Clinical trials provide hope in the battle against prostate cancer

Background

The battle against cancer has been a war between the medical community and the human body, with over $5.6 billion/year going into research (according to the National Cancer Institute). Recently, a major step towards the complete treatment of prostate cancer has been taken; two of the largest clinical trials of 2019 published their results in the New England Journal of Medicine and presented them at the annual ASCO meeting.

The ENZAMET and TITAN trials tested, respectively, the viability of enzalutamide and apalutamide treatment, in combination with ADT (androgen deprivation therapy) for castration-sensitive prostate cancer treatment (where the cancer is still responsive to hormone suppression therapies).

About the drugs

Enzalutamide (antiandrogen) is a hormone therapy drug used in the treatment of advanced prostate cancer, often sold under the brand name of Xtandi. In advanced prostate cancer, the cancer has metastasised and spread to other parts of the body. The drug is used when the cancer has stopped responding to other hormone therapies. Its efficacy stems from its ability to block the hormone testosterone acting on the cancer cells, preventing them from the cancer from growing, even if it has metastasised.

Enzalutamide is often used when the cancer fails to respond to the chemotherapy drug docetaxel. When the cancer stops responding to docetaxel, the main drugs of choice are enzalutamide or abiraterone, although enzalutamide is often used if the cancer has metastasised to the liver or the lungs.

Apalutamide is a non-steroidal antiandrogen drug used to treat prostate cancer, often sold under the brand name Erleada. Apalutamide is a structural analogue to enzalutamide (similar structurally expect from one segment). Apalutamide is an antiandrogen and binds to androgen receptors, preventing hormones such as testosterone and dihydrotestosterone from binding, thus inhibiting the onset of their effects in the prostate gland and elsewhere. This prevents the growth of prostate cancer cells.

Both drugs, during the trials, were coupled with hormone therapy. Commonly, hormone therapy is distinguished into 2 main methods: 1) inhibiting testosterone production 2) inhibiting testosterone’s effects acting on the prostate cancer cells. The testes are the primary source of testosterone production but some testosterone is produced by the adrenal glands as well. Testosterone can cause cancer cells to grow faster and hence it is necessary to inhibit its production or its effects. Hormone therapy aims to control the cancer rather than cure through it through the aforementioned philosophy of inhibition, although the therapy can be lifelong if the cancer is advanced.

Hormone therapy comes in 3 main forms: injections/ implants (ADT), tablets or orchidectomy surgery. During the trials, ADT was used alongside the drugs.

The results

Enzalutamide and apalutamide blocked the androgen receptor on cancer cells, reducing the prostate cancer growth. Men who received ADT and enzalutamide had a 33% reduced death risk compared to other antiandrogen drugs (standard treatment). The ENZAMET trial also measured the PFS (time until “the return of disease-related symptoms, the detection of new metastases on imaging scans, or the invitation of another cancer treatment for prostate cancer); during a 3 year period, the enzalutamide group had 63% alive with no clinical profession compared to 33% in the standard treatment group.

The TITAN trial involved a similar method, testing the efficacy of ADT/placebo against ADT/apalutamide on more than 1000 men. After 2 years, ADT/apalutamide group had a 33% reduced risk of death. The TITAN trial measured the radiographic PFS and a 2-year follow up showed that the ADT/apalutamide had a 50% improvement in radiographic PFS vis-à-vis the ADT/placebo group.

The impact

Current methods, such as docetaxel, work by killing the cancer cells; this means, however, that some cannot tolerate the damage to healthy cells in the vicinity. The newly tested drugs prevent androgen signalling instead, thereby treating cancer and preventing collateral damage to other cells. The success of both enzalutamide and apalutamide indicate a possible future provision of more effective drugs that are available to the wider population.

However, there are drawbacks. The ADT/enzalutamide test still had 80% survival rate – although this is an improvement to the 72%of the other test group, this is still quite far off from the complete treatment of prostate cancer. Likewise, the ADT/apalutamide had an 82% survival rate (compared to 74% ADT/placebo), which once again is significantly shy of 100%.

Nonetheless, these trials are paving the way for the future development of more effective treatments in the future and for the time being still provide an improvement in survival rate. Whilst FDA already approves enzalutamide and apalutamide, according to the National Cancer Institute, these “approvals are expected to based on these new data”.

Arnav Sharma