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Introduction
Prostate cancer is the second most frequently diagnosed cancer in the world.1 Androgen deprivation therapy is the main treatment for advanced disease. Androgen deprivation therapy (ADT) is a temporary measure but can accelerate osteoporosis, and bone metastases are common in advanced prostate cancer and are associated with significant morbidity, including pain. All patients eventually develop castration-resistant prostate cancer (CRPC). CRPC patients had a poor prognosis, with a median survival of about 18 months.2 Clearly, new drugs are needed to treat CRPC to slow disease progression and improve quality of life.
Endothelin, especially endothelin-1 (ET-1), plays a regulatory role in tumor growth and proliferation. ET-1 is produced by tumor cells and ACTS primarily by binding to cell surface endothelin A receptors (ETA) and B receptors (ETB) and altering the effects of other growth factors. Activation of ETA promotes cell growth, while activation of ETB induces cell death through apoptosis. In addition, the combination of ET-1 with ETB can cause ET-1 to be removed from the loop. Moreover, activation of ETA induces expression and activation of tumor proteases and promotes tumor proliferation and metastasis. In addition, activation of ETA leads to osteoblastic proliferation, bone remodeling, and growth factor release, and stimulates the survival and growth of metastatic prostate cancer cells in bone. Specific blocking of ETA provides an effective cancer treatment. On the contrary, antagonistic ETB may lead to adverse effects such as inhibition of apoptosis and reduction of ET-1 clearance rate. Therefore, a drug that is active only against ETA (that is, a specific ETA antagonist) is desirable.3
Figure 1 The effect of endothelin on cells
Pre-clinical development and pre-clinical
Zibotentan (ZD4054), an oral specific ETA receptor antagonist.
Chemical name and structure
N- (3-Methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide
Figure 2 Zibotentan (ZD4054) structure
Synthesis
In order to study the drug metabolism and pharmacokinetics of ZD4054, the synthesis of ZD4054 was labeled with isotopes.
Figure 3 [oxadiazol-5-14C]
Figure 4 [pyridyl-2,6-14C]
Figure 5 [phenyl-2,3,5,6-2H4]
Three different synthetic routes successfully inserted isotopic markers into 1,3, 4-oxadiazole, pyridine and phenyl rings in ZD4054.4
Receptor interaction/specificity
ZD4054 is an ETA receptor antagonist. Among the available endothelin receptor antagonists for oral administration, ZD4054 can bind ETA more selectively than ETB. In-vitro multi-receptor binding tests, ZD4054 has been shown to specifically and competitively bind to 125I-ET-1 and compete with the ETA receptor of cloned human cells, with an IC50 value of 21 nmol/L. ZD4054 did not bind to the ETB receptor when the concentration reached 100 mmol/ L.5
Clinical trials
Phase I
Treatment plan
The Zibotentan pill is taken orally once a day.In the first group (phase 1), Zibotentan started at 10 mg per day and gradually increased in the three-patient cohort (15 mg, 22.5 mg, 32.5 mg, and 50 mg), with an initial planned maximum of 200 mg per day.Patients who have evidence of clinical benefit and do not meet any exit criteria are allowed to receive Zibotentan at their current dose level until they are no longer receiving clinical benefit.6
Pharmacokinetic evaluation
During the treatment period, a maximum of 21 blood samples will be obtained from each patient, and 1 dose be given at the following times per infusion: 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours and 48 hours. Groove samples were collected on day 8 and day 15 before the next dose of Zibotentan. Steady-state plasma concentration-time distributions were obtained from blood samples taken immediately before cibotan administration on day 29, at 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 24 hours after the day 29 dose.The single-dose PK( pharmacokinetics) study of Zibotentan was performed in all 16 patients(Figure 6 and 7).6 Single-dose PK data showed a low apparent clearance rate and distribution volume, with an average final half-life between 7.0 and 9.2h. Minimum concentration accumulation of Zibotentan was observed after repeated administration, and steady-state concentration was reached at least 8 days after treatment (5 days per day). No change in time of Zibotentan PK was observed after repeated administration.
Figure 6 zibotentan plasma concentration-time curves
Figure 7 Single-dose PK of zibotentan
Dose toxicity
No DLTs (dose-limiting toxicity) were observed in patients who received an initial dose of 10 mg or 15 mg.Four patients were at the dose level of 22.5mg, and two of them experienced DLT. One patient received a 22.5mg dose, which was later reduced to 15 mg(Figure 8)6
Figure 8 Adverse events occurring in two or more patients overall
Phase 2
The study recruited men 18 years of age ≤HRPC and with bone metastases who had no pain or mild pain symptoms (no opioid analgesia required) and who had not received chemotherapy. The patient had prostatic adenocarcinoma confirmed histologically or cytologically, with evidence of bone metastasis.7
Treatment plan
Patients were randomly assigned a daily oral dose of ZD405410 mg or ZD405415 mg or placebo at a ratio of 1:1:1:1. Physically identical tablets and packages are used to ensure that patients and investigators are blinded. Patients were instructed to take a pill with a glass of water every morning.All patients received ZD4054 or placebo in the context of supportive care based on local practice.5
Study population
A total of 312 patients were randomly assigned to three treatment groups.(Figure 9)6
Figure 9 Trial profile(phase 2)
Efficacy
In the first data, 209 progress events occurred. No significant difference was observed between the ZD4054 treatment group and placebo group. Overall survival improved, although only 40 deaths occurred at this time. Taking into account the overall survival observed, a second analysis is planned when approximately 110 deaths occur. In the second data, 118 patients died and 167 (86%) of the remaining 194 patients were identified as having a survival status. The results of the second analysis confirm the results of the first analysis. There was no significant difference in progression time between the groups, but the results showed that overall survival was improved in the ZD4054 group compared to the placebo group. After discontinuation of the treatment, the treatment group was generally similar in the use of systemic anticancer therapies, particularly taxanes.6
Figure 10 First data for time to progression and overall survival
Figure 11 Second date for time to progression and overall survival
The study found no significant difference between ZD4054 and placebo for the primary end point of time to progression. However, compared with placebo, both doses of ZD4054 showed promise for prolonging patient overall survival. This information was evident in the first data after 40 deaths and was still present in the second data after 118 deaths.6
Phase 3
Treatment plan
Patients were randomized 1:1 to take Zibotentan10 mg daily or placebo. Patients receive standard support or treatment: chemotherapy. Other experiments agent is not allowed. Patients continued to be randomized until they met the withdrawal criteria.(Figure 12)8
Figure 12 Treatment plan flowchart
Efficacy
No statistically significant improvement was observed in overall survival(Figure 13). Overall survival results consistent with the prognosis and assessment of geographic subgroups, including age, PSA, and bisphosphonate use bone metastases(Figure 14).8
Figure 13 overall survival curve
Figure 14 overall survival for subgroup
No statistically significant differences were observed between treatments for pain progression time, chemotherapy use time, new bone metastasis time, and progression-free survival (PFS).At the time the data were obtained, the proportion of patients who received chemotherapy after randomization was the same in both groups(Figure 15).8
Figure 15 Secondary Efficacy Endpoint
Conclusions
ET receptor antagonistic drugs in the treatment of prostate cancer model is scientific and compelling. ET receptor antagonists can provide direct antitumor effects and affect the tumor environment by inhibiting osteoblasts proliferation, bone remodeling, and release of growth factors that may aid the spread of metastatic tumors in bone. Abt-627 (Abbott Laboratories) is a selective ET receptor antagonist that is also currently under clinical development. Previous studies have shown that atrasentan improves pain and has a tendency to improve progression time (compared to placebo), and clinical trials of the drug are ongoing.9,10
Zibotentan is a specific ETA receptor antagonist. By inhibiting ETA receptors only, the beneficial effects of ETB activation on apoptosis and harm-resistant perception should be preserved. In phase I trials, this phase I dose-escalation study of the specific ETA receptor antagonist Zibotentan in men with metastatic CRPC showed that continuous oral administration of 10 and 15 mg per day was well tolerated. The MWTD(maximum well-tolerated dose) was identified as 15 mg daily.
In the phase 2 trial, although the primary endpoint of progression was not achieved, the overall survival of patients with ZD4054 and asymptomatic or mildly symptomatic metastatic HRPC was expected to improve.The results of this study support ETAR-targeted prostate cancer treatment strategies and support the phase 3 clinical trial study of ZD4054.
In the phase 3 trial, optimal support of zibotentan 10mg daily did not lead to a significant improvement in overall survival in patients with CRPC and bone metastases who were pain-free or mildly symptomatic for pain. There are four possible reasons for this. (1) The primary endpoint in the phase 2 study was time to progress, not over survival.11(2)The placebo group in the phase 3 study survived longer than expected.12(3)Average drug exposure in the phase 2 study is shorter and data for the follow-up system against cancer treatment using less than half of the patients.11,13(4)There are demographic differences between the studies. The phase III trial, which included East Asian patients (from China, Hong Kong, Japan, Singapore, South Korea and Taiwan) and a pre-assigned subgroup analysis of overall survival, showed poorer outcomes for the Asian population compared with patients from other ethnic (mainly white) backgrounds.14,15
Although there was a significant effect on cancerbone interaction in preclinical models, ETA receptor antagonists showed disappointing results in phase 3 in patients with CRPC.16 For patients with CRPC and bone metastasis, with no pain or mild pain symptoms and without chemotherapy for metastatic disease, zibotentan 10mg daily plus standard treatment did not lead to significant OS improvement. As a result, zibotentan is no longer being studied as a potential treatment for prostate cancer patients.But other clinical trials of zibotentan as an ETA receptor antagonist for cancer drugs are still underway.
References and Formatting
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- Kasper S, Cookson MS. Mechanisms leading to the development of hormone-resistant prostate cancer. Urol Clin North Am. 2006, 33, 201-210.
- Morris. C D, Rose. A, Curwen. J, Hughes. A M, Wilson. D J and Webb. D J, British Journal of Cancer, 2005, DOI: 10.1038/sj.bjc.6602676.
- Julie A. Bergin, Helen Booth, Ryan A. Bragg, Nick Bushby, John R. Harding, Angela Jordan and Clare D. King, Journal of Labelled Compounds and Radiopharmaceuticals, 2007, DOI: 10.1002/jlcr.1177.
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- Nicholas D. James, Armelle Caty, Michael Borre, Bernard A. Zonnenberg, Philippe Beuzeboc, Thomas Morris; De Phung and Nancy A. Dawson, European Urology, 2009, DOI: 10.1016/j.eururo.2008.11.002.
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- Carducci MA, Padley RJ, Breul J, Vogelzang NJ, Zonnenberg BA, Daliani DD, Schulman CC, Nabulsi AA, Humerickhouse RA, Weinberg MA and Schmitt JL, J Clin Oncol, 2003, 21, 679–689
- Carducci MA, Saad F, Abrahamsson PA, Dearnaley DP, Schulman CC, North SA, Sleep DJ and Isaacson JD, Cancer, 2007, 110, 1959-1966.
- James ND, Caty A, Borre M and et al, Eur Urol, 2009, 55, 1112-1123.
- Tannock IF, de Wit R, Berry WR, et al. N Engl J Med, 2004, 351, 1502-1512.
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- Robbins AS, Koppie TM, Gomez SL, Parikh-Patel A and Mills PK, Cancer, 2007, 110, 1255-1263.
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