Phase II study of sunitinib in men with advanced prostate cancer

Abstract

Background: This study explored the efficacy and tolerability of sunitinib, an inhibitor of tyrosine kinase receptors, in men with castration-resistant prostate cancer (CRPC).

Methods: Men with no prior chemotherapy (group A) and men with docetaxel (Taxotere)-resistant prostate cancer (group B) were treated with sunitinib. The primary end point was confirmed 50% prostate-specific antigen (PSA) decline. Secondary end points included objective response rate and safety. Serum-soluble biomarkers were measured.

Results: Seventeen men were enrolled in each group. One confirmed PSA response was observed in each group, and an additional eight men and seven men had stable PSA at week 12 in groups A and B, respectively. Improvements in imaging were observed in the absence of post-treatment PSA declines. Common adverse effects included fatigue, nausea, diarrhea, myelosuppression and transaminase elevation. Significant changes following sunitinib treatment were observed in serum-soluble biomarkers including soluble vascular endothelial growth factor receptor-2, platelet-derived growth factor aa, placental growth factor and leptin.

Conclusions: Sunitinib monotherapy resulted in few confirmed 50% post-treatment declines in PSA in men with CRPC. Serum markers of angiogenesis confirmed on-target effects of sunitinib. Assessments of radiographic disease status were often discordant with changes in PSA, indicating that alternate end points are important in future trials.

Figures

Figure 1.

(A) Best PSA response. Each bar reflects the best percent change in PSA from baseline in an individual subject. The bars are colored according to patient cohort. The y-axis is truncated at 200%; the maximum value was +537%. Three men were not assessable for PSA changes. (B) PSA and radiological response at 12 weeks. Each bar reflects change in PSA from baseline to 12 weeks. The bars are colored according to radiological response at 12 weeks. The y-axis is truncated at 200%; the maximum value is +537%. Three patients were not assessable for PSA changes. PSA, prostate-specific antigen; PR, partial response; SD, stable disease; PD, progressive disease; NE, not assessable.

Figure 2.

Radiographic changes from baseline to 8 weeks in a subject in group A.

Figure 3.

Bone markers over time for cohorts combined: (A) bone-specific alkaline phosphatase (BSAP) (U/l); (B) N-telopeptide (NTx) (ng/ml). Median values are denoted by horizontal bars. Black circles are patients not on zoledronic acid; blue triangles are patients who were on zoledronic acid. C1D1 levels were not statistically different according to zoledronic use (BSAP, P = 0.72; NTx, P = 0.17).

Figure 4.

Serum angiogenic markers over time for both cohorts combined and according to prostate-specific antigen (PSA) response at 12 weeks. Serum levels of angiogenic markers were measured at C1D1 (cycle 1 day 1), C1D28, C2D1 and C2D28. Median values are denoted by horizontal bars. Each point represents an individual patient value. Statistically significant changes were observed in soluble vascular endothelial growth factor-2 (sVEGFR2), platelet-derived growth factor aa (PDGFaa), placental growth factor (PLGF) and leptin. Groups A and B were combined in this analysis.