A Multicentric, Randomized, Phase II Study Evaluating the Combination of METFORMIN With TAXOTERE®+Metformine Placebo Versus TAXOTERE®+Metformin for the Treatment of Metastatic Hormone-refractory Prostate Cancer.
Prostate cancer: the current issues In developed countries, prostate cancer represents a
major health issue and its incidence is rising globally, due to an aging society (Ferlay,
Autier et al. 2007; Damber and Aus 2008). Indeed, over 70% of patients with prostate cancer
are over the age of 65 years (Quinn and Babb 2002). In France, prostate cancer is the second
most common cause of death from cancer in men and represents 10 deaths about of 100 by
cancer (INVS 2009).
Although the screening and early detection have improved, a significant percentage of men
diagnosed with prostate cancer will develop metastasis, reducing dramatically the 5-year
relative survival (Jemal, Thun et al. 2008).
For patients with metastatic prostate cancer, the first-line treatment relies on androgen
suppression following medical therapy or surgical orchiectomy. In about 80 percent of men,
androgen ablation leads to symptomatic improvement; however, despite this treatment, the
risk of relapse is at a median period of 24 months following hormone manipulation and the
survival median is at about 3 years (1995; Sharifi, Dahut et al. 2005).
Clinical management of Castration-Resistant Prostate Cancer:
Currently, treatment for metastatic prostate cancer, when becoming unresponsiveness to
androgen deprivation therapy, is mostly resumed to a relatively ineffective chemotherapy.
Indeed, this disease state is considered the final stage of the disease in which the
morbidity and mortality outlook is extremely bleak, and therapeutic options remain only
Combined Docetaxel (TAXOTERE®) and prednisone is currently considered the standard of care
for men with castration-resistant prostate cancer and detectable metastatic disease, based
largely on the simultaneous publication in October 2004 of two larges randomized controlled
trials: SWOG 9916 et TAX 327, comparing this combination with the previous established
standard of Mitoxantrone and prednisone (Petrylak, Tangen et al. 2004; Tannock, de Wit et
al. 2004). While the use of Mitoxantrone led to pain reduction and quality of life
improvement, without survival improvement (Tannock, Osoba et al. 1996), Docetaxel became the
only approved systemic agent that has been shown to improve overall survival in conjunction
with palliative benefits.
Docetaxel (TAXOTERE®) use was based on its ability to induce microtubules polymerization and
on the discovery of Bcl-2 expression, an antiapoptotic protein, in prostate cancer cell line
from metastatic hormone resistant patients. Indeed, this taxane by phosphorylating Bcl-2
induced apoptosis in cells expressing the protein (McDonnell, Navone et al. 1997).
In the phase III TAX-327 study, median survival was 18.9 month in the 3-week Docetaxel plus
prednisone group and 16.5 month compared with mitoxantrone plus prednisone group.
Correspondingly, clinically apparent improvements were also reported in terms of PSA
response rate, pain response and quality of life, despite the increase in toxicity in the
group that received Docetaxel. However, most adverse events associated with Docetaxel were
of low grade and were bothersome rather than life-threatening (Tannock, de Wit et al. 2004).
In this study, the median duration of the PSA response ranged from 7.7 and 8.2 months and
did not differ significantly among the Docetaxel or Mitoxantrone group. In addition, the
most common manifestations of metastatic prostate cancer, bone mestastasis that occurs in 65
to 75% (Bubendorf, Schopfer et al. 2000; Roudier, True et al. 2003) are also difficult to
quantify accurately. Thus, in prostate cancer, PSA-based endpoint is used to surrogate
clinical benefit and demonstrate drug activity in clinical trial.
However, regarding the limited and modest gains of Docetaxel based chemotherapy, trials are
now focusing on improving the efficacy of Docetaxel by combining it with novel biological
agents, but to date without demonstrable improvements (Ramsay and Leung 2009; Singh, Yam et
Interest of the associate Docetaxel (TAXOTERE®) with Metformin in Hormone-Refractory
Prostate Cancer Metformin (N',N'-dimethylbiguanide) is a wildly used anti-diabetic drug
which has the clinical advantage of having few side effects except rare lactic acidosis in
patients with renal insufficiency (Lalau and Race 1999). Metformin is very effective in
treating disorders marked by insulin-resistance. Several recent publications have shown that
Metformin has anti-cancer properties
Epidemiologic and clinical evidences:
Several retrospective epidemiologic studies, in diabetic patients, showed that Metformin was
associated with reduced risk of all cancer types (Evans, Donnelly et al. 2005; Currie, Poole
et al. 2009). Thus, in a first retrospective cohort study of 62,809 type 2 diabetic patients
treated in UK, the authors examined the risk of development of solid tumors in relation to
treatment with oral agents, human insulin and insulin analogues. Results showed that people
on insulin or sulfonylurea were more likely to develop solid cancers than those on
Metformin. In this study, Metformin use was associated with lower risk of cancer of the
colon or pancreas, but did not seem to affect the risk of breast or prostate cancer (Currie,
Poole et al. 2009).
In another UK observational cohort study, cancer was diagnosed among 7.3% of 4,085 Metformin
users compared with 11.6% of 4,085 diabetic comparators who had never used Metformin. After
adjusting for baseline characteristics, there was still a significantly reduced risk of
cancer associated with Metformin (37% lower than the non Metformin users group)(Libby,
Donnelly et al. 2009).
In addition to these studies on all cancers, specific investigations reported that Metformin
use was also associated with a significant decrease in the relative risk of specific cancers
such as pancreatic cancer (Li, Yeung et al. 2009), hepatocellular carcinoma (Donadon, Balbi
et al. 2010; Hassan, Curley et al. 2010), prostate (Wright and Stanford 2009) and breast
cancers (Bodmer, Meier et al. 2010). Furthermore, in later years of follow up, high doses of
Metformin were associated with the greatest reduction in risk of cancer, further supporting
a protective effect of Metformin (Evans, Donnelly et al. 2005; Libby, Donnelly et al. 2009)
(see review: Beck and Scheen 2010).
Concerning prostate cancer, a Finish and an American study, have shown a significant
decrease of prostate cancer incidence in patients treated with Metformin (Murtola, Tammela
et al. 2008; Wright and Stanford 2009).
Results from a population-based case-control study in men aged 35-74 years diagnosed with
prostate cancer showed that Metformin use was more common in controls than in cases (4,7
versus 2,8%, p = 0,04) (Wright and Stanford 2009), resulting in a 44% risk reduction for
A recent pilot clinical study, performed on 25 non-diabetic patients, have shown that
Metformin reduced significantly the number of colorectal aberrant crypt foci (an endoscopic
surrogate marker of colorectal cancer) (Hosono, Endo et al. 2010). This study demonstrates
for the first time a beneficial effect of Metformin in anti-cancerous therapy.
Very recent preliminary data, presented at the 33rd Annual San Antonio Breast Cancer
Symposium, are consistent with these previous studies showing that Metformin may have
beneficial effects on cancer therapy (33rd annual San Antonio Breast Cancer Symposium,
December 2010, San Antonio, USA). At the cellular level, combined treatment of metformine
and erlotinib led to synergistic growth inhibitory effects in a proliferation assay and a
clonogenic assay on breast cancer cells. The combined treatment also robustly reduced
activation of EGFR, AKT, ERK and S6 signaling more than when either drug was used alone.
Moreover, in a pilot mouse xenograft study, the combination treatment has been shown to
shrink tumors by an average of approximately 25% (Meiers PJ 2010). Data from interim safety
analysis demonstrated that preoperative metformin, in early stage breast cancer,
significantly reduced cancer cell proliferation (as measured by change in Ki67 index) and
induced apoptosis (TUNEL, cleaved caspase 3) (Niraula S 2010). Effects of its use was also
associated with improved insulin resistance (Niraula S 2010). Those preliminary results
showed that meformin was well tolerated with expected mild grade 1 toxicities and no
significant QOL effects (Bonanni B 2010; Niraula S 2010). In addition, it has to be noted
that no changes in insulin and in glycaemia levels had been reported with metformin use
(Bonanni B 2010), except a slight decrease of BMI (Niraula S 2010).
In a xenograft model, Metformin has been shown to inhibit human prostate cancer cell
proliferation as well as to decrease significantly tumor growth (Ben Sahra, Laurent et al.
2008). Other investigations demonstrated a direct inhibitory effect of Metformin on the
growth of cancer cells originated from breast (Zakikhani, Dowling et al. 2006), ovary
(Rattan, Giri et al. 2009), pancreas (Kisfalvi, Eibl et al. 2009) and colon (Buzzai, Jones
et al. 2007) as well as on tumor growth in mice models (see review: Ben Sahra, Le
Marchand-Brustel et al. 2010)). At the cellular level, Metformin provoked a cell arrest at
the G0/G1 stage and induced apoptosis in several cell types.
The mTOR and Akt pathways are frequently activated in cancers, which has been correlated
with a poor prognosis. In prostate cancer cells, Tanti's team showed that Metformin strongly
inhibited mTOR pathway and down regulated cyclin D1 expression, a protein associated with
cellular transformation (Ben Sahra, Laurent et al. 2008). Preclinical preliminary studies,
performed in this laboratory, also showed that, combinating Metformin with TAXOTERE®,
potentiated significantly the anti-proliferative effect of TAXOTERE®. Furthermore, Metformin
also increased TAXOTERE®-induced apoptosis in prostate cancer cells.
2. Location of the work in the context of the current knowledge :
Therefore, by targeting specifically cancer cell metabolism, Metformin offers new promising
therapeutic strategies. Indeed, Metformin is very well tolerated and has been used for more
than 30 years for the treatment of type II diabetes. The efficiency of Metformin as an
anti-proliferative and an anti-tumoral agent in mice and according to recent clinical
reports in breast field, raise the possibility that Metformin could be a potential candidate
in novel treatment for cancer, especially in human prostate cancer. Here, we hypothesized
that Metformin may improve TAXOTERE® efficacy in patient with hormone refractory prostate
The primary objective of this randomized study is to evaluate the biological efficacy of
Metformin combination with TAXOTERE® in patients with metastatic hormone-refractory prostate
cancer. To achieve this purpose, PSA response rate will be evaluated according to ASTRO
definitions (Bubley, Carducci et al. 1999). Concurrently, secondary endpoints will be under
investigation in order to evaluate the clinical response according to RECIST criteria, the
overall and free-progression survival and the quality of life. Toxicity assessment will also
be performed regarding to this drug combination.
Considering the well tolerability of Metformin and the first clinical and pre-clinical data
reports of it use in cancer treatment, combining Docetaxel (TAXOTERE®) with Metformin may
represent a promising strategy for treatment of hormone-refractory prostate cancer.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
PSA response rate
Time until main objective analysis is 5 years
Jean-Marc FERRERO, PhD
Centre Antoine Lacassagne
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)