Second-generation antiandrogens

We learn about new treatment options for advanced prostate cancer: second-generation antiandrogens.

You can listen to this article below, or by using your favourite podcast player at pod.link/oncologybuddies

What is advanced prostate cancer (APC)?

APC is diagnosed when treatments for localised prostate cancer have failed or when men present with symptoms of advanced disease.

Prostate cancer (PC) initially starts to grow in the prostate and in the early stages the cancer is contained there (localised PC).

If the cancer continues to grow and is left untreated, it eventually breaks out of the prostate and begins to invade the surrounding tissues and structures (locally advanced PC).

If left untreated, the cancer may spread to the lymph and blood vessels that surround the prostate. Once the cancer cells enter these vessels they can be transported to other areas of the body, including bone, distant lymph nodes and soft tissue organs, such as the liver and kidneys, where they may settle and grow to form secondary tumours or metastases. This is called metastatic prostate cancer (mPC) and it’s considered to be advanced disease. These tumours are still made up of PC cells. In mPC, the cancer can’t be cured.

Treatments for APC

Men with APC may be at very different stages of the disease and life expectancy, complications from metastases, and symptoms may differ considerably. The objective of treatment is to delay disease progression, improve overall survival and minimise symptoms.

PC cells are dependent on androgens for growth. Androgens are male hormones (testosterone), although they include the various hormones that testosterone is broken down into. Androgens are mainly produced in the testes, but some are produced by the adrenal glands and by PC cells. By reducing the levels of androgens in the body, tumour cells are deprived of fuel and they shrink, and cancer cell growth is slowed. This is called androgen deprivation therapy (ADT) or hormone therapy.

ADT reverses or reduces the complications from metastases. These complications can include fractures, spinal cord compression, obstruction of urine flow from the kidneys to the bladder, and pain.

Castration can be achieved by either surgically removing the testes as this is where most androgens are made, or by using medication to stop the testes from making androgens. The drugs used for this include GnRH agonists and antagonists.

ADT has traditionally been used alone as the initial first-line treatment for mPC. However, it’s only effective for a limited period, as some androgens are made by the adrenal glands and by PC cells. This means that PC cells eventually start growing again and become resistant to ADT.

At this stage, the disease is called castrate resistant prostate cancer (CRPC). In the past, various drugs were added to ADT or other strategies were used to try and delay the onset of CRPC but none of these made a significant difference in terms of improving life expectancy. Some of these drugs were referred to as first-generation antiandrogens.

Second-generation antiandrogens

Abiraterone acetate was the first second-generation antiandrogen. It blocks an enzyme which stops testosterone production in the testes, adrenal glands and cancer cells. It still needs to be taken together with ADT, and is given with low-dose corticosteroids, because it affects certain functions of the adrenal glands. Patients need to be closely monitored for changes to liver function, blood pressure, potassium levels and for fluid retention.

The first of the new androgen receptor pathway inhibitors (ARTA’s) to be launched were enzalutamide, followed by apalutamide and darolutamide.

For PC cells to grow, androgens have to attach themselves to a protein called an androgen receptor inside the PC cell and then move to the nucleus of the cell to produce more cancer cells.

These new second-generation antiandrogens block this pathway, hence their name. The benefits of combining ADT with ARTA’s is that they increase life expectancy and delay the progression to CRPC. For the best outcomes, they should be given when ADT is started.

Because of the improved outcomes of the combination of ADT and the new second-generation ARTA’s, ADT alone is no longer considered standard of care in many developed countries. Recommendations are that they should be combined with one of the second-generation antiandrogens for optimal outcomes. However, due to the cost of these new medications this isn’t always possible within the SA context.

Adapted with permission from Mutambirwa SM. Understanding recurrent and metastatic prostate cancer. Med-Ed. A division of Ronin-do (Pty) Ltd. 2022