Darolutamide Delays the Spread of Prostate Cancer in Men with Non-Metastatic, Hormone-Resistant Disease.

Results from a Phase 3 clinical trial reveal that adding the androgen receptor inhibitor darolutamide to androgen deprivation (hormone) therapy (ADT) extends by 22 months the time men with hormone-resistant prostate cancer live without metastasis and without increasing the incidence of adverse events. The treatment also extended survival, time to pain progression, time until chemotherapy was needed, and kept patients alive and progression-free for longer periods than ADT alone, researchers reported.

The investigational drug darolutamide can help delay the spread of prostate cancer to other parts of the body in men with non-metastatic, hormone-resistant disease, according to results from the ARAMIS clinical trial. In addition, trial results showed that the drug appears to lack some of the side effects seen with similar drugs used to treat men with this form of prostate cancer.

Until recently, there had been no effective treatment options for patients with non-metastatic, hormone-resistant prostate cancer. These men have prostate tumors that continue to grow even after receiving androgen deprivation (hormone) therapy (ADT)  to keep androgen (testosterone) levels in the body extremely low or undetectable. But over the last 2 years, two drugs have been approved by the Food and Drug Administration (FDA) to treat this form of the disease and some researchers expect that, based on the results of this new trial, darolutamide may be next.

The darolutamide findings, from an interim analysis of the ARAMIS clinical trial, were published in the New England Journal of Medicine and presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco on February 14.

The drug has a very favorable safety profile. The incidence of side effects was generally similar between the darolutamide group and the placebo group, noted study coauthor Karim Fizazi, M.D., Ph.D., of the Gustave Roussy Institute, University of Paris, who presented the results in San Francisco. Darolutamide was not associated with a higher incidence of side effects such as seizures, falls, fractures, cognitive changes, or hypertension. The ARAMIS climical trial results “strongly support the use of darolutamide” in patients with non-metastatic, hormone-resistant prostate cancer, said William Dahut, M.D., head of the Prostate Cancer Clinical Research Section of the National Cancer Institute’s (NCI) Center for Cancer Research.

Darolutamide, jointly developed by Bayer and Orion, belongs to a class of oral drugs called androgen (testosterone) receptor inhibitors.  It prevents the binding of testosterone to the androgen receptor on a cell, thus blocking signals that prostate cancer cells require to grow and proliferate. In the body, these agents compete with androgens for binding to the androgen receptor, which reduces the ability of androgens to promote the growth of prostate cancer cells.

In 2018, the Food and Drug Administration (FDA) approved both apalutamide (Erleada) and  enzalutamide (Xtandi) for men with non-metastatic, hormone-resistant prostate cancer. In the clinical trials that led to these approvals, the drugs were shown to improve the median time from random assignment until the tumor spread or the patient died—known as metastasis-free survival—in men with this form of prostate cancer. Treatment with both drugs, however, was associated with side effects related to the central nervous system, including fatigue, falls, and cognitive changes. In both trials, treatment with the respective drugs more than doubled metastasis-free survival compared with men who received a placebo: 40 versus 16 months in the apalutamide trial and 36.6 versus 14.7 months in the enzaluatmide trial.

The ARAMIS trial, which was sponsored by Bayer and Orion Corporation—the co-developers of darolutamide—included men whose prostate-specific antigen (PSA) levels were rising at a rate that has been associated with an increased risk of metastasis and death in previous studies. Metastasis-free survival was the primary endpoint of the trial; secondary endpoints included overall survival and the amount of time until a patient’s pain worsened.

The randomized trial included more than 1,509 men with non-metastatic, hormone-resistant prostate cancer whose PSA levels were rapidly rising while receiving hormone therapy. These men were considered to be at increased risk of having the disease spread to other parts of the body. All participants received ADT plus either darolutamide or a placebo. At a median follow-up of 17.9 months, the median metastasis-free survival was 40.4 months for patients receiving darolutamide plus ADT, compared with 18.4 months for patients receiving placebo plus ADT. The risk of metastasis or death from any cause was reduced by 59%. While more than half of patients were alive at the time of the analysis, the interim analysis pointed toward a 29% reduction in the risk of death for patients taking darolutamide. Also, the treatment extended the time patients lived without disease progression — 36.8 months versus 14.8 months — representing a 62% reduction in the risk of disease worsening or death. The 3-year overall survival rates were 83% in the darolutamide group and 73% in the placebo group, the researchers found. The median overall survival has not yet been reached in the study. The median amount of time until a patient’s pain got worse was longer in the darolutamide group than in the placebo group (40.3 months versus 25.4 months). It lowered the risk of needing a chemotherapeutic medication by 57%. The time to first skeletal event — such as radiation therapy to the bone, bone fractures, spinal cord compression, or bone surgery — was also longer with darolutamide.

Darolutamide has a different chemical structure than apalutamide and enzalutamide whose structures as similar, which the study authors believe may explain why it has fewer side effects. Darolutamide basically does not penetrate the blood-brain barrier, whereas apalutamide and enzalutamide do. The low incidence of central nervous system-related side effects seen in the trial was consistent with its rodent studies. Side effects likely to be related to the drug reaching the central nervous system include fatigue, dizziness, cognitive impairment, and seizures, according to the researchers. There was no detectable difference in the incidence of these side effects between patients treated with darolutamide and those who received a placebo, he added, noting that patients with a history of seizures were not excluded from the trial. In the trial, fatigue was the only side effect that occurred in more than 10% of participants in either group. A low incidence of side effects is particularly important for men who do not have symptoms of the disease, researchers noted. The percentage of participants who stopped taking either the drug or the placebo because of side effects was similar, i.e. about 9%.

In the coming years, researchers and patients hope to learn more about patient preferences for darolutamide, enzalutamide, and apalutamide. For example, an ongoing clinical trial is comparing two of these androgen receptor inhibitors, darolutamide and enzalutamide in men with metastatic hormone-resistant prostate cancer to determine which drug patients prefer based on their responses to a questionnaire. Patients will first take one drug and then the other. In the meantime, darolutamide has already received Fast Track designation by the U.S. Food and Drug Administration for the treatment of non-metastatic, hormone-resistant prostate cancer patients.

The information above appeared in the National Cancer Institute (NCI) e mail periodical, NCI@updates.cancer.gov, dated March 15th, 2019.

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