Why has Xtandi (enzalutamide) stopped working and what do I take next?

Xtandi (enzalutamide) is a hormone therapy used to treat advanced prostate cancer. It doesn't cure prostate cancer, but can control it by slowing the progression and spread of the disease - often for several years.

Most prostate cancers will eventually become resistant to hormone therapy and when they do, treatments like Xtandi stop working. If prostate-specific antigen (PSA) levels start rising again during treatment, this may be a sign that the prostate cancer is becoming resistant to treatment.

Why has Xtandi stopped working?

Xtandi is an androgen receptor inhibitor that works by blocking the action of testosterone at the androgen receptor, which is necessary for the initiation, growth and progression of prostate cancer cells.

Cancer cells, like bacteria, can evolve over time and become resistant to treatments, including androgen receptor inhibitors. The cancer cells work to reprogram their environment and develop strategies that enable them to transform and survive.

Studies have shown that in some prostate cancers the tumor suppressor gene protein kinase C lambda/iota is downregulated, which leads to the development of treatment-resistant tumors.

The aggressive neuroendocrine prostate cancer (NEPC) cells also upregulate the synthesis of a non-essential amino acid called serine. They use the mTORC1/ATF4 communication pathway to accelerate the synthesis of serine and this allows tumor cells to grow more rapidly and switch to a more aggressive form of prostate cancer.

Prostate cancer cells can also utilize a protein that regulates the positions of lysosomes, which are involved in cell degradation, to help tumors transform. In addition, prostate cancer cells also make use of epigenetic alterations - modifications to DNA - to become resistant to treatments.

What are the treatment options when Xtandi stops working?

If your doctor thinks Xtandi has stopped working they will advise you to stop taking it.

In about 50 percent of the men whose PSA level starts to rise again while on antiandrogen therapy, stopping treatment will lead to antiandrogen withdrawal syndrome or antiandrogen withdrawal response (AAWR).

An AAWR can cause prostate cancer to stop growing or shrink and typically lasts 6-8 months, but it may last as long as 2 years in some cases.

Treatment options for advanced prostate cancer that is not responding to treatment include:

• Chemotherapy. Chemotherapy is sometimes given alongside hormone therapy, but it is also used when hormone therapy fails. Taxotere (docetaxel) is commonly used in combination with prednisone. If this fails then Jevtana (cabazitaxel) or other agents can be used.
• Immunotherapy. Immunotherapy can be used to stimulate the immune system to fight off prostate cancer. Examples include the cancer vaccine Provenge (sipuleucel-T) and immune checkpoint inhibitors, such as the PD-1 inhibitor called Keytruda (pembrolizumab).
• Targeted therapy. These types of therapies are designed to do less damage to normal cells and specifically target cancer cells instead. The PARP inhibitors Rubraca (rucaparib) and Lynparza (olaparib) are two targeted therapies used for advanced prostate cancer.
• Radiotherapy. External radiotherapy or treatment with radium 223, a radioactive liquid, may also be used to treat advanced prostate cancer. This type of treatment is used to control prostate cancer and relieve the symptoms. It is particularly useful when the cancer has spread to the bones and can help to control pain.