Pharmacogenetic Study in Castration-resistant Prostate Cancer Patients Treated With Abiraterone Acetate
Condition: Pharmacogenetic Study
MeSH terms: Prostatic Neoplasms
Study type: Interventional

Summary: 
      Prostate cancer is the 2nd leading cause of mortality in men in developed countries. For
      metastatic prostate cancer patients, the 1st-line treatment relies on hormone therapy.
      However, the efficacy of androgen deprivation therapy remains limited in time and most
      patients eventually develop castration-resistant prostate cancer (CRPC), while remaining
      androgen-dependent.

      Docetaxel is currently the standard of care for metastatic CPRC. It has been shown that
      testosterone levels within metastatic tumoral tissue from men receiving hormone therapy were
      significantly higher than those from primitive tumors of untreated prostate cancers. Among
      the mechanistic explanations for this observation, it has been shown that CYP17A1, a key
      enzyme in de novo steroid synthesis localized in testis and adrenal gland, is up-regulated in
      CRPC metastases. The existence of de novo CYP17A1-dependent androgen biosynthesis at the
      tumor level has supported the development of novel antiandrogens, including abiraterone
      acetate (AA), an irreversible CYP17A1 inhibitor. Based on a placebo-controlled phase III
      trial, demonstrating that abiraterone prolonged overall survival (14.8 vs 10.9 months) and
      increased PSA response rate (29% vs 6%) in patients with metastatic CRPC who previously
      received docetaxel, AA was recently approved by the FDA and French Health Authorities. AA is
      well-tolerated and main toxicities are urinary tract infections (2%) and a syndrome of
      secondary mineralocorticoid excess characterized by fluid overload, hypertension and
      hypokaliema (1% to 4% of grade 3-4).

      Almost concomitantly, a novel taxane-class cytotoxic agent, cabazitaxel, has proven efficacy
      in CRPC treatment after failure to docetaxel, and has recently been approved by the FDA and
      French Health Authority. Although cabazitaxel exhibits a less favorable toxicity profile,
      this precise context creates a need to dispose of objective individual criteria so as to
      orientate patients to treatment towards AA or towards cabazitaxel. To this purpose, several
      approaches are of potential interest for identifying good candidates for a treatment by AA:
      tumor-specific TMPRSS2-ERG gene fusion measurement, circulating tumor cell analysis, tumoral
      CYP17A1 expression, analysis of splicing forms of the androgen receptor. However, the
      clinical relevance of these potential predictive factors remains to be established in this
      setting.

      Pharmacogenetics examines germinal gene polymorphisms likely to influence the
      pharmacodynamics of anticancer agents. Encouraging results have recently been reported by our
      group for irinotecan pharmacogenetics with concrete possibilities of individual dose
      adaptations, and very recently by other investigators for sunitinib pharmacogenetics.
      Concerning AA, one can hypothesize that tumors with elevated CYP17A1 expression will be more
      likely to respond better to AA. This hypothesis is indirectly supported by the observation
      that in CPRC patients receiving AA, PSA-based response is higher in patients with elevated
      pre-treatment blood concentration of DHEA and androstenedione.

      The CYP17A1 gene presents numerous single nucleotide polymorphisms (SNPs), whose frequencies
      of rare alleles are at least 12%. Their functional impact has been suggested for nine of
      them, which were linked either to the risk of developing prostate cancer or to survival of
      prostate cancer patients. So far, no study has examined the links between these polymorphisms
      and the efficacy of a CYP17A1 inhibitor. Also, relationships with the efficacy of androgen
      deprivation therapy have recently been reported for SNPs of genes involved in the
      membrane-transport testosterone and dehydroepiandrosterone, namely SLCO2B1 and SLCO1B3. One
      can make the hypothesis that gene polymorphisms of these transporters may play a role for the
      intratumoral concentration of testosterone locally-produced through the mediation of CYP17A1
      activity.

      To resume, two second-line treatments of metastatic CRPC cancers are currently available,
      thus is raising the question in practice of which treatment is more appropriate for a given
      patient. Herein, the present study proposes an original pharmacogenetic approach in order to
      highlight a relationship between AA activity and patient's genetic profile. Ultimately, this
      could reveal evidences of genetic predispositions for potentially good responders to AA
      treatment.
    


Intervention name(s): Abiraterone Acetate
Intervention type(s): Drug
Intervention MeSH terms: Abiraterone Acetate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other