Patients

Prostate cancers depend upon the male hormone testosterone for their growth. Lowering testosterone levels
(either by removing all or part of both testes, or by giving anti-hormone treatment) slows the growth of
prostate cancers. This type of treatment is called hormone treatment or androgen deprivation therapy (ADT)
and is often used when prostate cancers have spread outside the prostate gland. Although hormone treatment
is usually successful at stopping the cancer growing for a period of time, the cancer will begin to grow
again in most men.

There are increasing numbers of treatments available for advanced prostate cancer. These treatments are
usually used in prostate cancer when hormone treatment is no longer effective and the cancer has started
to grow again. The aim of this trial, which is called STAMPEDE, is to assess some of these treatments,
given earlier in the course of the disease in combination with the current standard-of-care. 

The treatments that have been, or are being, assessed during the trial are:

1. Zoledronic acid (now closed to recruitment): Prostate cancer cells can spread to bones and weaken them.
Zoledronic acid is a drug that reduces bone destruction and hardens bones cells. Recruitment to this
treatment has been completed and the results show that the addition of zoledronic acid does not
prolong survival.

2. Docetaxel (now closed to recruitment): A drug that stops cells replicating that is currently being used
to treat a range of cancers including lung, breast and ovarian cancer as well as prostate cancer. Docetaxel
prolongs survival in men with relapsed metastatic prostate cancer. Recruitment to this treatment has been
completed and the results show that the addition of docetaxel to hormone treatment does improve survival in
men with metastatic disease and delays the time to progression for men with locally advanced and metastatic
disease. Docetaxel may now be given as part of standard treatment to all men entering STAMPEDE
(from Protocol version 14.0).

3. Celecoxib (now closed to recruitment):: An aspirin-like drug that is used to treat arthritis. It slows
down the growth of cancer cells in the laboratory. We wished to see if it had the same effect on cancer
cells in patients. Recruitment stopped early as a planned intermediate analysis failed to demonstrate
sufficient effect of this drug.

4. Abiraterone (in single use included from Protocol version 8.0; in combination with enzalutamide included
from Protocol 12.0): An inhibitor of steroid hormone synthesis that blocks prostate cancer cells from
generating their own male hormones. This is thought to be a major way in which prostate cancer cells resume
growth following anti-hormonal therapies. Abiraterone has been shown to prolonging surival in men with
advanced disease when given before and after chemotherapy.

5. Prostate radiotherapy (included from Protocol version 9.0): treatment with high-energy x-rays targeted to
the prostate gland. This treatment is now mandatory for patients with cancer that is confined to the prostate
gland as large trials have shown it improves survival times. We are not certain whether we should give
radiotherapy to the prostate if the cancer has already spread and so we are investigating this in STAMPEDE.
Recruitment to this treatment group will close on 02-Sept-2016.

6. Enzalutamide (in combination with abiraterone included from Protocol version 12.0): This is a blocker of
androgen receptors. These stimulate the cancer when hormone therapies have failed. Enzalutamide may be
mutually complementary to abiraterone in terms of blocking mechanisms of resistance. The agent prolongs
survival when given to men following failure of docetaxel chemotherapy. Recruitment to this treatment group
is now completed.

7. Metformin (included from Protocol version 15.0): This anti-diabetic medication is proposed to have both
anti-cancer effects and may help prevent the adverse metabolic effects of long term ADT. STAMPEDE will
investigate whether adding metformin to the current standard-of-care for non diabetic men can improve
all-cause survival. Recruitment to this treatment group will open on 05-Sept-2016.

STAMPEDE will look at the effect of combining one or two of the treatments described above with hormone
treatment. A computer program will be used to allocate which treatment each participant receives, using a
chance process. The trial will look at the effects of the combined treatments on quality of life and find
out whether the new treatment combinations control prostate cancer growth and enable men to live longer. The
study will also look at which treatment provides the greater value for money for the health service. More than
9,000 men will join the trial with answers becoming available throughout the trial.