Targeted Therapies Added to Docetaxel Do Not Extend Survival in Metastatic Prostate Cancer

Phoebe Starr

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The latest in a string of failed trials of targeted therapies added to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) were presented at the 2013 Genitourinary Cancers Symposium. No survival benefit was observed with the addition of aflibercept to docetaxel/prednisone in the VENICE trial¹ or with the addition of dasatinib to docetaxel/prednisone in the READY trial.²
These trials are expensive to mount and manage, and the medical community, including patients, invests a great deal of time and energy into these trials in the hope of identifying a treatment that improves outcomes. Formal discussant of these trials, William Oh, MD, Mt. Sinai School of Medicine, New York City, stated that much stronger phase 2 evidence is needed before mounting yet another trial of a new agent added to docetaxel in this setting. He suggested that novel trial designs based on molecular-guided enrollment would be a step forward.

VENICE Trial

The large multinational double-blind VENICE trial randomized 1224 men with mCRPC with progressive disease on hormonal therapy or surgical castration to first-line therapy with aflibercept plus docetaxel versus docetaxel. Aflibercept is a potent antiangiogenic fusion protein that binds VEGF-A, VEGF-B, and placental growth factor, with preclinical data to support its use.
At a median follow-up of 35 months, no difference in overall survival (OS), the primary end point, was observed. OS was 22.1% in the aflibercept arm versus 21.1% in the placebo arm. Progression-free survival (PFS) was a median of 6.9 months versus 6.2 months, respectively. Time to first skeletal-related event (SRE) was almost identical: median of 15.3 months versus 15 months, respectively.
Patients in the aflibercept arm had a higher rate of toxicities, including serious adverse events, compared with the placebo arm. Grade 3/4 adverse events were reported in 77% of the aflibercept arm versus 48.5% in the placebo arm.

“This study provides a lesson that when we design large phase 3 trials, we need strong evidence of improved activity with the agent we want to study. As yet, no added agent has improved upon docetaxel plus prednisone in men with mCRPC,� stated presenting author Ian Tannock, MD, Princess Margaret Cancer Centre,Toronto, Canada.

READY Trial

Based on preclinical data showing synergy for dasatinib, an Src kinase inhibitor, plus docetaxel and phase 2 safety data, the READY trial randomized 1522 patients with progressive mCRPC to dasatinib or placebo; all patients were treated with docetaxel plus prednisone.

“It is disappointing, but dasatinib did not improve median OS versus docetaxel alone,� said presenting author John Araujo, MD, MD Anderson Cancer Center, Houston, Texas.

Survival curves were virtually identical: 21.5 months for dasatinib and 21.2 months for docetaxel. No OS benefit was observed for dasatinib in any of the subgroups analyzed.

No meaningful changes were seen between the arms in response rates, bone turnover markers, PFS, or pain reduction. However, time to first SRE was a median of 31.1 months in the placebo group and not reached in the dasatinib group.
Treatment-emergent adverse events were observed in 18% of patients on the dasatinib arm versus 9% on the placebo arm.
Thirty percent of patients in both arms had serious adverse events.

References
1. Tannock I, Fizazi K, Ivanov S, et al. Aflibercept versus placebo in combination with docetaxel/prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC): results from the multinational phase III trial (VENICE). J Clin Oncol. 2013;31(suppl 6). Abstract 13.
2. Araujo JC, Trudel GC, Saad F, et al. Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): results from the randomized phase III READY trial. J Clin Oncol. 2013;31(suppl 6). Abstract LBA8.

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