Effects of androgen receptor pathway inhibitors (ARPI's) for hormone-sensitive metastatic prostate cancer: pairwise and network meta-analyses of individual participant data

The prostate is a small, walnut-sized gland found only in men. It sits just below the bladder and in front of the rectum, and its main job is to make fluid that helps carry sperm in semen. The prostate gland needs a male hormone called testosterone to work properly and produce sperm. Testosterone is one of a few male hormones that are important for a healthy prostate. These male hormones are also called androgens.

Prostate cancer happens when some cells in the prostate start to multiply in an uncontrolled way, and androgens can increase this. These abnormal cells can form a lump (called a tumour). If not treated, the cancer can spread from the tumour to other parts of the body such as the lymph nodes or bones and when this happens it is called advanced or metastatic prostate cancer.

Prostate cancer is very common and affects millions of men around the world. It is likely that the number of people diagnosed with prostate cancer every year will increase from about one and half million in 2020 to nearly three million by 2040. This also means that the number of people dying from prostate cancer will probably increase from about 400,000 in 2020 to almost 700,000 by 2040 (2). So, we need treatments that help men with advanced cancer to live longer and better. For many years, standard hormone therapy has been used to treat advanced prostate cancer. It is a treatment that stops the testicles from making testosterone or to lower the amount they make. Having less testosterone, can slow down or shrink prostate cancer. But over time, most prostate cancers stop responding to this type of hormone therapy.

Therefore, over the last 10 years, clinical trials have looked at adding other treatments to standard hormone therapy to see if this could help people with advanced prostate cancer live longer. These treatments have included docetaxel chemotherapy, which can slow down or stop the growth and spread of cancer cells. Also, newer hormone therapies (often called androgen receptor pathway inhibitors or ARPIs) have been looked at. These block the activity of androgens involved in stimulating the growth of certain cancers, particularly prostate cancer. Unlike standard hormone therapy, which mainly stops or reduces testosterone production, ARPIs stop androgens from attaching to androgen receptors in the prostate. This helps prevent androgens from making cancer cells grow and multiply. These ARPIs include abiraterone (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), darolutamide (Nubeqa) and orteronel (TAK-700).

Clinical trials have shown that adding docetaxel (3-5) or these ARPIs (6-15) to standard hormone therapy, clearly helps men to live longer. However, we are not sure if adding ARPIs helps all men equally. And we want to know if having all three treatments – an ARPI, docetaxel and hormone therapy is better than having just two of them. But there are no clinical trials comparing three treatments with two treatments. If we can work out which treatments work best for which groups of men, then men can get treatments most suited to them. Plus, they can avoid treatments that do not benefit them and the extra side effects that go with them.

The most reliable way to work out how the different treatments and treatment combinations work for different groups of men is by collecting data on individual participants from all the important clinical trials worldwide and combining them using a method called meta-analysis. When we did a similar meta-analysis recently (16), we showed that docetaxel worked best in men with a bigger amount of metastases (the spread of cancer cells). People who were first diagnosed with localised prostate cancer that then spread and who had just a small amount of metastases, did not benefit from docetaxel. These men don’t need docetaxel chemotherapy and can be given other treatments instead.

The ARASENS trial (13) looked at the effects of adding an ARPI, darolutamide and docetaxel to standard hormone therapy (a "triplet therapy") compared to adding docetaxel to hormone therapy (a "doublet therapy"). The ARANOTE trial (15) looked at the effects of adding darolutamide to standard hormone therapy. The ARCHES (10) and China ARCHES (14) trials looked at the effects of adding the ARPI, enzalutamide, to standard hormone therapy (with or without docetaxel). These two trials will add information about the effects of enzalutamide to the data we have already obtained from the ENZAMET trial (9)

The data from these trials (from ARASENS (13) and ARCHES (10) to begin with) will be very important in helping us to find out which of these doublet and triplet therapies work best and for which groups of men. This will allow patients and doctors to choose the right treatment options to improve men’s health and wellbeing and avoid unnecessary side effects.