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Protocol # 22-386




Researchers are looking for a better way to treat men who have biochemically recurrent hormone-naïve prostate cancer. Hormone-naïve prostate cancer is a prostate cancer that has not yet been treated with hormonal therapy including androgen deprivation therapy (ADT). Biochemically recurrence (BCR) means that patients who received local treatment (surgery or radiation therapy) for prostate cancer now present with a rise in the blood level of a specific protein called PSA (prostate-specific antigen) but no detectable cancer or cancer spreading after a treatment that aimed to cure their prostate cancer (e.g. surgery and radiation). This may mean that the cancer has come back as the PSA level can be taken as a marker for prostate cancer development. Although men with BCR may not have symptoms for many years, proper treatment for BCR is important as the cancer may spread to other parts of the body in 7-8 years. In prostate cancer patients, male sex hormones like testosterone (also called androgens) can sometimes help the cancer spread and grow. To reduce androgen levels in these patients, androgen deprivation therapy (ADT) is often used. Second generation androgen receptor inhibitors including Darolutamide and Enzalutamide are available for the treatment of prostate cancer in addition to ADT. These inhibitors work by blocking androgen receptors and preventing it from attaching to proteins in cancer cells in the prostate. It is already known that men with prostate cancer benefit from these treatments. But besides benefits, Darolutamide and Enzalutamide are not without side effects. Clinical studies have shown that treatment with Enzalutamide increase testosterone level in serum, probably because it can pass blood brain barrier and goes into the central nervous system (CNS). The increased testosterone levels are thought to cause some specific side effects including so called feminizing side effects like overdevelopment of the breast tissue in men, and breast tenderness. Darolutamide has a distinct chemical structure and reduced ability to enter the CNS compared with Enzalutamide. That means that Darolutamide potentially leads to fewer and less severe side effects than Enzalutamide. In this study researchers will collect more data to learn to what extent Darolutamide affects serum testosterone levels in men with BCR in hormone-naïve prostate cancer. This study will consist of 2 stages. In stage 1 (also called lead-in phase) all participants will take Darolutamide by mouth twice a day. The study team will monitor and measure testosterone levels in the blood after: - 12 weeks - 24 weeks and - 52 weeks of treatment. The second stage (also called randomized phase) is conditional and depends on the results from the stage 1. It will be conducted if after 24 weeks of treatment with Darolutamide in stage 1: - a mean change in blood testosterone levels is below 45% and - if the feminizing side effects (including overdevelopment of the breast tissue in men, and breast tenderness) will occur less frequently than previously reported. In the second stage of this study all participants will be randomly (by chance) assigned into two treatment groups, taking either Darolutamide twice daily or Enzalutamide once daily by mouth for a minimum of 12 and a maximum of 52 weeks. During both stages of this study the study team will: - do physical examinations - take blood and urine samples - examine heart health using ECG - examine heart and lung health using CPET - check bone density using x-ray scan (DEXA) - check vital signs - check if the participants' cancer has grown and/or spread using CT (computed tomography) or MRI (magnetic resonance imaging) and, if needed, bone scan - ask the participants questions about how they are feeling and what adverse events they are having. An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think the adverse events might be related to the study treatments. The study participants who receive Darolutamide in stage 2 can continue to receive their treatments as long as they benefit from the treatment. The participants from the Enzalutamide group can also switch to treatment with Darolutamide after finishing stage 2. The study team will continue to check the participants' health and collect information about medical problems that might be related to Darolutamide until up to 30 days of last dose for those participants who continue on treatment with Darolutamide.


  • Biochemically Recurrent Prostate Cancer


  • Darolutamide(BAY1841788, Nubeqa)
  • Enzalutamide


Phase 2

Study Type


Further Study Details

Primary Outcome:

  • Lead-in phase: Change in serum testosterone
  • Randomized Phase: Change in serum testosterone

Secondary Outcome:

  • Lead-in phase: Change in serum testosterone
  • Lead-in phase: Serum Prostate-specific antigen (PSA)
  • Lead-in phase: Number of participants with Adverse Event (AE)
  • Randomized Phase: Change in serum testosterone
  • Randomized Phase: Serum PSA
  • Randomized Phase: Number of participants with Adverse Event (AE)
  • Randomized Phase: Quality of life (QoL) assessments
  • Randomized Phase: Changes in the blood levels of dihydrotestosterone (DHT)
  • Randomized Phase: Changes in the blood levels of dehydroepiandrosterone (DHEA), sex hormone-binding globulin (SHBG), Androstenedione and Prolactin
  • Randomized Phase: Changes in the blood levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
  • Randomized Phase: Changes in the blood levels of Estradiol
  • Randomized Phase: Changes in the blood levels of Total cholesterol, High-density and low-density lipoproteins, Triglycerides and Fasting glucose
  • Randomized Phase: Changes in the blood levels of Haemoglobin A1c
  • Randomized Phase: Changes in the blood levels of Fat body mass and Lean body mass



Study Start Date

December 19, 2022


  • Gender:     Male
  • Minimum age:     18 Years
  • Maximum age:     N/A
  • Healthy volunteers:     No





Official title

A 2-stage, Lead-in and Randomized, Phase 2, Open-label Study of Darolutamide Versus Enzalutamide as Monotherapy on Testosterone Levels Change in Men With Hormone-Naïve Prostate Cancer Identifier



Source: Through our founding membership in the Dana-Farber/Harvard Cancer Center, an NCI-designated Comprehensive Cancer Center, these clinical trials are conducted at the Massachusetts General Hospital Cancer Center and may be available at other partner institutions.