RE-AKT
Research type
Research Study
Full title
A randomised Phase II study of Enzalutamide (MDV3100) in combination with AZD5363 in Patients with Metastatic Castration - Resistant Prostate Cancer
IRAS ID
134883
Contact name
Johann De Bono
Contact email
Sponsor organisation
The Royal Marsden NHS Foundation Trust
Eudract number
2013-004091-34
ISRCTN Number
n/a
Research summary
Prostate cancer is the most common male cancer in the UK with more than 11,000 deaths every year. The two most common genetic defects in this disease are androgen receptor (AR) driven rearranged oncogenes and PI3K/AKT pathway activation. Currently in the UK docetaxel followed by abiraterone is the standard of care for patients with advanced prostate cancer (APC). For patients with disease progression after treatment with abiraterone and docetaxel, options are cabazitaxel, participation in clinical trials or supportive care.
About 50% of post-chemotherapy patients with APC will be eligible for RE-AKT; a trial of enzalutamide with the novel AKT inhibitor AZD5363.
Enzalutamide is an anti-androgen with distinct properties that blocks testosterone binding to the AR, impacts AR transport into the nucleus and inhibits binding of the AR to DNA. AZD5363 inhibits the AKT protein which helps cancer cells grow, multiply and spread.. By combining enzalutamide and AZD5363 it is hoped the cancer cells stop growing and the growth and spread of those that do is slowed.
RE-AKT has three parts;
- Phase I safety-run in phase to determine the dose of AZD5363 to use
- Phase II randomised, double blind trial to measure how effective the combination treatment is
- Single stage phase II expansion cohort where AZD5363 is added to enzaluatmaide at progression to explore whether AZD5363 can reverse resistance to enzalutamide.Enzalutamide and AZD5363 are taken orally and are taken as long as they are helping to prevent the cancer getting worse. Participants will have regular check-ups at the hospital. Participants will be asked to donate blood, urine, tumour, hair, buccal (cheek) swab and saliva samples during the study to see if there are any drug to drug interactions and to see if there is anything that will predict who this combination treatment will work best for.
Lay Summary of Results
RE-AKT
Can a new drug combination (Capivasertib and Enzalutamide) be an effective treatment for metastatic castration resistant prostate cancer?
Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer: results from the RE-AKT trial.We have provided you with this information because several years ago, you kindly took part in a clinical trial called RE-AKT as part of your treatment for prostate cancer. Now the trial has completed, we would like to thank you for taking part and share results.
Who carried out the study?
The RE-AKT trial was funded by AstraZeneca and Astellas, who provided the drugs. The Chief Investigator is Professor Johann de Bono of The Royal Marsden Hospital NHS Foundation Trust and The Institute of Cancer Research. RE-AKT is coordinated by the Clinical Trials and Statistics Unit at The Institute of Cancer Research (ICR-CTSU).What was the aim of the study?
The RE-AKT clinical trial is a study for men who have had treatment for prostate cancer and whose cancer continues to grow. The main aim of the RE-AKT trial was to:
• Find out if a drug called Enzalutamide given in combination with a newer drug called Capivasertib could stop the cancer from progressing;
• know more about the sides effects of having the two drugs together;
• Identify the genetic markers that may make the treatment more effective in some people.Why was the research needed?
Doctors usually treat advanced prostate cancer with hormone therapy and chemotherapy. These can work well for a period of time, but the cancer can start to grow again.
Enzalutamide is a type of hormone therapy that is used for men with advanced prostate cancer who have already had other types of hormone therapy and a type of chemotherapy called docetaxel. Capivasertib is a newer drug which stops signals that cancer cells use to divide and grow. Researchers wanted to see if the combination of the two drugs would help control the growth of the cancer for longer.Who participated in the study and what treatment did they receive?
In the main part of the study, 137 men previously treated with Abiraterone volunteered to take part from 15 hospitals in the UK between July 2016 and September 2019. 100 were well enough to take part. They were randomly allocated to receive either enzalutamide and capiversatib or enzalutamide and a dummy tablet (placebo). Neither patients nor clinicians knew which treatment was given to make the study more robust.
A further 31 patients who had previously been treated with Enzalutamide alone also volunteered to take part from 5 hospitals in the UK between September 2016 and April 2018. 13 patients in this group were all given the drug combination.What happened during the study?
Capivasertib (or placebo) was taken twice a day for 4 days with a 3 day break for a 28-day cycle. 160mg Enzalutamide was taken once a day every day without a break.
The effect of the drugs on the cancer was measured by blood tests as well as by CT scans and bone scans. The research team were looking whether the prostate cancer was stable or it “responded” to treatment.What did the trial show?
In the group of patients who had received enzalutamide before joining the study, only one of the thirteen patients receiving the combination treatment had a cancer that responded . The combination treatment did not seem to be effective in this group and this part of the study was stopped early on the recommendation of the independent committees monitoring the trial.In the main part of the study, for those patients on treatment where response could be measured 12 weeks after start of treatment:
• 9 out of 47 patients (19.1%) were considered to have had a response to treatment in the enzalutamide/capivasertib group vs 9 out of 48 patients (18.8%) enzalutamide/placebo group.
In the main part of the study, the results were also analysed by the presence (or not) of a specific marker (PTEN loss) in the genetic make-up of their tumour. 26 patients had tumours that had the PTEN loss genetic marker, and 62 patients had tumours that did not (the tumours were what is called PTEN normal). Regardless of the treatment received:
• 1 out of 26 (3.8%) patients whose tumour carried the PTEN loss marker experienced a response.
• 17 out of 62 (27.4%) patients whose tumour was PTEN normal experienced a response.Did the treatments have side effects?
- The most common side effects reported for the combination treatment were fatigue (6 out of 10 patients), diarrhoea (7 out of 10 patients) , decreased appetite (4 out of 10 patients) and nausea (4 out of 10 patients)
- Those side effects were generally mild and the symptoms could usually be relieved.What do these results mean?
Although the combination treatment was shown to be safe and tolerable, treatment with Enzalutamide and Capivasertib did not perform better than enzalutamide alone for patients with advanced prostate cancer. The trial however did confirm that the PTEN loss biomarker was helpful in predicting patients whose prognosis was worse and whose tumour did not respond well to the treatment. This will lead to targeted further research into this specific patient group to understand the reasons for this and identify effective treatments.What does this mean for you?
You may now wish to know which treatment you received. If so, then please contact your research nurse or hospital doctor.If you have any additional questions about the results from the RE-AKT trial, please discuss this information sheet with your local cancer doctor or a member of their team who will be happy to help you.
Whichever treatment you received, your involvement with the RE-AKT trial has helped to increase the knowledge on prostate cancer and treatments, and we would like to thank you sincerely for taking part and sharing your data with us.Where can you learn more about this study?
For further information, please visit the RE-AKT trial page on the Institute of Cancer Research Clinical Trials and Statistics Unit’s website: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fwww.icr.ac.uk%252Four-research%252Fcentres-and-collaborations%252Fcentres-at-the-icr%252Fclinical-trials-and-statistics-unit%252Four-research%252Fclinical-trials%252Fre-akt%2FNBTI%2FTRC-AQ%2FAQ%2F57dc473c-a2b8-4a14-af24-a7a97cd0d601%2F2%2FeRxK9xuG6z&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7Cfaa874e22ce24415958108ddd0d7ab67%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638896346919321609%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=4vzc8T%2Bj0FYphg3UeONg5nkt7UrgG3oLyFePEGNvs1E%3D&reserved=0Would you like to help influence cancer research in the future?
We are recruiting trial participants to become patient advocates to help us to develop and deliver our research. You can find out more about our work at the Institute of Cancer Research Clinical Trials and Statistics Unit on our website: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fwww.icr.ac.uk%252Four-research%252Fcentres-and-collaborations%252Fcentres-at-the-icr%252Fclinical-trials-and-statistics-unit%2FNBTI%2FTRC-AQ%2FAQ%2F57dc473c-a2b8-4a14-af24-a7a97cd0d601%2F3%2FeKJeJqrMVm&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7Cfaa874e22ce24415958108ddd0d7ab67%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638896346919337059%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=uydcIu2eu0wkEauMr0eCMhBHr2mxO3%2FYMfpZ7NoCK3s%3D&reserved=0If you would like to help us, then please contact us via email on ppi-icrctsu@icr.ac.uk and we will send you further details.
Has the registry been updated to include summary results?: Yes
If yes - please enter the URL to summary results: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fwww.clinicaltrialsregister.eu%252Fctr-search%252Ftrial%252F2013-004091-34%252Fresults%2FNBTI%2FTRC-AQ%2FAQ%2F57dc473c-a2b8-4a14-af24-a7a97cd0d601%2F4%2FpUXiJ6xS3I&data=05%7C02%7Csurreyborders.rec%40hra.nhs.uk%7Cfaa874e22ce24415958108ddd0d7ab67%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638896346919351561%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=Kn1N8BvihSUbi2E2i81HdUAKYBa2WCil7zdaug3KB2M%3D&reserved=0
If no – why not?:
Did you follow your dissemination plan submitted in the IRAS application form (Q A51)?: Yes
If yes, describe or provide URLs to disseminated materials: Yes. Results for the phase I of the study have been presented at GU ASCO in 2017, and subsequently published in Annals of Oncology (Kolinsky, MP et al. "A phase I dose-escalation study of enzalutamidein combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer." Annals of oncology: official journal of the European Society for MedicalOncology vol. 31,5 (2020): 619-625. doi:10.1016/j.annonc.2020.01.074). Results for the phase 2studies have been presented internally to the investigators, and a manuscript submitted for publication, currently under review.
If pending, date when dissemination is expected:
If no, explain why you didn't follow it:
Have participants been informed of the results of the study?: Yes
If yes, describe and/or provide URLs to materials shared and how they were shared: A lay summary of the results of the phase I of the study has been disseminated to the participants via the participating site clinicians. A similar lay summary has been drafted and will be sent to the participating sites on publication of results.
If pending, date when feedback is expected:
If no, explain why they haven't:
Have you enabled sharing of study data with others?: Yes
If yes, describe or provide URLs to how it has been shared: Please see the description in the question below.
If no, explain why sharing hasn't been enabled:
Have you enabled sharing of tissue samples and associated data with others?: Yes
If yes, describe or provide a URL: The ICR-CTSU supports the wider dissemination of information from its research and increased cooperation between investigators. Formal requests for data sharing are considered in line with ICR-CTSU procedures with due regard given to funder and sponsor guidelines. Requests are via a standard proforma describing the nature of the proposed research and extent of data requirements. Data recipients are required to enter a formal data sharing agreement that describes the conditions for release and requirements for data transfer, storage, archiving, publication, and intellectual property .Requests are reviewed by the Trial Management Group (TMG) in terms of scientific merit and ethical considerations including patient consent. Data sharing is undertaken if proposed projects have a sound scientific or patient benefit rationale as agreed by the TMG and approved by the Independent Data Monitoring and Steering Committee as required. Restrictions relating to patient confidentiality and consent will be limited by aggregating and anonymising identifiable patient data. Additionally, all indirect identifiers that could lead to deductive disclosures will be removed in line with Cancer Research UK Data Sharing Guidelines.
If no, explain why:
Captcha: 03AFcWeA73A2Ll-iSBuNM9JXM96iFLs95zll1oIj8SqxRx9BVDHriY1unVKzGh8-PNIXFlf8MMBeERJr2igaPJrAov8ZVvYYnnSSW61SsPssyR66lTCSIkq6Rxxlqmec3G3UrpvbozBzsI0b6oBE0vC27uo6zXsSuoGYISyBCKiUFQhhjulkKH6q8EGYkKiZTLa27UKgxWrbW9nRgHYJywas5uEjHqYK_rWC_UnEvZZk1hAKl_n3yp-Fr09lrhIl_PDdY9LJWtCNF386JejVbi7kwZTocAVescZykC83dDyjERjWh7PgioqqZA9z7dFaR6vacIpvosZjILpLTbVxyNG89KzLSFOkYdyfEBuMECQtJJF8BxRYilKunDnA_UrD7SMhLWbhVyE3KhE8j3234Xa9ZImqNx3TFXQdHx_HzblJuFmKbpcyNZBV4xEoLLLEqAxRf5wDjQ9apUFuQg-lavmQGCkfSgRmrt14zpd49Qv6rYBoMXmDv-HXRErvyAnl4HZgE0KqlUZWslbFNbxEhWCA2sLmuIG8vjcoD-WUT_X4dqzWxFRjg8gikNvDP7E9uobPd2Vj051y4oyRbMQc3ns6UpNg0KsxKCNlv5mf3GG0WDEx8Y7oWQCfJzKL6tPAJnXBFFuGaG_dQoQkTGzzAVrpVS5mLhrV7aC-2iJc8UtxrsapHYzGT0ijMRG1HDbmPo0F8yINEMohep9z9C5QrMK1v5ozPfbBa3ADbtXftExlLzjTYX2vpg2p0ozZdXLm1UE4L7Q41ljBFJtU86FzHJLA4Q-vgy_Rj8FRbakqAR-EpMJYV7II5_HODgBDbbK-NYYtUezPTr_t3v0pNV2Mg-qQRi4i4dHLLb3F-e8Nzgou9A486qAsHXtU2srAxyR8n94-WSsfkpSgQ4v_AEwePf484KStiBTHrQX_zSxAxpUw8onH_90R8G1X4REC name
London - Surrey Borders Research Ethics Committee
REC reference
14/LO/0259
Date of REC Opinion
19 Mar 2014
REC opinion
Favourable Opinion