Randomized phase II trial of Custirsen (OGX-011) in combination with docetaxel or mitoxantrone as second-line therapy in patients with metastatic castrate-resistant prostate cancer progressing after first-line docetaxel: CUOG trial P-06c.

Abstract

PURPOSE:

Clusterin (CLU) is an antiapoptotic, stress-induced protein conferring treatment resistance when overexpressed. This study tested custirsen, a CLU inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or within 6 months of initial docetaxel therapy.

PATIENTS AND METHODS:

Men were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC).

RESULTS:

Forty-two patients received study treatment. Toxicity was similar in both arms. Twenty patients treated with DPC received a median of 8 cycles; overall survival (OS) was 15.8 months. Median time to pain progression (TTPP) was 10.0 months; 10 of 13 (77%) evaluable patients had pain responses. Three of 13 (23%) evaluable patients had objective partial responses. Prostate-specific antigen (PSA) declines of 90% or more, 50% or more, and 30% or more occurred in 4 (20%), 8 (40%), and 11 (55%) patients, respectively. Twenty-two patients treated with MPC received a median of 6 cycles; OS was 11.5 months. The median TTPP was 5.2 months; 6 of 13 (46%) evaluable patients had pain responses. No objective responses were observed. PSA declines of 50% or more and 30% or more occurred in 6 (27%) and 7 (32%) patients, respectively. Low serum CLU levels during treatment showed superior survival for patients based on modeling with proportional hazard regression with a time-dependent covariate and different landmarks.

CONCLUSIONS:

Custirsen plus either docetaxel or mitoxantrone was feasible in patients with progressive mCRPC following first-line docetaxel therapy. Pain relief was higher than expected, with interesting correlations between serum CLU and survival. A phase III trial evaluating the pain palliation benefit of custirsen with taxane therapy is ongoing.

• Authors: Fred Saad, Sebastien Hotte, Scott North, Bernie Eigl, Kim Chi, Piotr Czaykowski, Lori Wood, Michael Pollak, Scott Berry, Jean-Baptiste Lattouf, Som D Mukherjee, Martin Gleave, Eric Winquist, Canadian Uro-Oncology Group
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 17 Pg. 5765-73 (Sep 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21788353 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Clusterin
• OGX-011
• Taxoids
• Thionucleotides
• Docetaxel
• Mitoxantrone
• Prednisone

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Clusterin (antagonists & inhibitors, blood)
• Docetaxel
• Drug Resistance, Neoplasm
• Humans
• Male
• Middle Aged
• Mitoxantrone (administration & dosage)
• Neoplasm Metastasis
• Orchiectomy
• Prednisone (administration & dosage, pharmacology, therapeutic use)
• Prostatic Neoplasms (drug therapy, pathology)
• Taxoids (administration & dosage, therapeutic use)
• Thionucleotides (administration & dosage)
• Treatment Outcome