Prostate disease and the pharmaceutical industry

Prostate Cancer

Medicines for BPH and prostate cancer in the development pipeline

Research continues to clarify the role of alpha-1 receptors in BPH. Various receptor sub-types are known and Pfizer has a series of quinoline and quinazoline derived inhibitors at the pre-clinical stage. They have possible advantages in terms of their selectivity for prostate receptors and survival time in the body.

In prostate cancer, LHRH antagonists are in development (an antagonist is the opposite of an agonist – i.e. it blocks activity, rather than mimicking it). These are designed to overcome the testosterone and symptom flare seen when LHRH agonists (buserelin, goserelin, leuprorelin, triptorelin) are used. Promising products in development here are abarelix (Sanofi-Synthélabo) and cetrorelix (Asta Medica).

Abarelix is in Phase 3 clinical trials. Rather than causing the pituitary to be desensitised and lose its LHRH receptors, abarelix works by blockading them so that they cannot be activated. Hence, there is no LH release. Consequently, testosterone levels fall without the initial flare or the flare in symptoms. PSA levels also decline quickly and prostate size decreases sufficiently for brachytherapy to be carried out. Cetrorelix works in a similar way and has completed Phase 1 studies.

The need for new medicines to treat hormone-escaped tumours has been mentioned already. One agent derived from a mushroom toxin is MGI-114 (MGI Pharma). It has shown potent anti-tumour activity and is now in Phase 2 trials.

Another possible approach is to design inhibitors of a group of enzymes called tyrosine kinase, whose action causes cancer cells to multiply after activation of growth factor receptors on the membranes of cells. Two potential medicines of this type are CEP-701 (from the US firm Cephalon, but under development in Europe by Schwarz Pharma) and ZD1839 (AstraZeneca). In laboratory studies, CEP-701 slowed the growth of both hormone-dependent and hormone-resistant tumour cells. The compound, which is given by mouth, has completed Phase 1 studies in the USA and Phase 2 trials are planned for 2000. ZD1839 is expected to start Phase 2 studies in 2000 in hormone-resistant prostate cancer, both alone and in combination with other medicines.

Bone pain in this late stage appears to arise in part from chemicals released by the tumour which stimulate specialised bone-resorbing cells called osteoclasts. Their activity contributes to bone pain and bone weakness that can lead to fractures. To try to combat this, Novartis has developed a medicine called zoledronic acid for the prevention and treatment of bone metastases. This belongs to a class called the bis-phosphonates, which have a high affinity for calcium, a property that has already proved beneficial in other diseases of bone, including bony metastases in breast cancer. The compound is in late-stage trials in advanced prostate cancer and is being used as an addition to some of the anti-cancer medicines discussed above. The expectation is that it will help reduce the number of people who develop bone complications.