A trial looking at pembrolizumab and enzalutamide with hormone therapy for prostate cancer (KEYNOTE-991)

Please note - this trial is no longer recruiting patients. We hope to add results when they are available.

Cancer type:

Prostate cancer
Secondary cancers

Status:

Closed

Phase:

Phase 3

This trial is comparing two treatments. One treatment is pembrolizumab, enzalutamide and hormone treatment. The other is enzalutamide and hormone treatment. The trial is for men with prostate cancer that has spread. 

More about this trial

Advanced prostate cancer is cancer that has spread in the body.  The male sex hormone testosterone helps advanced prostate cancer to grow. There are different ways to reduce the level of testosterone in the body. You can have:

This is called androgen deprivation therapy. 

Enzalutamide is a hormone therapy. Doctors use it to treat advanced prostate cancer. 

Pembrolizumab is an immunotherapy. It works by stimulating the immune system Open a glossary item to fight cancer. Doctor use it as treatment for a number of cancers but not prostate cancer. 

Researchers think that pembrolizumab and enzalutamide might work well for advanced prostate cancer. In this trial half the people have pembrolizumab, enzalutamide and androgen deprivation therapy. And the other half have a dummy drug (placebo Open a glossary item), enzalutamide and androgen deprivation therapy. 

The main aims of the trial are to find:

  • how safe the combination of pembrolizumab, enzalutamide and androgen deprivation therapy is
  • how well the combination works
  • how this combination affects quality of life Open a glossary item 

Who can enter

The following bullet points list the entry conditions for this trial. Talk to your doctor or the trial team if you are unsure about any of these. They will be able to advise you. 

Who can take part

You may be able to join this trial if all of the following apply. You:

  • have adenocarcinoma of the prostate that has spread to the bones or organs  
  • have had a scan Open a glossary item that shows where the cancer has spread to 
  • have satisfactory blood tests results
  • are willing to take hormone therapy during the trial or to have had surgery to remove your testicles 
  • have a sample of tissue (biopsy Open a glossary item) from where the cancer has spread that the trial team can ask for or if this isn’t the case you are willing to have a fresh biopsy taken
  • are active but might not be able to do heavy physical work (performance status 0 or 1)
  • are willing to use a condom when having sex with anyone else and not donate sperm during the study and for at least 120 days after your last trial treatment
  • are at least 18 years old

Who can’t take part

Cancer related

You cannot join this trial if any of these apply. You:

  • have small cell prostate cancer 
  • have cancer that has spread to the lymph nodes Open a glossary item only
  • have or might have cancer spread to the brain or spinal cord
  • have had certain previous treatments for your prostate cancer spread. Your doctor can tell you about this. 
  • have already had hormone treatment for more than 3 years and 3 months (39 months) or you have had hormone treatment within 9 months of randomisation Open a glossary item or your disease has gotten worse while you were on hormone treatment
  • have had treatment with a newer type of hormone treatment such as abiraterone, enzalutamide, apalutamide or doralutamide 
  • are having bone restoring drugs such as bisphosphonates Open a glossary item or denosumab unless you have been on a stable dose for at least 4 weeks before randomisation in this trial
  • have had another cancer in the past 3 years that has got worse or needed treatment apart from successfully treated non melanoma skin cancer Open a glossary item or a carcinoma in situ Open a glossary item

Medical condition

You cannot join this trial if any of these apply. You:

  • have had treatment for an autoimmune disease Open a glossary item in the past 2 years unless it was treatment to replace something the body produces such as hormones for thyroid problems or insulin for diabetes
  • have an immune system that isn’t working well (immunodeficiency) or you are taking a large dose of steroids or another medication that affects your immune system within 7 days of the first dose of treatment
  • have major surgery within 28 days of randomisation and you have not recovered from any side effects or complications
  • have a problem with your digestive system Open a glossary item that affects how well your gut absorbs medication
  • are not able to swallow tablets or capsules
  • have an active infection that needs treatment that reaches your whole body
  • have HIV, hepatitis B or hepatitis C
  • have inflammation of the lung (pneumonitis) that isn’t caused by an infection or you had treatment (steroids) for it in the past
  • have had or might have fits (seizures) or you have had loss of consciousness within the past year
  • had a heart attack or uncontrolled chest pain (angina) in the past 6 months or another heart problem that might affect you taking part
  • have or have had a history of other heart problems. Your doctor can review this with you. 
  • have high blood pressure (hypertension) or low blood pressure (hypotension) that isn’t controlled
  • are allergic to the treatments or any of their ingredients used in this trial
  • have had treatment that stimulates the immune system (an immunotherapy drug)
  • have taken herbal preparations such as saw palmetto that affects PSA levels within 4 weeks of randomisation
  • are taking certain drugs that affect testosterone such as finasteride, dutasteride or cyproterone acetate within 4 weeks of randomisation
  • are taking an experimental drug or using a device as part of another clinical trial within 4 weeks of randomisation 
  • have had a type of bone scan called a superscan bone scan
  • have had a bone marrow or stem cell transplant from someone else (allogeneic transplant) or you have had an organ transplant
  • have any other medical condition or mental health problem that your doctor or the trial team think could affect you taking part
  • have a live vaccine Open a glossary item within 30 days of randomisation

Trial design

This is an international phase 3 trial. The team need 1,232 men to take part with about 60 men taking part in the UK.

It is a randomised, double blinded trial. Neither you nor your doctor can choose which group you are in. And neither you nor your doctor know which treatment you are getting. There are 2 groups:

  • pembrolizumab, enzalutamide and androgen depravation therapy
  • dummy drug (placebo), enzalutamide and androgen depravation therapy


You have pembrolizumab or the dummy drug as a drip into a vein. You have it once every 3 weeks. This is a cycle of treatment Open a glossary item. You have 35 cycles of treatment (about 2 years) as long as it is helping and the side effects aren’t too bad. 

You have enzalutamide either as capsules or tablets. Your doctor tells you how many to take. You take it once a day at the same time with a glass of water. You continue having enzalutamide as long as it is helping and the side effects aren’t too bad. 

Androgen depravation therapy is either hormone therapy or surgery to remove your testicles. If you have had surgery you don’t need to have hormone therapy. If you haven’t had surgery and are already taking hormone therapy you continue with it. If you haven’t had surgery and aren’t taking hormone therapy your doctor will start you on hormone therapy. 

Quality of life
You fill in a few questionnaires:

  • before you start treatment
  • at regular times during treatment 
  • at the end of treatment

The questions ask about:

  • any side effect or symptoms
  • your general health
  • what you can do
  • your quality of life

These are quality of life questionnaires

Research samples
You give blood samples and tissue samples (biopsy Open a glossary item) during the trial. Your doctor will tell how many and how often. 

The trial team use these samples to look for substances (biomarkers Open a glossary item) that might tell them:

  • how well the treatment works
  • how your body responds to treatment
  • why it works better for some men and not others

Hospital visits

You see the doctor to have tests before taking part. These tests include:

  • a physical examination
  • blood tests
  • taking a fresh sample of tissue (biopsy) that is if there is a suitable area to take it from. If you have had a biopsy within the last 12 months, this may be used instead. If you have not had a recent biopsy, and if it is not possible to take a fresh biopsy, an older tissue sample (taken more than 12 months ago) might be able to be  used.
  • CT scan or MRI scan
  • bone scan
  • heart trace (ECG Open a glossary item)

During treatment you see the doctor every 3 weeks for bloods and to see how you are. You have a CT scan or MRI scan every 12 weeks. 

You see the doctor a month after you finish pembrolizumab or the dummy drug. You then see the doctor every 3 months or a member of the trial team will phone to see how you are.   

Side effects

The trial team monitor you during treatment and afterwards. Contact your advice line or tell your doctor or nurse if any side effects are bad or not getting better. 

Pembrolizumab can affect the immune system. It may cause inflammation in different parts of the body which can cause serious side effects. They could happen during treatment, or some months after treatment has finished. Rarely, these side effects could be life threatening.

If you have any of these side effects, you should tell the doctor or nurse as soon as possible that you are on or have been on an immunotherapy. 

The common side effects of pembrolizumab are:

  • itchy skin, rash
  • diarrhoea 
  • cough
  • pain in the joints, back or tummy (abdomen)
  • high temperature (fever)
  • loss of skin colour
  • a decrease in the amount of hormone the thyroid makes (hypothyroidism) causing tiredness, weight gain, feeling cold or constipation
  • a low level of salt in the blood causing tiredness, confusion, headaches, muscle cramps and, or feeling sick 

We have more information about pembrolizumab

We have information about:

Recruitment start:

Recruitment end:

How to join a clinical trial

Please note: In order to join a trial you will need to discuss it with your doctor, unless otherwise specified.

Please note - unless we state otherwise in the summary, you need to talk to your doctor about joining a trial.

Chief Investigator

Dr Vincent Khoo

Supported by

Merck, Sharp & Dohme

Freephone 0808 800 4040

Last review date

CRUK internal database number:

17102

Please note - unless we state otherwise in the summary, you need to talk to your doctor about joining a trial.

Wendy took part in a new trial studying the possible side effect of hearing loss

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"I was delighted to take part in a clinical trial as it has the potential to really help others in the future.”

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