Abiraterone Received FDA Approval in Hormone-Sensitive Metastatic Prostate Cancer

On 7 February 2018, the United States Food and Drug Administration, FDA, approved abiraterone (brand name Zytiga) for high-risk metastatic hormone-sensitive prostate cancer.

What do hormone-sensitive and hormone-resistant mean in prostate cancer?

Male hormones (androgens) stimulate prostate cancer cell growth and proliferation. After this relationship was discovered in the 1940s, hormone-suppressing drugs that prevent cancer cells from encountering androgens (best known as testosterone) or prevent testosterone production became the foundation of treatment. However, cancer cells are not biologically stable; they may change over time and become treatment-resistant. Initially dependent on male hormones, some tumor cells later proliferate independently. This is called castration- or hormone-resistant prostate cancer .

At this stage, options include chemotherapy (docetaxel), enzalutamide, abiraterone, goserelin, Sipuleucel-T (a cancer vaccine) and radium 223. Patients with bone metastases also receive zoledronic acid or denosumab (all except Sipuleucel-T and radium-223 are available in our country). Enzalutamide and abiraterone are next-generation hormonal treatments preventing prostate cancer cells from accessing testosterone.

Male hormones (androgens) have two sources:

1. Testicles
2. Adrenal glands

Older-generation hormonal treatments still in use are:

1. Surgical removal of testicles (orchiectomy = surgical castration)
2. Nonsurgical (medical) castration using abdominal injections monthly or every 3 months, such as LHRH agonists Eligard, Zoladex and Lucrin
3. Antiandrogens preventing androgen hormones from binding to androgen receptors on prostate cancer cell surfaces (Casodex and Eulexin).

Abiraterone and enzalutamide are next-generation hormonal treatments for prostate cancer. Abiraterone suppresses androgen production in the adrenal gland, whereas enzalutamide (Xtandi) binds prostate cancer cell androgen receptors more effectively than older antiandrogens. Their mechanisms are shown below.

Abiraterone inhibits the CYP17 enzyme in the pathway from cholesterol to androgen production in the adrenal gland. While stopping androgen production, it increases mineralocorticoid hormones, causing salt and water retention, edema and hypertension. These hormones also cause potassium loss through the kidneys. This unwanted effect is prevented with low-dose cortisol (a 5 mg prednisone tablet once or twice daily). Abiraterone therefore cannot be used alone.

- A story, a cancer, a drug, a team: The history of prostate cancer and discovery of abiraterone

Hormone-suppressing drugs and other systemic prostate cancer treatments are used in a sequence, a form of stepwise treatment. For some time, however, the question has been "can effective hormonal treatments such as abiraterone and enzalutamide improve outcomes if given before prostate cancer cells become resistant to hormonal therapy"? The FDA’s earlier-stage approval of abiraterone answers this question.

The FDA approved abiraterone in 2011 for metastatic hormone-resistant prostate cancer after chemotherapy. In 2012, the approval expanded, removing the prior-chemotherapy requirement. The current approval is for metastatic hormone-sensitive prostate cancer.

The new approval was based on LATITUDE, involving 1199 patients with high-risk metastatic (stage 4) hormone-sensitive prostate cancer. Patients were divided into two groups: one received daily abiraterone 1000 mg with 5 mg prednisone (cortisone) tablets; the other received placebo tablets. All also received androgen-lowering LHRH agonists or had undergone orchiectomy.

The study defined high-risk factors as Gleason score of 8 or higher, more than three bone metastases or spread to internal organs.

According to the study results:

• Median survival was not yet reached in the abiraterone arm (most patients were still responding); it was 34.7 months with placebo.
• Abiraterone reduced mortality risk by 38% compared with placebo.
• Median time to starting chemotherapy was not yet reached with abiraterone, versus 38.9 months with placebo.

- ASCO 2017 presented LATITUDE, whose details we shared in our article "A new era in prostate cancer treatment begins".

In LATITUDE, at least 5% of patients receiving abiraterone reported common side effects included hypertension, hot flashes, low potassium, increased liver enzymes (ALT and AST), headache, urinary tract infection, upper respiratory tract infection and cough .

For metastatic hormone-sensitive prostate cancer, Zytiga’s recommended dose is 1000 mg daily orally, equivalent to 4 tablets, plus a once-daily 5 mg prednisone tablet. Patients must also receive an LHRH agonist (monthly injections) or have undergone orchiectomy.

Related Topic:

- Prostate Cancer Patients Should Know Their Risk Group Before Starting Treatment