Efficacy and Safety of Emerging Agents for the Treatment of Metastatic Prostate Cancer: Abituzumab, Sorafenib, and AT13387
Abituzumab is a humanized monoclonal IgG2 antibody targeting aV integrins. After a phase 1 safety trial in patients with metastatic castrate-resistant prostate cancer (mCRPC) in which the drug was well tolerated, an exploratory double-blinded trial investigated the efficacy of abituzumab 750 mg or 1500 mg intravenously every 3 weeks versus placebo added to standard of care in patients with mCRPC (Miller K, et al. ESMO 2014: Abstract 772P).
A total of 180 patients were randomized in a 1:1:1 ratio to 1 of these 3 treatments, and treatment continued until radiologic disease progression (rPD) in bone or in soft tissues was noted, or until a skeletal event, death, or unacceptable toxicity occurred. The median progression-free survival (PFS) was 3.3 months, 3.4 months, and 4.3 months, respectively, in the groups receiving placebo, abituzumab 750 mg, and abituzumab 1500 mg. rPD was reported in 72%, 68%, and 65% of patients in these groups, respectively, including bone lesions in 42% of the placebo arm versus 23% in each of the abituzumab arms. The safety profile of abituzumab was previously confirmed, and the generation of antibodies directed against abituzumab was low.
The researchers concluded that median PFS with abituzumab 1500 mg is modestly longer than with abituzumab 750 mg or with placebo, and patients receiving abituzumab experienced less frequent bone rPD. Although these are encouraging early results, further assessment of the efficacy and safety of abituzumab in this patient population is needed. In patients with mCRPC, sorafenib (an oral multikinase inhibitor that targets the RAS/RAF kinase pathway, vascular endothelial growth factor, and platelet-derived growth factor receptor) has been shown to have moderate activity as a second-line therapy (Aragon-Ching JB, et al. BJU Int. 2009;103:1636).
At ESMO 2014, Kramer and colleagues reported results of a phase 2 clinical trial examining the activity of sorafenib in stabilizing disease after failure of docetaxel chemotherapy in men with mCRPC (Kramer G, et al. ESMO 2014: Abstract 773P). In this double-blind, placebo-controlled trial, 51 men with docetaxel-refractory mCRPC were randomized to receive sorafenib 400 mg twice daily or best supportive care for 12 weeks. Tumor stabilization was observed in 33.3% of patients in the sorafenib group versus 7.4% in the best supportive care group (P = .024). This included 2 patients with a partial response and 6 with stable disease in the sorafenib group, and 2 with stable disease in the best supportive care group.
Median PFS was significantly higher in the sorafenib group compared with the best supportive care group (100 vs 89 days; P = .019), and overall survival was numerically greater in the sorafenib group compared with best supportive care (369 vs 249 days), but this difference did not reach statistical significance. Moreover, serum values of M65, a prognostic biomarker of tumor progression, stabilized during sorafenib treatment but increased with placebo. The rates of fatigue, diarrhea, appetite loss, hand-foot syndrome, and hypertension were higher with sorafenib than with placebo, but were reported as manageable. The investigators concluded that sorafenib may be an option for patients with mCRPC in the post-docetaxel setting.
AT13387 is a synthetic Hsp90 inhibitor that was tested in a 2-part phase 1/2 randomized clinical trial to investigate its activity in combination with abiraterone acetate plus prednisone in patients with mCRPC that was progressing with abiraterone therapy alone (Ferraldeschi R, et al. ESMO 2014: Abstract 776P). However, this combination at the doses tested resulted in grade ?3 dose-limiting diarrhea and fatigue, with transient decreases in prostate-specific antigen (PSA) but no PCWG2 PSA responses or objective RECIST tumor responses. It is unclear at this time whether these results suggest that AT13387 is not a viable candidate in the mCRPC setting, or if Hsp90 is not a useful molecular target for this patient population.