Enzalutamide for the treatment of metastatic castration-resistant prostate cancer, "Beyond the Abstract," by Cora. N. Sternberg and Peter Mulders

BERKELEY, CA (UroToday.com) - The treatment of metastatic castration-resistant prostate cancer (mCRPC) has evolved rapidly with the recent approval of a number of treatments and agents that include docetaxel, sipuleucel-T, abiraterone, cabazitaxel, radium-223, and enzalutamide.

A rationale exists for clinical benefit with androgen receptor (AR) inhibition in hormone resistant prostate cancer cells which have been shown to increase ARs on their membrane surface and are still sensitive to stimulation and growth by androgenic hormones.[1] There is also evidence that prostate cancer cells, themselves, have the capacity to synthesize androgen and stimulate their own growth (autocrine mechanism). Enzalutamide is an oral AR inhibitor that blocks multiple steps in the AR signaling pathway (Figure).[2] The mechanism of action for enzalutamide is threefold: it is a potent, competitive binder of androgens at the level of the AR; it prevents the translocation of the AR from the cytoplasm to the nucleus; and it inhibits AR interaction with DNA, which prevents further transcription of tumor genes.

Figure: Mechanism of action of enzalutamide.
bta sternbergmulder fig1 thumb

The randomized phase III AFFIRM study, which explored the efficacy of enzalutamide in the post-chemotherapy CRPC setting, demonstrated significant improvements in a number of efficacy endpoints, including the primary endpoint of overall survival and secondary endpoints of progression-free survival, and time to prostate-specific antigen progression (see Table).[3] Consistent with these results, further analysis by age group (< 75 years and ≥ 75 years) confirmed that clinical benefit of a similar magnitude in all clinical endpoints was observed in both younger and older patients with enzalutamide.[4]

Table: Summary of Efficacy Endpoints in AFFIRM: Intent to Treat Population and Age Group Cohorts.

 

Enzalutamide

Placebo

Enzalutamide

Placebo

Enzalutamide

Placebo

 

Age

<75 Years

(n=601)

Age

<75 Years

(n=295)

Age

≥75 Years

(n=199)

Age

≥75 Years

(n=104)

ITT Population

(n=896)

ITT Population

(n=896)

OS, months, median (95% CI)

NYR
(17.3–NYR)

13.6
(11.0–15.5)

18.2
(15.4–NYR)

13.3
(9.8–17.6)

18.4
(17.3–NYR)

13.6
(11.3–15.8)

HR (95% CI)
P-Value

0.63 (0.52–0.78); <0.001

0.61 (0.43–0.86); 0.004

0.63 (0.53–0.75); 0.001

rPFS, months

8.3
(8.0–9.0)

2.9
(2.8–3.8)

9.9
(8.2–11.0)

2.8
(2.7–4.2)

8.3
(8.2–9.4)

2.9
(2.8–3.4)

HR (95% CI)
P-Value

0.45 (0.38–0.53); <0.001

0.27 (0.20–0.37); <0.001

0.40 (0.35–0.47); <0.001

Time to PSA progression, months

8.2
(5.7–8.3)

3.1
(2.9–3.7)

8.4
(8.2–11.1)

2.9
(2.8–3.0)

8.3
(5.8–8.3)

3.0
(2.9–3.7)

HR (95% CI)
P-Value

0.29 (0.23–0.36); <0.001

0.14 (0.09–0.21) <0.001

0.25 (0.20–0.30); <0.001

PSA response rate, %†a

51.6%

1.6%

61.3%

1.2%

54.0%

2.0%

P-value

<0.001

<0.001

<0.001


†All outcomes except for PSA response rate have a HR. aA confirmed PSA response reflected a 50% decline from baseline. NYR, not yet reached.

Enzalutamide was well tolerated. Adverse events were similar between the two enzalutamide age groups, with the exception of an increase in patients ≥ 75 years in the rates of all grade peripheral edema (22.1% vs 12.5%), fatigue (39.7% vs 31.6%), and diarrhea (26.6% vs 19.6%). Overall, grade ≥ 3 adverse event rates were low with no major difference in frequency or severity between age groups or treatment arms. Seizures were reported in 5 patients (3 in the < 75 year and 2 in the ≥ 75 years groups) in the enzalutamide arm.

In addition, enzalutamide has shown a survival benefit in chemotherapy-naïve patients. Results from the randomized phase III PREVAIL trial in patients with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic prostate cancer that progressed on androgen deprivation therapy showed significant benefits with a 30% reduction in the risk of death (OS: HR=0.70, 95% CI 0.59–0.83; P< 0.0001) and an 81% reduction in the risk of radiographic progression or death by 81% (rPFS: HR=0.19, 95% CI 0.15–0.23; P< 0.0001).[5] The observed safety profile in PREVAIL was similar to that reported in AFFIRM. Two seizure events were reported in the trial, one in each arm. Enzalutamide was well tolerated over a prolonged treatment period.

Enzalutamide comes with the convenience of oral dosing that can be taken with or without food, and does not require co-administration of corticosteroids. Enzalutamide provided significant and clinically meaningful benefits to older patients and younger patients, with similar safety and tolerability profiles.

References:

  1. Mohler, J.C. (2008) Castration–recurrent prostate cancer is not androgen independent. Adv Exp Med Biol 617: 223-234.
  2. Tran, C., Ouk, S., Clegg, N.J., Chen, Y., Watson, P.A., Arora, V., et al. (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324: 787–790.
  3. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–1197.
  4. Sternberg CN, de Bono JS, Chi KN, et al. Improved outcomes in elderly patients with metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: results from the phase III AFFIRM trial. Ann Oncol. 2014;25(2):429–434.
  5. Beer TM, Armstrong AJ, Sternberg CN, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. J Clin Oncol. 32, 2014 (suppl 4; abstr LBA1^). 

Written by:
Cora. N. Sternberga and Peter Muldersb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

aSan Camillo and Forlanini Hospitals, Rome, Italy.
bRadboud University Medical Centre, Nijmegen, Netherlands.

Improved outcomes in elderly patients with metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial - Abstract

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