One story, one cancer, one drug, one team: Prostate cancer and Abiraterone

The story of the prostate cancer drug Abiraterone begins in the 1990s, when scientists affiliated with Cancer Research UK at a London cancer research institute sought ways to stop male hormone production.

Prostate cancer development depends largely on testosterone. One treatment approach therefore blocks testosterone activity. Over time, however, cancer cells stop responding to this hormone therapy and learn to multiply without depending on testosterone.

Researchers began working on an alternative theory: testosterone is produced not only in the testicles and adrenal glands, but also by prostate cancer cells. This explained why cancer continued growing after a period in people undergoing orchiectomy, removal of the testicles. A new target emerged: blocking testosterone synthesis.

Abiraterone research team

Researchers first studied ketoconazole, which inhibits prostate cancer cell growth by blocking CYP17, the enzyme responsible for male hormone production. Subsequent studies found efficacy very low, leading to design of a more effective CYP17 inhibitor.

The molecule designed next, code-named CB7598, blocks CYP17 more sensitively and irreversibly, stopping testosterone production anywhere in the body. It was subsequently named Abiraterone (brand name Zytiga).

The first exciting steps: laboratory studies

The molecule was tested in animal and cancer cell models. Preclinical studies blocked androgen (male hormone) production and showed marked reduction in androgen levels in animal models. These findings suggested potential for assessing the drug’s efficacy in patients.

In 1996, German company Boehringer Ingelheim licensed abiraterone and began phase 1 clinical trials. Phase 1 trials showed it targeted the correct enzyme and lowered male hormone levels.

While laboratory results were successful, concerns grew that blocking CYP17 could cause serious side effects, especially life-threatening adrenal insufficiency. Development stalled as interest in hormonal treatment for prostate cancer declined, mainly because late-stage disease was called “refractory.” This described cancer cells gaining resistance to hormone blockade and continuing to grow independently of androgens. Many scientists and clinicians then believed blocking male hormones would not work in advanced (metastatic = stage 4) disease. These concerns led the license-holding company to abandon abiraterone.

Professor Johann de Bono, who joined Cancer Research UK in 2003, proposed its use in advanced prostate cancer patients.

Professor Johann de Bono;

argued that advanced prostate cancers are not “hormone-resistant” but “castration-resistant” (resistant to surgical removal of organs producing male hormones). He explained that these cells still depend on testosterone, can obtain it anywhere in the body and can even produce it themselves.

It was also shown that “adrenal insufficiency,” a major concern, was unrelated to abiraterone and did not occur when it blocked CYP17. These conclusions led Cancer Research UK to restart clinical trials. However, by inhibiting CYP17 on the path from cholesterol to adrenal androgen synthesis, abiraterone both stops male hormone production and increases mineralocorticoids, hormones causing water and salt retention, edema and hypertension. They also cause potassium loss through the kidneys. This unwanted effect is prevented with low-dose cortisol, using 5 mg prednisone tablets twice daily. Such an important drug therefore cannot be used alone.

In 2004, abiraterone was licensed to Ortho Biotech Oncology Research, securing sufficient trial funding. Phase 1 trials included 21 advanced prostate cancer patients. The drug was safe, with significant tumor shrinkage and reduced PSA. Less than 1 year later, larger phase 1/2 results were published. In a study of 54 patients, 70 percent responded, with substantial benefit and tumor shrinkage over 8 months.

Following these promising developments, American company Johnson&Johnson purchased the license and began phase 3 trials. In 2010, phase 3 trials showed abiraterone patients lived an average of 15.8 months longer.

After this exciting journey, abiraterone received American Food and Drug Administration FDA approval for prostate cancer in 2011. It subsequently entered use in many countries, including ours.

Its discovery story is an excellent example of how a process beginning with basic molecular biology research takes shape with researchers, doctors and industry, developing a drug that now substantially prolongs patients’ lives.

It must be emphasized that modern cancer drugs are designed through carefully controlled processes and coordinated work in medicine, genetics, biochemistry and other sciences. Cancer, involving complex genetic and biological mechanisms, can be treated only through modern medicine’s resources.

Until another science story of the week, we hope to meet again…

Production and signaling pathways of male hormones, androgens