need for further studies with insulin therapy. 33 Other studies have examined the effects of HbA1c and BMI on patients with CRPC and showed a decrease in progression-free survival in patients with higher HbA1c and an increase in progression-free survival in patients with higher BMI. 9 They also showed worse survival with increased HbA1c levels in patients receiving abiraterone, but they did not show a statistical difference in survival with increased HbA1c in patients given enzalutamide.…”

Section: Discussionmentioning

confidence: 99%

Effect of BMI and hemoglobin A1c on survival of veterans with metastatic castration‐resistant prostate cancer treated with abiraterone or enzalutamide

Govindan,

Cheranda,

Riekhof

et al. 2023

The Prostate

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BackgroundAbiraterone acetate and enzalutamide are two common therapies for metastatic castration‐resistant prostate cancer (mCRPC) that have shown improved overall survival (OS). The drugs have different mechanisms of action with limited comparative trials to evaluate treatment in patients with comorbidities such as obesity and diabetes. This is important since abiraterone requires the co‐administration of prednisone. We assessed the relationship between body mass index (BMI), hemoglobin A1c (HbA1c), treatment, and survival in mCRPC.MethodsVeterans treated with abiraterone or enzalutamide within the Veterans Health Administration between September 10, 2014 and June 2, 2017 with BMI and HbA1c were identified. Additional variables included age, baseline prostate‐specific antigen at first treatment for mCRPC, race, and the Charlson comorbidity index. Differences in survival were compared using the Kaplan–Meier method. Cox proportional hazards regression modeling was used to assess the association between initial treatment, BMI, and HbA1c while adjusting for confounding variables.ResultsA total of 5231 patients were identified with a mean age of 75.2 years and 1241 (23.7%) were of black race. BMI was associated with OS with longest median survival of 29.8 months in BMI ≥ 30 (n = 1903), 23.9 months in BMI 25–30 (n = 1879), 15.9 months in BMI 18.5–25 (n = 1336), and 9.2 months in BMI < 18.5 (n = 113, p < 0.001). In a multivariable model compared to normal BMI, increased mortality was observed in BMI < 18.5 (adjusted hazard ratio (aHR) = 1.583, 95% confidence interval [CI]: 1.29–1.94) and a decreased mortality in BMI 25–30 (aHR = 0.751, 95% CI: 0.69–0.81) and BMI > 30 (aHR = 0.644, 95% CI: 0.59–0.70). In 3761 patients with BMI > 25, there was longer OS in patients treated with enzalutamide (28.4 months, n = 1615) compared to abiraterone (25.8 months, n = 2146, p = 0.002). In 1470 patients with BMI < 25, there was no difference in OS between patients treated with enzalutamide (16.0 months, n = 597, p = 0.513) or abiraterone (16.1 months, n = 873). In 1333 veterans with HbA1c ≥ 6.5%, initial prescription of enzalutamide was associated with longer OS compared with abiraterone (24.4 vs. 20.5 months, p = 0.0005). In 2088 patients with HbA1c < 6.5%, there was no difference in OS in patients who were initially prescribed enzalutamide versus abiraterone (25.7 vs. 23.5 months, p = 0.334).ConclusionsIn veterans with mCRPC, increased BMI was associated with longer survival. Veterans with BMI > 25 had longer survival with enzalutamide compared to abiraterone. In patients with HbA1c ≥ 6.5%, enzalutamide was associated with longer survival compared to abiraterone. These results may facilitate prognostication of survival and improve treatment selection based on patient comorbidities.

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Section: Discussionmentioning

confidence: 99%

Effect of BMI and hemoglobin A1c on survival of veterans with metastatic castration‐resistant prostate cancer treated with abiraterone or enzalutamide

Govindan,

Cheranda,

Riekhof

et al. 2023

The Prostate

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“…Their incidence of all‐cause mortality (7.8%) was also much lower than in our study (62.4%), suggesting that our study may be better powered to examine the associations between metformin use and mortality risks. Recently, the protective role of metformin in PCa has been called into question again as contradictive results were shown in prospective trials, 32 , 33 whereby the addition of metformin to docetaxel or abiraterone did not suppress PCa progression in patients with metastatic CRPC in the TAXOMET trial (NCT01796028) 32 and MetAb‐Pro trial (NCT01677897), 33 respectively. Nonetheless, the TAXOMET trial examined a nondiabetic population, which is inherently different from our study design.…”

Section: Discussionmentioning

confidence: 99%

Metformin use and mortality in Asian, diabetic patients with prostate cancer on androgen deprivation therapy: A population‐based study

et al. 2022

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Background This study aims to examine the associations between metformin use concurrent with androgen deprivation therapy (ADT) and mortality risks in Asian, diabetic patients with prostate cancer (PCa). Methods This study identified diabetic adults with PCa receiving any ADT attending public hospitals in Hong Kong between December 1999 and March 2021 retrospectively, with follow‐up until September 2021. Patients with <6 months of medical castration without subsequent bilateral orchidectomy, <6 months of concurrent metformin use and ADT, or missing baseline HbA1c were excluded. Metformin users had ≥180 days of concurrent metformin use and ADT, while non‐users had no concurrent metformin use and ADT or never used metformin. The primary outcome was PCa‐related mortality. The secondary outcome was all‐cause mortality. The study used inverse probability treatment weighting to balance covariates. Results The analyzed cohort consisted of 1971 patients (1284 metformin users and 687 non‐users; mean age 76.2 ± 7.8 years). Over a mean follow‐up of 4.1 ± 3.2 years, metformin users had significantly lower risks of PCa‐related mortality (weighted hazard ratio [wHR]: 0.49 [95% confidence interval, CI: 0.39–0.61], p < 0.001) and all‐cause mortality (wHR 0.53 [0.46–0.61], p < 0.001), independent of diabetic control or status of chronic kidney disease. Such effects appeared stronger in patients with less advanced PCa, which is reflected by the absence of androgen receptor antagonist or chemotherapy use (p value for interaction: 0.017 for PCa‐related mortality; 0.048 for all‐cause mortality). Conclusions Metformin use concurrent with ADT was associated with lower risks of mortality in Asian, diabetic patients with PCa.

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“…There have been several phase II studies to evaluate the anti-cancer activity of MF in various cancers with varied findings [ 15 , 25 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Brown et al reported that MF is associated with better-than-expected overall survival in 38 patients with epithelial ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Metformin with Temozolomide for Newly Diagnosed Glioblastoma: Results of Phase I Study and a Brief Review of Relevant Studies

Ohno¹,

Kitanaka

Miyakita³

et al. 2022

Cancers

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Glioblastoma (GBM) inevitably recurs due to a resistance to current standard therapy. We showed that the antidiabetic drug metformin (MF) can induce the differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation. In this study, we design a phase I/II study to examine the clinical effect of MF. We aim to determine a recommended phase II MF dose with maintenance temozolomide (TMZ) in patients with newly diagnosed GBM who completed standard concomitant radiotherapy and TMZ. MF dose-escalation was planned using a 3 + 3 design. Dose-limiting toxicities (DLTs) were assessed during the first six weeks after MF initiation. Three patients were treated with 1500 mg/day MF and four patients were treated with 2250 mg/day MF between February 2021 and January 2022. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, all of which were manageable. Two patients experienced tumor progression at 6.0 and 6.1 months, and one died 12.2 months after initial surgery. The other five patients remained stable at the last follow-up session. The MF dose of up to 2250 mg/day combined with maintenance TMZ appeared to be well tolerated, and we proceeded to a phase II study with 2250 mg/day MF.

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TAXOMET: A French Prospective Multicentric Randomized Phase II Study of Docetaxel Plus Metformin Versus Docetaxel Plus Placebo in Metastatic Castration-Resistant Prostate Cancer

Cited by 25 publications

References 42 publications

Effect of BMI and hemoglobin A1c on survival of veterans with metastatic castration‐resistant prostate cancer treated with abiraterone or enzalutamide

Effect of BMI and hemoglobin A1c on survival of veterans with metastatic castration‐resistant prostate cancer treated with abiraterone or enzalutamide

Metformin use and mortality in Asian, diabetic patients with prostate cancer on androgen deprivation therapy: A population‐based study

Metformin with Temozolomide for Newly Diagnosed Glioblastoma: Results of Phase I Study and a Brief Review of Relevant Studies

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