Everolimus combined with gefitinib in patients with metastatic castration-resistant prostate cancer: Phase 1/2 results and signaling pathway implications

Cancer. 2015 Nov 1;121(21):3853-61. doi: 10.1002/cncr.29578. Epub 2015 Jul 15.

Abstract

Background: The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in phosphatase and tensin homolog-null tumors. Thus, this study tested the combination of mTOR inhibition (everolimus) and epidermal growth factor receptor inhibition (gefitinib) in castration-resistant prostate cancer (CRPC).

Methods: In phase 1, 12 patients (10 with CRPC and 2 with glioblastoma) received daily gefitinib (250 mg) with weekly everolimus (30, 50, or 70 mg). In phase 2, 27 CRPC patients received gefitinib with everolimus (70 mg).

Results: Phase 1 revealed no pharmacokinetic interactions and no dose-limiting toxicities. In phase 2, 18 of 27 patients (67%) discontinued treatment before the 12-week evaluation because of progression as evidenced by prostate-specific antigen (PSA) levels (n = 6) or imaging (n = 5) or because of a grade 2 or higher toxicity (n = 7). Thirteen of the 37 CRPC patients (35%) exhibited a rapidly rising PSA level after they had begun treatment, and this declined upon discontinuation. Fluorodeoxyglucose positron emission tomography 24 to 72 hours after the initiation of treatment showed a decrease in the standardized uptake value consistent with mTOR inhibition in 27 of the 33 evaluable patients (82%); there was a corresponding rise in PSA in 20 of these 27 patients (74%).

Conclusions: The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data showing that phosphoinositide 3-kinase (PI3K) pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC.

Keywords: mammalian target of rapamycin (mTOR); pharmacokinetics; prostatic neoplasms; quinazolines (gefitinib); sirolimus derivatives (everolimus); target of rapamycin (TOR) serine-threonine kinases.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • ErbB Receptors / antagonists & inhibitors
  • Everolimus / adverse effects
  • Everolimus / pharmacology
  • Everolimus / therapeutic use*
  • Gefitinib
  • Humans
  • Male
  • Middle Aged
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms, Castration-Resistant / blood
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / physiopathology*
  • Quinazolines / adverse effects
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use*
  • Receptors, Androgen / drug effects
  • Receptors, Androgen / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Quinazolines
  • Receptors, Androgen
  • Everolimus
  • MTOR protein, human
  • ErbB Receptors
  • TOR Serine-Threonine Kinases
  • Prostate-Specific Antigen
  • Gefitinib