According to William Kevin Kelly, DO, of Thomas Jefferson University, the addition of bevacizumab (Avastin) to the combination of docetaxel and prednisone offers no survival advantage compared with docetaxel and prednisone alone in men with metastatic castrate-resistant prostate cancer (CRPC). Dr. Kelly presented final survival results of the CALGB 90401 trial at the 2010 ASCO Annual Meeting.¹ CALGB 90401 was a randomized, double-blind, placebo-controlled phase III trial conducted in collaboration with the Cancer and Leukemia Group B (CALGB) and Eastern Cooperative Oncology Group (ECOG).

Previous studies had demonstrated that plasma vascular endothelial growth factor (VEGF) levels were predictive of survival in CRPC, providing the rationale for therapeutic targeting of this protein.² Results of a subsequent CALGB phase II trial suggested that in chemonaive patients with CRPC, the addition of bevacizumab to a docetaxel-based regimen produced more favorable responses than chemotherapy alone.³ CALGB 90401 was designed to confirm these findings and evaluate whether the addition of bevacizumab to docetaxel/prednisone could significantly improve survival in patients with CRPC.

Study Design and Results

The study randomly assigned, in a 1:1 fashion, 1,050 chemonaive men with metastatic CRPC who had evidence of progressive disease despite castrate testosterone levels (< 50 ng/ mL) and antiandrogen withdrawal. Eligibility criteria included ECOG performance status ≤ 2 and adequate bone marrow, hepatic function, and renal function. Eligible patients must have demonstrated recent disease progression, ie, measurable disease progression, progression by bone scan, or prostate-specific antigen (PSA) progression, despite a recent change in therapy, including antiandrogen withdrawal. Because bevacizumab was used, eligibility criteria also included no history of significant bleeding events within the past 6 months or deep-vein thrombosis/pulmonary embolism within the past year, no serious nonhealing wound, ulcer, or bone fracture within 12 months, and no uncontrolled hypertension. No prior cytotoxic chemotherapy or antiangiogenic therapy was allowed.

Patients were stratified by 24-month predicted survival (< 10%, 10%-29%, ≥ 30%) using the Halabi nomogram. Treatment consisted of docetaxel at 75 mg/m2 IV every 3 weeks plus prednisone at 10 mg daily and either bevacizumab, 15 mg/kg IV every 21 days, or placebo, following docetaxel. Both groups received oral dexamethasone, 8 mg, at 12 hours, 3 hours, and 1 hour prior to docetaxel therapy. The primary endpoint was overall survival (OS), with secondary endpoints of progression-free survival (PFS), response rate, and PSA response. The study was powered to detect an increase in OS from 19 to 25 months (α = 0.05).

Patients were well balanced with respect to baseline characteristics. A median of eight cycles of therapy was administered on both arms. Although a statistically significant increase was shown in median PFS with the bevacizumab regimen (9.9 vs 7.5 months; HR = 0.77; P < .0001), this was not the case for median OS (22.6 vs 21.5 months; HR = 0.91, P = .181). Objective response was greater on the bevacizumab arm (53.2% vs 42.1%; P = .0113), as was decrease in PSA (≥ 50% decline in PSA: 69.5% vs 57.9%; P = .0002). Subgroup analysis revealed that patients who may have a more favorable benefit on the bevacizumab regimen include those with low hemoglobin, increased LDH, low testosterone levels, and elevated serum alkaline phosphatase.

Toxicity was significantly greater with the addition of bevacizumab. Treatment-related adverse events of grade 3 or higher occurred in 74.8% of patients who received bevacizumab compared with 55.3% of patients on the control arm (P < .001). The proportion of patients who died while on study (mainly due to infection) was greater with bevacizumab (3.8% vs 1.1%).

Unanswered Question

Dr. Kelly noted that the OS of 21.5 months in the control arm exceeded the 19.2 months previously observed in the TAX327 trial.4 This suggests the possibility of stage migration in the current study, which is supported by the increased percentage of good-risk patients in the CALGB 90401 trial (47% of men had a 24-month predicted survival > 30%). Although the addition of bevacizumab to docetaxel and prednisone increased PFS, response rate, and PSA decline ≥ 50%, it did not improve OS and was associated with greater morbidity and mortality. "This may indicate that subsequent treatments may have an effect on the primary outcome of the study," concluded Dr. Kelly. ■

References

1. Kelly WK, Halabi S, Carducci MA, et al: A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): Survival results of CALGB 90401. 2010 ASCO Annual Meeting. Abstract LBA4511. Presented June 6, 2010.

2. George DJ, Halabi S, Shepard TF, et al: Cancer and Leukemia Group B 9480. Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. Clin Cancer Res 7:1932-1936, 2001.

3. Picus J, et al: Cancer. In press.

4. Tannock IF, de Wit R, Berry WR, et al: TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004.