AEZS-108 (zoptarelin doxorubicin) is a cytotoxic hybrid molecule consisting of doxorubicin covalently coupled with a luteinizing hormone-releasing hormone (LHRH) analogue, which selectively targets doxorubicin to tumor cells expressing LHRH receptors. We report the clinical efficacy of AEZS-108 in a phase II trial in men with metastatic castrate-resistant prostate cancer who had disease progression after taxane-based chemotherapy.
Patients and Methods
Patients received AEZS-108 210 mg/m2 intravenously every 3 weeks. The primary end point was clinical benefit defined as nonprogression at 12 weeks with no dose-limiting toxicities (DLTs) or other toxicities requiring termination of treatment. Secondary end points included response rate, pain response, progression-free survival (PFS), and overall survival (OS). Circulating tumor cells (CTCs) were captured and tested for LHRH receptors, as well as for internalization of AEZS-108 using autofluorescence.
Twenty-five patients were enrolled; 20 patients had at least 1 measurable lesion at baseline. Patients received a median of 5 cycles (range, 1-9) and 44% of patients received at least 6 cycles with 2 patients who completed ≥ 8 cycles. Considering clinical benefits, 13 patients (52%) remained progression-free at 12 weeks with no DLT or other toxicities requiring termination of treatment. For clinical response according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, 1 patient (4%) experienced a confirmed partial response (PR) within 12 weeks, 14 patients (56%) had stable disease (SD), and 8 patients (32%) had disease progression. For maximal prostate-specific antigen (PSA) response, 1 patient (4%) experienced a confirmed PR within 12 weeks, 21 patients (84%) had SD, and 3 patients (12%) had disease progression as denoted by their best PSA response. Pain improved in 13 (59%) patients. The median PFS was 3.8 months (95% confidence interval [CI], 2.1-4.4), and median OS was 6.0 months (95% CI, 4.2-10.1) with a median follow-up of 16.1 months (range, 3.2-36.1). Baseline CTC enumeration was an independent predictor of OS but not PFS.
AEZS-108 showed activity in patients who were pretreated, a subset typically very difficult to treat, and maintained an acceptable safety profile.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Clinical Genitourinary Cancer
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.N Engl J Med. 2015; 373: 737-774
- American Society of Clinical Oncology endorsement of the Cancer Care Ontario Practice Guideline on nonhormonal therapy for men with metastatic hormone-refractory (castration-resistant) prostate cancer.J Clin Oncol. 2007; 25: 5313
- Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.N Engl J Med. 2004; 351: 1502-1512
- Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.N Engl J Med. 2004; 351: 1513-1520
- Circumventing tumor resistance to chemotherapy by nanotechnology.Methods Mol Biol. 2010; 596: 467-488
- Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.J Clin Oncol. 2008; 26: 1148-1159
- EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer.Eur Urol. 2014; 65: 467-479
- Targeted therapies: a new generation of cancer treatments.Am Fam Physician. 2008; 77: 311-319
- Preclinical evaluation of targeted cytotoxic luteinizing hormone-releasing hormone analogue AN-152 in androgen-sensitive and insensitive prostate cancers.Clin Cancer Res. 2003; 9: 4505-4513
- Targeted cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AEZS-108 (AN-152), inhibits the growth of DU-145 human castration-resistant prostate cancer in vivo and in vitro through elevating P21 and ROS levels.Oncotarget. 2014; 5: 4567-4578
- High incidence of receptors for luteinizing hormone-releasing hormone (LHRH) and LHRH receptor gene expression in human prostate cancers.J Urol. 2000; 163: 623-629
- Expression of receptors for luteinizing hormone-releasing hormone (LHRH) in prostate cancers following therapy with LHRH agonists.Clin Cancer Res. 2010; 16: 4675-4680
- Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors.Eur J Endocrinol. 1999; 141: 1-14
- New approaches to treatment of various cancers based on cytotoxic analogs of LHRH, somatostatin and bombesin.Life Sci. 2003; 72: 2305-2320
- Targeting cytotoxic conjugates of somatostatin, luteinizing hormone-releasing hormone and bombesin to cancers expressing their receptors: a smarter chemotherapy.Curr Pharm Des. 2005; 11: 1167-1180
- Internalization of cytotoxic analog AN-152 of luteinizing hormone-releasing hormone induces apoptosis in human endometrial and ovarian cancer cell lines independent of multidrug resistance-1 (MDR-1) system.Am J Obstet Gynecol. 2004; 191: 1164-1172
- Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors.Gynecol Oncol. 2010; 119: 457-461
- A randomized, phase II trial of AEZS-108 in chemotherapy refractory triple-negative (ER/PR/HER2-negative) LHRH-R positive metastatic breast cancer.J Clin Oncol. 2013; 31 (abstract TPS11124)
- Efficacy and safety of AEZS-108 (LHRH agonist linked to doxorubicin) in women with advanced or recurrent endometrial cancer expressing LHRH receptors: a multicenter phase 2 trial (AGO-GYN5).Int J Gynecol Cancer. 2014; 24: 260-265
- Phase I, dose-escalation study of the targeted cytotoxic LHRH analog AEZS-108 in patients with castration- and taxane-resistant prostate cancer.Clin Cancer Res. 2014; 20: 6277-6283
- Prostate-Specific Antigen Working Group guidelines on prostate-specific antigen doubling time.J Urol. 2008; 179: 2181-2185
US FDA. FDA approval document Nr K050245. 2005. Available at: https://www.cellsearchctc.com/.
- Increased survival with enzalutamide in prostate cancer after chemotherapy.N Engl J Med. 2012; 367: 1187
- Abiraterone and increased survival in metastatic prostate cancer.N Engl J Med. 2011; 364: 1995-2005
- Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.Lancet. 2010; 376: 1147-1154
- Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer.Clin Cancer Res. 2008; 14: 6302-6309
- Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer.Clin Cancer Res. 2007; 13: 7053-7058
- The use of circulating tumor cells in guiding treatment decisions for patients with metastatic castration-resistant prostate cancer.Cancer Treat Rev. 2016; 46: 42-50
Published online: June 07, 2017
Accepted: June 2, 2017
Received in revised form: May 29, 2017
Received: April 3, 2017
© 2017 Elsevier Inc. All rights reserved.