Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer

Abstract

Background Treatment options for patients with metastatic castration-resistance prostate cancer are unsatisfactory. Docetaxel monotherapy offers promising results with a tolerable toxicity profile. However, enhancing the clinical index of Docetaxel-based therapy remains the ultimate goal. Methods We conducted a phase II, open label, multinational prospective trial to evaluate the efficacy of weekly Docetaxel combined with Zoledronic acid and Celecoxib. Eligible patients received 25 mg/m(2) Docetaxel weekly for 3 consecutive weeks every 4 weeks, 4 mg Zoledronic acid every 4 weeks, and 200 mg oral Celecoxib twice daily. Enrollment was terminated prematurely upon the publication of reports of cardiac toxicity associated with cyclooxygenase (COX) 2 inhibitors. Results Our study enrolled 22 patients with a median of 4.7 cycles per patient. The median overall survival (OS) was 9.8 months (range 0.7 to 24.1 months) with 36 % and 4.5 % survival rates at 1 and 2 years, respectively. Our patients had a biologic response in 40.1 % of cases and a palliative response in 72.7 %. Among the eight patients with measurable disease, three had partial responses, two had stable disease, and three had progressive disease, leading to a response rate (RR) of 62.5 %. The observed toxicities were mild and limited to grade 3 events. Nine patients had anemia (40.1 %), 5 had sensory neuropathy (22.7 %) and 2 had stomatitis (9.1 %). Conclusion The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials.

Efficacy of gefitinib‑celecoxib combination therapy in docetaxel‑resistant prostate cancer

“…It has been suggested that EGFR and COX-2 play an important role in the development of docetaxel resistance in PCa. Their inhibition enhances the efficacy of docetaxel treatment (14)(15)(16)(17)20). However, these studies were conducted in docetaxel-sensitive CRPC cells, rather than docetaxel-resistant.…”

“…Accumulating evidence has indicated that targeting epidermal growth factor receptor (EGFR) (14,15) and cyclooxygenase-2 (COX-2) (16,17) could be a promising strategy for preventing or delaying docetaxel resistance. Furthermore, a direct interaction between EGFR signaling and COX-2 activity has been suggested to occur in many types of cancer (18,19).…”

The Potential Preventive and Therapeutic Roles of NSAIDs in Prostate Cancer

“…In addition, CXB (400 mg twice daily for 4 weeks) has been shown to upregulate several tumor suppressors such as p73 and downregulate survivin [149]. However, other clinical trials (CXB; 400 mg twice daily for 4 weeks or 200 mg twice daily) did not show any significant changes in the apoptosis index, AR or PGE2 levels of prostate tumor tissue [150,151]. CXB (400 mg twice daily for 4 weeks) administration has been shown to decrease proliferation indices (MIB-1 and Ki67) and angiogenesis (VEGF, KDR and HIF-1) while increasing apoptosis [152].…”

Targeting androgen-independent pathways: new chances for patients with prostate cancer?

“…Non-steroidal anti-inflammatory drugs, such as sulindac and celecoxib block the Wnt signaling, decreasing nuclear compartmentalization or enhancing localization of β-catenin to the plasma membrane (Clapper et al, 2004;Lu et al, 2009). Clinical trials investigated the efficacy of celecoxib and sulindac in combination with chemotherapy in unselected populations of patients with CRPCs, but these drugs did not add any benefit to chemotherapy alone (Carles et al, 2007;Kattan et al, 2016;Ryan et al, 2005;Sinibaldi et al, 2006). Small-molecule therapeutics or even biologics that target the Wnt pathway are still in their infancy and therefore further studies are warranted to understand the potential anti-tumor activity of Wnt pathway inhibition (Kahn, 2014).…”