Dual antiangiogenic therapy plus chemo is active in advanced prostate cancer

ABSTRACT: The combination of bevacizumab and thalidomide with docetaxel yields “very encouraging” time to progression.

CHICAGO-A combination of two antiangiogenic agents-bevacizumab (Avastin) and thalidomide (Thalomid)-with docetaxel (Taxotere) is associated with a median progression-free survival of about a year and a half among men with metastatic, hormone-refractory prostate cancer, finds a phase II trial presented at ASCO 2008 (abstract 5000).

Angiogenesis appears to be critical for the metastatic progression of prostate cancer, said lead author Yang-min Ning, MD, PhD, a medical officer at FDA’s Medical Oncology Branch who has been doing clinical research development at NCI/NIH under the leadership of William Dahut, MD, principal investigator of the study.

“Tumor angiogenesis is a complex interplay of multiple angiogenic factors and pathways, and targeting only one of them may be easily overcome by the tumor through activating or amplifying other factors or pathways,” he said, noting that bevacizumab and thalidomide have different antiangiogenic mechanisms. “We hypothesized that simultaneous blockage of multiple angiogenic factors or pathways may be associated with enhanced anti-tumor activity of chemotherapy.”

Eligible patients had metastatic, hormone-refractory prostate cancer and had not received prior chemotherapy or antiangiogenic therapy for their metastases.

Treatment consisted of docetaxel and bevacizumab on day 1 of a 21-day cycle, plus daily thalidomide and prednisone. In addition, all

patients were given enoxaparin (Lovenox) prophylaxis. The 60 patients received a median of 15 cycles of treatment (range, 2 to 51 cycles).

Response rates

The overall response rate among the 33 patients with measurable disease was 64%. Median progression-free survival was 18.2 months. “Compared to the Halabi model-based prediction of median overall survival of 14.7 months, this time to progression result is very encouraging,” Dr. Ning commented.

Some 90% of the subset with PSA-positive disease (58 of the 60 patients) had at least a 50% reduction in PSA levels, and 76% had a reduction exceeding 75% (see Figure). The median duration of PSA response of more than 50% was 10 months.

Relative to their counterparts with a reduction in PSA level of less than 75%, patients with a greater reduction had a significant increase from baseline in the number of circulating apoptotic endothelial cells at 6 weeks (5,000 vs –40,000). This finding suggests “that this triple combination may be hitting the angiogenesis target,” Dr. Ning said.

Well tolerated

The combination was generally well tolerated. “Although the toxicities may be higher than with docetaxel alone, they are manageable,” Dr. Ning noted. The most common grade 3-4 adverse events were syncope (12%), febrile neutropenia (10%), thrombosis (5%), and hemorrhage (5%).

Of the 55 patients (92%) who were also receiving the bisphosphonate zoledronic acid (Zometa), 18% developed grade 2 osteonecrosis of the jaw. This is higher than the rates reported historically and may suggest some interaction between antiangiogenesis and zoledronic acid, Dr. Ning speculated.

“Overall, our results demonstrate that combined antiangiogenic therapy is highly active and feasible, justifying further study of its efficacy and safety in combination with chemotherapy in the treatment of patients with castration-resistant prostate cancer,” Dr. Ning concluded.

The next step, he told ONI, is to replace thalidomide with lenalidomide (Revlimid) in the regimen. “This is intended to alleviate adverse reactions associated with this regimen,” he said.