Eastern Cooperative Oncology Group Phase II Trial of lapatinib in men with biochemically relapsed, androgen dependent prostate cancer

Abstract

Purpose: Activation of the epidermal growth factor pathway is important in prostate cancer development and the transcription of androgen receptor regulated genes. This study evaluated the potential activity of lapatinib in men with biochemically-relapsed androgen-dependent (stage D0) prostate cancer.

Patients and methods: Patients with a rising PSA after primary therapy for prostate cancer were enrolled. A PSA doubling time (PSADT) <12 months was required. Lapatinib was administered at 1,500 mg orally daily. Outcome measures were changes in PSA kinetics. Primary tumor blocks were obtained and assessed for EGFR expression, EGFR Q787Q polymorphism, and Kras 38 mutational status.

Results: Forty-nine patients were enrolled (14 ineligible), resulting in 35 patients for analysis. No PSA response was observed; best response was stable disease (n = 28, 80.0%). Pretreatment average slope was 0.19 log (PSA)/month (PSADT = 3.70 months), in contrast to on-treatment average slope of 0.13 log (PSA)/month (PSADT = 5.44 months) using linear mixed effects models (P = 0.006). Median progression-free survival (PFS) was 17.4 months for the high EGFR group and 6.0 months for the low EGFR group (P = 0.50). Patients with Kras 38 mutation had shorter PFS than those without Kras 38 mutation (P = 0.09).

Conclusion: Although no PSA responses (primary endpoint) was observed, lapatinib may have biologic activity in men with stage D0 prostate cancer as evidenced by a decrease in PSA slope in this non-randomized study. Additional trials assessing the role of EGFR overexpression and Kras wild type status in prostate cancer should be investigated.

Conflict of interest statement

Financial Disclosures: All authors have confirmed that no conflicts of interest/financial disclosure are present.

Copyright © 2013 Elsevier Inc. All rights reserved.

Figures

Figure 1

Estimated population average PSA slopes (thicker line) and individual patient changes in PSA over time (thin lines) among all eligible patients.

Figure 2

Progression-free survival by EGFR expression level

Figure 3

Progression-free survival by Kras 38 mutational status

Figure 4

Change in PSADT (months) from pre-registration to on-study. Of note, the change in PSADT for the two patients shown on the far right were much greater than 10 months (one had a negative PSADT and the other a PSA slope near zero). Where available, the EGFR expression level (high or low) and Kras status (wild type or mutant) are included. Bars above the line reflect increases in PSADT, whereas bars below reflect a decrease.