Developing an oncology portfolio of anticancer drugs: the experience of one pharmaceutical company.

For a company or institute that wishes to develop new anti-cancer agents, it is necessary to establish a portfolio of agents to reduce the risk of failure. Success rates for developing new agents are low and therefore different biological effect areas should be explored to ensure that at least one agent targeting cancer or a specific histological sub-type of cancer is effectively developed. This paper describes how one pharmaceutical company has developed a range of different agents with the ultimate aim of developing as many of these as is technically feasible into useful new medicines for the treatment of cancer.

[Anti angiogenesis].

Based on presentations on the basic concepts and scientific rationale of anti-angiogenic approaches to cancer therapy and the possible applications in the area of prostate cancer, gastrointestinal cancer, lung cancer and breast cancer it is easy to conclude that development of anti-angiogenic approaches into clinical therapies is extremely challenging. It is now well established that cancer growth is increased by angiogenic factors and that inhibition of angiogenesis decreases growth and metastatic potential. Anti-angiogenic effect can be obtained through interference with multiple targets.

Gefitinib ('Iressa', ZD1839) and new epidermal growth factor receptor inhibitors.

The epidermal growth factor receptor (EGFR) is a promising target for cancer therapy and a number of EGFR-targeted agents have been developed. Those most advanced in development are the EGFR tyrosine kinase inhibitors gefitinib ('Iressa', ZD1839) and erlotinib ('Tarceva', OSI-774), and the monoclonal antibody cetuximab ('Erbitux', IMC-C225). This review provides a clinical overview of these agents, highlighting their antitumour activities in different tumour types.

Growth factor receptor tyrosine kinase inhibitors; clinical development and potential for prostate cancer therapy.

Purpose: The development of effective, novel, targeted cancer therapies with minimal side effects has long been a goal in cancer research. A key group of targets identified for drug development consists of the receptor tyrosine kinases, which have pivotal roles in the growth factor signaling that is subverted in carcinogenesis and in the host processes, such as angiogenesis, involved in tumor progression.

Materials And Methods: A literature review of the role of receptor tyrosine kinases in human malignancies is followed by a discussion of the potential use of inhibitors of receptor tyrosine kinases as anticancer therapy, focusing on the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839, AstraZeneca, Macclesfield, United Kingdom).

[Globalization of clinical trials].

Based on reviews of the Japanese clinical trial situation in lung cancer, gastric cancer, prostate cancer and breast cancer, it was clear that much progress has been made in short time. There are considerable differences between Japan and the West and also differences between clinical areas in Japan. For regulatory purposes bridging studies have become increasingly important.

Anti-EGF receptor therapy.

The epidermal growth factor receptor (EGFR) signalling pathway contributes to a number of processes important to tumour progression, including cell proliferation, apoptosis, angiogenesis and metastatic spread. EGFR signalling is thought to be an important cell survival mechanism in hormone-resistant prostate cancer. ZD1839 ('Iressa') is an orally active, selective EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks signal transduction pathways implicated in promoting cancer growth.

Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity.

The non-steroidal antiandrogens flutamide (Eulexin((R))), nilutamide (Anandron((R))) and bicalutamide (Casodex((R))) are widely used in the treatment of advanced prostate cancer, particularly in combination with castration. The naturally occurring ligand 5alpha-DHT has higher binding affinity at the androgen receptor than the non-steroidal antiandrogens. Bicalutamide has an affinity two to four times higher than 2-hydroxyflutamide, the active metabolite of flutamide, and around two times higher than nilutamide for wild-type rat and human prostate androgen receptors.

[Post launch studies].

Evidence Based Medicine (EBM) is a growing concept in Japan as it is elsewhere. Central to improving the use of EBM is generation of data through well conducted controlled clinical studies. There are many problems associated with conduct of clinical studies after launch in Japan, and many initiatives are ongoing to improve the situation.

[Globalization of anti-cancer therapies].

Based on short reviews of lung, gastric, colorectal, prostate, breast and ovarian cancer, there remain significant differences between Japan and the West in the therapeutic regimen for most cancers. Some of the differences are due to differences in stage of disease at diagnosis or historical factors affecting availability of products. In both Japan and the West, there are initiatives to prepare treatment guidelines based on published data.

[Comparison of management of advanced cancer in various organs].

The management of advanced cancer presents the greatest challenge to physicians involved in oncology. There will usually be a large burden of disease; cure is unlikely; and the needs of the patient in terms of pain control and palliation will also be important over and above the direct treatment of the disease. Different issues will arise depending on the site and pathological type of the cancer.

Growth factors and their receptors: new targets for prostate cancer therapy.

Stimulation of the signal transduction pathway of the epidermal growth-factor receptor (EGFR) tyrosine kinase family of receptors in tumor cells enhances cellular proliferation, prevents apoptosis, and promotes tumor-cell mobility, adhesion, and invasion. Therapeutic approaches used to target the EGFR and its signal transduction cascade include (1) monoclonal antibodies (eg, cetuximab [IMC-C225]) directed against the extracellular binding domain of the receptor; and (2) trastuzumab, a monoclonal antibody binding to the HER2 receptor; immunotoxin conjugates use an antibody directed against EGFR joined to a cell toxin. All are in clinical trials for a number of cancers, including prostate cancer.

[Development of molecular targeting drugs for the treatment of cancer-therapeutic potential and issues to be addressed in global development].

A survey of cancer treatment in a sample of hospitals > 100 beds conducted in 1998 compared with experience in the US showed that good progress has been achieved in Japan in the screening and early treatment of gastric cancer, and that the prognosis for breast cancer is better than in the West. Although in the past, the cytotoxic therapies available to physicians in Japan vs the West have been different, recent acceleration of regulatory review will result in a convergence of treatment paradigms and some improvement in acute response in many tumour types. However, world wide there is a need for new improved therapies in all cancers evaluated.

A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer.

Objectives: To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer.

Methods: A total of 1,453 patients with either confirmed metastatic disease (M1), or T3/T4 non-metastatic disease with elevated prostate-specific antigen (M0) were recruited into one of two identical, multicentre, randomised studies to compare 'Casodex' 150 mg/day with castration. The protocols allowed for combined analysis.

New developments in cancer treatment with the novel thymidylate synthase inhibitor raltitrexed ('Tomudex').

Following the demonstration of efficacy, tolerability and quality-of-life benefits of raltitrexed ('Tomudex'), principally in advanced colorectal but also in other cancers, an extensive evaluation of combination therapy with other agents in patients with colorectal and other tumour types is being undertaken. This work has been prompted by preclinical observations of enhanced activity of raltitrexed when coadministered with other cytotoxic agents or radiotherapy and by preliminary results showing the activity of raltitrexed in patients with cancers other than colorectal. Raltitrexed is currently being investigated as monotherapy in phase I and II cancer studies, including head and neck cancer, hormone-resistant prostate cancer, paediatric and adult leukaemias and solid tumours, and soft tissue sarcoma.

Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: results from two multicenter randomized trials at a median follow-up of 4 years.

Objectives: To compare the efficacy, tolerability, and quality of life benefits of bicalutamide (Casodex) 150-mg/day monotherapy and castration in previously untreated nonmetastatic (M0) advanced prostate cancer.

Methods: A total of 480 patients with Stage T3/T4 nonmetastatic disease randomly received oral bicalutamide 150 mg/day or castration (either bilateral orchiectomy or goserelin acetate [Zoladex] 3.6 mg every 28 days) in a 2:1 ratio in two open multicenter studies (studies 306 and 307).

Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development.

Background: Bicalutamide (Casodex) is a new nonsteroidal antiandrogen developed for use in patients with prostate cancer. The efficacy and tolerability of bicalutamide as monotherapy and as combination therapy for patients with advanced prostate cancer have been evaluated in randomized clinical trials. Clinical trials are currently in progress to further evaluate bicalutamide as monotherapy in patients with advanced stages of disease and as adjuvant or first-line therapy in patients with early-stage disease.

Casodex (bicalutamide): overview of a new antiandrogen developed for the treatment of prostate cancer.

Casodex (bicalutamide, Zeneca Ltd), has been developed for prostate cancer therapy. Its preclinical, pharmacokinetic, pharmacodynamic, clinical efficacy and tolerability data are described. Casodex is a potent and specific non-steroidal antiandrogen.

A randomised phase III cross-over study of tamoxifen versus megestrol acetate in advanced and recurrent breast cancer.

139 peri- and postmenopausal women with advanced or recurrent breast cancer who had not received prior hormonal therapy were randomised in an open, cross-over study comparing the synthetic progestogen megestrol acetate with tamoxifen. The response rate (CR/PR) to megestrol acetate (25%; 95% confidence interval (CI) 15-35%) was not significantly different from that produced by tamoxifen (33%, CI 22-44%). Time-to-treatment failure was also similar in the two groups.

Bicalutamide: a new antiandrogen for use in combination with castration for patients with advanced prostate cancer.

Maximum androgen blockade, a relatively recent development in the treatment of prostate cancer, combines medical or surgical castration with antiandrogen therapy. A large randomized study comparing the non-steroidal antiandrogen, bicalutamide, with flutamide, each in combination with luteinizing hormone-releasing hormone (LHRH) analogs, showed that after a median follow-up of 49 weeks, the time to treatment failure was significantly longer for the bicalutamide patients compared with the flutamide patients (p = 0.005).

Clinical progress with a new antiandrogen, Casodex (bicalutamide).

Casodex (bicalutamide, Zeneca Limited) is a nonsteroidal competitive inhibitor of androgens at the androgen receptor. The drug was developed to fulfil a number of needs for the treatment of prostate cancer. The specific aim was to demonstrate pharmacological activity, which would translate into clinical efficacy, good tolerability in the context of its use, oral availability, a convenient and forgiving dosing regimen, and clinical acceptability.

Worldwide activity and safety of bicalutamide: a summary review.

Objectives: To evaluate bicalutamide as a therapy in nearly 3000 patients with advanced prostate cancer and to determine the dose-ranging, pharmacodynamic, and pharmacokinetic properties of bicalutamide. To evaluate bicalutamide as a monotherapy or in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy.

Results: Bicalutamide is a potent, nonsteroidal antiandrogen with a plasma half-life consistent with a once-daily schedule.