Enzalutamide for Nonmetastatic but Hormone-Resistant Prostate Cancer

The United States Food and Drug Administration FDA, on 13 July 2018, approved, for prostate cancer resistant to hormone suppression but not yet metastatic, enzalutamide(brand name Xtandi).

In prostate cancer, at diagnosis, the rate of metastasis is only %4, so most patients are diagnosed early. Male hormones enable normal prostate tissue growth, and similarly stimulate prostate cancer cell growth, including testosterone. Early-stage patients benefit considerably from male hormone suppression treatment (called castration in oncology), but within an average of 1 year, resistance to hormonal therapy develops.

Hormone suppression resistance has different mechanisms in prostate cancer, with the main ones being:

• Male hormones such as testosterone and dehydroepiandrosterone (DHEA) bind to androgen receptors, which acquire the ability to function independently of hormonal stimulation,
• The tumor itself begins producing testosterone and other male hormones,
• Increased androgen receptor gene activity greatly increases receptor numbers in cells, making prostate cancer cells sensitive even to very small hormone amounts.

One drug developed to suppress this hormonal pathway more effectively is enzalutamide (Xtandi capsules).

Because earlier studies showed enzalutamide prolonged survival in prostate cancer, in patients previously given docetaxel chemotherapy for castration-resistant metastatic prostate cancer, in 2012 it received FDA approval, and it has been used in our country since 2017.

These developments led to investigation of whether enzalutamide would benefit earlier-stage prostate cancer before metastasis. The PROSPER clinical trialconducted for this purpose published results in NEJM on 28 June 2018.

Details of the PROSPER Study

In nonmetastatic prostate cancer resistant to hormone suppression (castration), rapidly rising PSA is one indicator of high metastatic risk. Researchers hypothesized that enzalutamide, effective in advanced disease, would delay rapidly rising PSA in nonmetastatic but hormone-resistant prostate cancer.

Patients whose PSA doubled within 10 months or less during ongoing hormone suppression were enrolled, with 2-fold PSA increases in 1401 prostate cancer patients. They were randomized at a 2-to-1 ratio into two arms. The treatment arm received enzalutamide 1 time daily at 160 mg, and controls received placebo . The primary endpoint was metastasis-free survival (metastasis-free survivalwas defined as the time from treatment initiation until radiological evidence of disease worsening or death).

Study results

• The 1401 patients had a median PSA doubling time of 3.7 months
• As of 28 June 2017, in the enzalutamide group of 933 patients, 219 (% 23) had metastasis or died; in the placebo group of 468 patients, 228 (% 49) had metastasis or died. 
• Median metastasis-free survival was 36.6 months with enzalutamide and 14.7 months with placebo
• Enzalutamide reduced the risk of metastasis or death by %71.
• Time to first use of subsequent cancer treatment was longer with enzalutamide than placebo (39.6 versus 17.7 months; %15 versus %48 of patients).
• Time to PSA progression (worsening) was 37.2 versus 3.9 months; enzalutamide therefore reduced PSA progression risk by %93.
• Although insufficient time had passed to calculate overall survival, interim analysis showed death in %11 receiving enzalutamide versus %13 receiving placebo. 
• Grade 3 or more severe side effectsoccurred in %23 receiving placebo and %31 receiving enzalutamide.

Conclusion / comment

In nonmetastatic, hormone suppression-resistant prostate cancer with rapidly rising PSA, enzalutamide produced a %71 lower risk of metastasis or death than placebo, a highly clinically meaningful result. Side effects were consistent with earlier enzalutamide studies.

Previously, in February 2018, another new-generation prostate cancer hormone suppression treatment, abiraterone, received FDA approval for nonmetastatic but “hormone-sensitive” prostate cancer, an earlier stage. Enzalutamide shows effectiveness at a different point: “hormone-resistant” but not yet metastatic disease. Examining both drugs’ mechanisms of action and resistance helps explain this difference.

A welcome development in recent years is testing cancer drugs developed over decades of intensive work through new clinical trial designs that aim to find their most appropriate place. Efforts to mask drug results and side effects and prove effectiveness in every cancer subgroup or stage have decreased. This has accelerated the translation of new drugs into clinical practice.

In conclusion, a new treatment option has emerged for nonmetastatic prostate cancer patients at high metastatic risk because they have become castration-resistant. We will follow and share whether enzalutamide receives FDA and domestic approval for this purpose.

Related Topic:

- Advances in prostate cancer treatment – 2017 and 2018