Results from the Phase III PROSPER trial (NCT02003924) in patients with non-metastatic (M0) Castration-Resistant Prostate Cancer (CRPC) were presented at the 2018 Genitourinary Cancers Symposium in San Francisco.[1]

Prostate cancer is the second most common cancer in men worldwide.[2] More than 164,000 men in the United States are estimated to be newly diagnosed with prostate cancer in 2018.[3] In the European Union, the estimated number of new prostate cancer cases in 2015 was 365,000.[4]

Castration-resistant prostate cancer (CRPC) refers to the subset of men whose prostate cancer progresses despite castration levels of testosterone.[5] Non-metastatic CRPC means there is no clinically detectable evidence of the cancer spreading to other parts of the body (metastases), and there is a rising prostate-specific antigen (PSA) level.[6] Many men with non-metastatic CRPC and a rapidly rising PSA level go on to develop metastatic CRPC.[7]

In patients with non-metastatic CRPC, there is a high unmet need to delay development of metastases and the progression to advanced prostate cancer. There are currently no approved systemic therapies for patients with non-metastatic CRPC in the U.S.

Reducing risk
The study results show that enzalutamide (Xtandi?; Astellas Pharma US), an androgen receptor inhibitor indicated for the treatment of patients with metastatic castration-resistant prostate cancer, plus androgen deprivation therapy (ADT) significantly reduced the risk of developing metastases or death by 71% compared to ADT alone. The median for the primary endpoint, metastasis-free survival (MFS), was 36.6 months for men who received enzalutamide compared to 14.7 months with ADT alone (n=1401; HR=0.29 [95% CI: 0.24-0.35]; p<0.0001). These data will be presented

Photo 1.0: Maha Hussain, M.D., Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Based on the results of the PROSPER-study, marketing applications have been submitted to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

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The FDA and EMA each have a filing review period during which they evaluate whether an application is complete and acceptable for filing. The data are also being submitted to additional regulatory authorities around the world.

The Phase III randomized, double-blind, placebo-controlled, multi-national trial enrolled approximately 1,400 patients with non-metastatic castration-resistant prostate cancer (CRPC) at sites in the United States, Canada, Europe, South America and the Asia-Pacific region.

The PROSPER trial enrolled patients with prostate cancer that had progressed, based on a rising prostate-specific antigen (PSA) level despite androgen deprivation therapy (ADT), but who had no symptoms and no prior or present evidence of metastatic disease. The trial evaluated enzalutamide at a dose of 160 mg taken orally once daily plus ADT, versus placebo plus ADT.

The primary endpoint of the PROSPER trial, metastasis-free survival (MFS), is a measure of the amount of time that passes until a cancer can be radiographically detected as having metastasized, or until death, within 112 days of treatment discontinuation. Secondary endpoints included time to PSA progression, time to first use of antineoplastic therapy and overall survival.

?In patients with non-metastatic CRPC, there is a high unmet need to delay development of metastases and the progression to advanced prostate cancer. There are currently no approved systemic therapies for patients with non-metastatic CRPC in the U.S.,? said Maha Hussain, M.D., Robert H. Lurie Comprehensive Cancer Center of Northwestern University, who will present the data.

?In the PROSPER trial, treatment with enzalutamide plus ADT delayed the development of metastases compared to standard of care ADT alone and, if approved, may provide men with non-metastatic CRPC an important new treatment option,? Hussain added.

Time to prostate-specific antigen progression
The PROSPER trial also investigated time to prostate-specific antigen (PSA) progression, time to first use of new antineoplastic therapy and overall survival (OS) as key secondary endpoints. The analysis demonstrated that patients who received enzalutamide plus ADT had a 93% reduction in relative risk of PSA progression compared to patients who received ADT alone (HR=0.07 [95% CI: 0.05-0.08]; P<0.0001).

Enzalutamide plus ADT delayed the median time to PSA progression by 33.3 months (37.2 months [95% CI: 33.1-NR] versus 3.9 months with ADT alone [95% CI: 3.8-4.0]).

Enzalutamide plus ADT prolonged the median time to first use of new antineoplastic therapy by 21.9 months versus ADT alone (39.6 months [95% CI: 37.7-NR] vs. 17.7 months [95% CI: 16.2-19.7]), a 79 percent relative risk reduction (HR=0.21 [95% CI: 0.17-0.26]; p<0.0001). At the time of the first interim analysis, median OS had not yet been reached in either treatment arm. However, these interim results demonstrated a trend in favor of enzalutamide that was not statistically significant (HR=0.80 [95% CI: 0.58-1.09]; p=0.1519).

Adverse events
Adverse events in the PROSPER trial were generally consistent with those reported in prior enzalutamide clinical trials in patients with metastatic CRPC. Grade 3 or higher adverse events were reported in 31% of men treated with enzalutamide plus ADT and in 23 percent of men treated with ADT alone. The most common (?2%) Grade 3 or higher adverse events that were reported more often in enzalutamide plus ADT-treated patients included hypertension (5% vs. 2%) and fatigue (3% vs. 1%). Major adverse cardiovascular events were reported in 5 percent of patients who received enzalutamide plus ADT and 3% with ADT alone. Three seizures (<1%) were reported with enzalutamide plus ADT patients and none were reported for those who received ADT alone.

The percentage of patients in whom adverse events were the primary reason leading to treatment discontinuation was low in both study arms (9% with enzalutamide plus ADT versus 6% with ADT alone).

In October 2009, Medivation, which is now part of Pfizer, and Astellas entered into a global agreement to jointly develop and commercialize enzalutamide. Today the companies are collaborating on a comprehensive development program that includes studies to develop enzalutamide across the full spectrum of advanced prostate cancer as well as other cancers.

Ongoing studies of enzalutamide in prostate cancer include the ARCHES trial in metastatic hormone-sensitive prostate cancer and the EMBARK trial in non-metastatic hormone-sensitive prostate cancer. [8][9]

Medivation (Pfizer) and Astellas jointly commercialize enzalutamide in the United States and Astellas has responsibility for manufacturing and all additional regulatory filings globally, as well as commercializing enzalutamide outside the United States.

Last Editorial Review: February 8, 2018

Featured Image: Prostate Cancer.?Courtesy: ? 2010 – 2017 Fotolia. Used with permission. Photo 1.0. Maha Hussain, M.D. Courtesy: ? 2010 – 2017 | Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Used with permission.

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