Bipolar Androgen Therapy with Darolutamide for Metastatic Castration-Resistant Prostate Cancer—Varying Testosterone Levels as a New Therapeutic Approach

Prostate cancer is one of the most common cancers in men. The growth of tumor cells is typically stimulated by the male sex hormone testosterone. Standard treatment therefore usually consists of hormone deprivation therapy (androgen deprivation therapy) to keep testosterone levels permanently low (at castration levels). This is achieved through surgical castration (removal of the testicles) or with medication. In addition, so-called androgen receptor inhibitors are used. These prevent the testosterone still circulating in the bloodstream from binding to the cancer cells, thereby inhibiting cancer growth. If the tumor continues to grow and spread throughout the body (metastasize) despite these low hormone levels, the condition is referred to as metastatic castration-resistant prostate cancer (mCRPC). In this situation, modern hormone blockers or chemotherapy are often used, but resistance to these medications can develop over time.

A new scientific approach to overcoming this resistance is bipolar androgen therapy (BAT). In this approach, the tumor is alternately exposed to high doses of testosterone and severe hormone deprivation. The theory is that the sudden surge in testosterone can “shock” and kill the cancer cells, which have become accustomed to low hormone levels. In addition, this alternation is intended to restore the remaining cancer cells’ sensitivity to the effects of androgen receptor inhibitors (such as the study drug darolutamide). In Germany, darolutamide is already approved, among other indications, for the treatment of non-metastatic castration-resistant prostate cancer and metastatic hormone-sensitive prostate cancer. The goal of this Phase 2 study is to determine whether this combination of BAT and darolutamide can delay disease progression more effectively than the current standard of care. To this end, patients will be randomly assigned in a 2:1 ratio to two groups. Group 1 (the study arm) will initially receive testosterone once daily in the form of a gel (Testogel®), which is absorbed through the skin. This therapy is administered for 2 cycles of 28 days each, followed by treatment with darolutamide. Depending on the measured prostate-specific antigen (PSA) level, the entire treatment may then be repeated. Group 2 (control arm) receives standard therapy as chosen by the treating physicians (e.g., abiraterone, enzalutamide, docetaxel, or cabazitaxel). The study is open-label, meaning that both patients and physicians know which treatment is being administered. The primary endpoint is progression-free survival—that is, the length of time during which the tumor does not grow further—as well as the patients’ quality of life.

Men aged 18 and older with metastatic castration-resistant prostate cancer whose disease has progressed while on androgen deprivation therapy plus an androgen receptor inhibitor (apalutamide, darolutamide, or enzalutamide) are eligible to participate. Patients should have no or only mild symptoms and no metastases in the internal organs (visceral metastases).