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EAU 2018

EAU 2018: Prostate-Specific Antigen Response in Men with Nonmetastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide: Results from PROSPER

Copenhagen, Denmark (UroToday.com)  Androgen deprivation therapy (ADT) is the standard treatment recommended for hormone-sensitive prostate cancer. Since their initial introduction as alternatives to docetaxel for metastatic castrate resistant prostate cancer (mCRPC), abiraterone and enzalutamide have been standard of care, and docetaxel itself was promoted to first-line therapy for metastatic hormone sensitive prostate cancer (MHSPC), especially in the setting of high-volume disease. LATITUDE [1] and STAMPEDE [2], which demonstrated significant survival benefit with the use of abiraterone in conjunction with ADT for MHSPC, have caused abiraterone to be regarded as standard of care in this disease stage as well.

However, patients with non-metastatic CRPC (nmCRPC) had no standard of care therapy. As a result, these patients are often managed expectantly. Unfortunately, most of these men eventually progress to metastatic disease, at varying rates. A recent retrospective series identified that among nmCRPC men, nearly 60% developed metastatic disease during the first 5-years, with most of the metastasis occurring within the first 3 years. [3]

At the EAU 2018 meeting in Copenhagen, Dr. Cora Sternberg presented a poster of a prospective randomized phase 3 double blind, placebo controlled multinational clinical trial (NCT02003924) specifically assessing the treatment of men who were nmCRPC patients.  The PROSPER study, initially presented at GU-ASCO 2018 in San-Francisco, specifically assesses the effect enzalutamide has in these patients. For the purpose of this trial, the following patients were enrolled:

  1. Men with asymptomatic M0 CRPC
  2. With PSA doubling time ≤ 10 months 
  3. PSA ≥ 2 ng/mL at screening with testosterone < 50 ng/dl
The stratification factors included PSA doubling time< 6 months vs. 6-10 months.

All men continued ADT (medical or surgical castration) and were randomized 2:1 to enzalutamide 160 mg with ADT or placebo + ADT (Figure 1). The primary endpoint was metastasis free survival (MFS) (defined as the time from randomization to radiographic progression or death on study). 

The secondary endpoints included:

  1. Time PSA progression
  2. Time to use of new antineoplastic therapy 
  3. Time to PSA progression
  4. PSA response 
  5. Overall survival (OS)
  6. Safety
A total of 1401 men were enrolled and randomized, with 930 men in the enzalutamide arm, and 465 in the placebo arm. Baseline characteristics were well balanced between the treatment arms. PROSPER demonstrated that compared to placebo, enzalutamide significantly reduced (Figure 2):

  1. Risk of MFS (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.24-0.35; P < .0001) 
  2. Time to first use of new antineoplastic therapy (HR 0.21; 95% CI 0.17-0.26; P < .0001) 
  3. Time to PSA progression (HR 0.07; 95% CI 0.05-0.08; P < .0001)

In the first interim analysis of OS there was a trend in favor of enzalutamide (HR 0.80; 95% CI 0.58-1.09; P = .1519).

A significantly greater proportion of men had confirmed PSA responses with enzalutamide compared to placebo with:

  1. ≥ 50% decline (76.3% vs 2.4%; P < .0001) 
  2.  ≥ 90% decline (55.9% vs 0.4%; P < .0001) 
  3. Undetectable levels below the limit of quantification (9.6% vs 0%; P < .0001)
Median duration of treatment was 18.4 months vs 11.1 months for enzalutamide vs placebo. Adverse events (AEs) were higher with enzalutamide vs placebo:

  1. Any grade: 87% vs 77% 
  2. Grade ≥ 3: 31% vs 23% 
  3. Grade > 5: 3.4% vs 0.6%
In total, 9.4% of patients in the enzalutamide arm discontinued treatment due to AEs vs 6% in the placebo arm.

In conclusion, in men with nmCRPC and rapidly rising PSA, treatment with enzalutamide resulted in a clinically meaningful and statistically significant reduction in the risk of developing M1 CRPC, with a 71% relative risk reduction of metastasis or death compared to placebo. There was a significantly greater PSA response with enzalutamide compared to placebo. A significant increase in the median time to PSA progression, and time to use of new antineoplastic drug was noted in the enzalutamide arm. Furthermore, there was a positive trend for OS with enzalutamide. Lastly, AEs were consistent with the established safety profile of enzalutamide, which was generally well tolerated.

Figure 1 – PROSPER study design:

PROSPER1


Figure 2 – PROSPER results  - primary and secondary endpoints:

PROSPER2

PROSPER3


Watch: Changing the Standard of Care in the M0 CRPC Patient: PROSPER - A Conversation with Cora Sternberg
View Results from PROSPER - Poster #604


Presented by: Cora Sternberg, San Camillo and Forlanini Hospitals, Dept. of Medical Oncology, Rome, Italy

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, twitter: @GoldbergHanan at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark

References:

1. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.
2. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-351.
3. Moreira DM, Freedland SJ, et al. Predictors of Time to Metastasis in Castration-resistant Prostate Cancer. Urology. 2016 Oct;96:171-176. doi: 10.1016/j.urology.2016.06.011. Epub 2016 Jun 16.

More Related Content:

 Patient-Reported Outcome Measures in Men with Non-Metastatic Castration-Resistant Prostate Cancer: Baseline Data from the PROSPER Trial
Watch: Meeting an Unmet Need in the Non-Metastatic Castration Resistant Prostate Cancer Patient Population - Maha Hussain
Watch: Discussion on PROSPER: Safety and Efficacy Study of Enzalutamide in Patients with nmCRPC - Thomas Keane
 First Presentation - PROSPER: Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC)
Review of First Presentation: SPARTAN and PROSPER