Fulvestrant versus exemestane following prior non-steroidal aromatase inhibitor therapy: first results from EFFECT, a randomized, phase III trial in postmenopausal women with advanced breast cancer

Reviewer: John P. Plastaras, MD, PhD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 16, 2006

Presenter: W. Gradishar
Affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University


  • Recent trial results have shown that adjuvant first-line aromatase inhibitors give superior disease free survival compared to tamoxifen in hormone receptor-positive breast cancer
  • When these women recur, it is unclear what the optimal choice and sequence of additional aromatase inhibitors after aromatase inhibitor failure


  • 693 post-menopausal women with hormone receptor positive breast cancer that progressed/recurred after prior non-steroidal AI therapy
  • Randomized, double-blind, double-dummy, multicenter, phase III, two-arms:
    • fulvestrant (Faslodex) (n = 351)
    • exemestane (Aromasin) (n = 342)
  • Dosing: For fulvestrant, a loading-dose regimen was used: 500 mg on Day 0, 250 mg on days 14, 28, and 250 mg every 28 days +/- 3 days, thereafter. This was used to more rapidly achieve the desired serum concentrations. Exemestane was 25 mg po once daily.
  • Treatment was continued until progression, death, or withdrawal
  • Enrollment was between 8/03 to 11/05
  • Endpoints:
    • Primary: time to progression (TTP)
    • Secondary: objective response rate, duration of response, clinical benefit rate, and tolerability


  • Patients: The arms were well-balanced. The patients were relatively heavily pre-treated (~60% had received >/=2 prior treatments).
  • Time to progression was identical between the two arms (3.7 months)
  • Objective response rates were similar, but low: Fulvestrant, 7.4%; Exemestane, 6.7%, p=0.74
  • Clinical benefit rate was the similar: Fulvestrant, 23.3%; Exemestane, 18.5%, p=0.17
  • Duration of response was similar: Fulvestrant, 13.5 months; Exemestane, 9.8 months
  • Duration of clinical benefit was similar: Fulvestrant, 9.3 months; Exemestane, 8.3 months
  • There was no effect of co-variates on time to progression
  • Safety
    • Withdrawal due to adverse events was low: Fulvestrant, 2.0%; Exemestane, 2.6%
  • Pharmacokinetics: the loading dose methods of fulvestrant achieved the desired early increase in serum-levels.

Author's Conclusions

  • This trial confirmed the efficacy of either fulvestrant or exemestane after AI failure
  • The fulvestrant loading-dose regimen was well tolerated and brings serum levels into the therapeutic range rapidly
  • Neither drug is clearly superior in this setting, laying to rest biases from smaller early phase trials that may have implied superiority of one drug over another

Clinical/Scientific Implications

  • As aromatase inhibitors become more and more common in the adjuvant setting, the optimal sequence of second and third line hormonal therapies are important clinical questions.
  • The authors should be commended for carrying out and reporting this phase III trial to actually test these agents in a head to head fashion as second line treatment following non-steroidal AI failure. Even trials showing no difference between regimens add important clinical information, although it may not have been too surprising that neither agent was superior. These results give patients and physicians more flexibility when choosing the next hormonal agent.