Darolutamide Delays Metastasis in High-risk CRPC Patients, Phase 3 Trial Shows

Adding the androgen receptor inhibitor darolutamide to androgen deprivation therapy (ADT) extends by 22 months the time men with castration-resistant prostate cancer live without metastasis, without increasing the incidence of adverse events, results from a Phase 3 trial show.

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.

Findings from the ARAMIS Phase 3 trial (NCT02200614) were recently presented during the 2019 Genitourinary Cancers Symposium in San Francisco. They were also published in The New England Journal of Medicine in the study “Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer.”

Metastasis is a major cause of complications and death among men with prostate cancer, and investigators have been focusing on the prevention of metastasis in men at risk, which may significantly extend their lives and improve their quality of life.

Currently, two androgen receptor inhibitors — Erleada (apalutamide) and Xtandi (enzalutamide) — are approved to delay metastasis formation in non-metastatic CRPC patients. These treatments, however, seem to induce some toxicity that may affect patients’ quality of life.

“In addition to a benefit in [metastasis-free survival], a favorable safety profile is critical for these largely asymptomatic non-metastatic CRPC patients because treatment decisions can impact their overall well-being, prognosis, compliance with the treatment, as well as other medications that are typical for this patient population,” Karim Fizazi, MD, PhD, professor of medicine at the Institut Gustave Roussy, University of Paris Sud, France, said in a press release.

Darolutamide, jointly developed by Bayer and Orion, is an oral agent that prevents the binding of testosterone to the androgen receptor, blocking signals that prostate cancer cells require to grow and proliferate. The investigational treatment has a distinct structure of other inhibitors of the androgen receptor, potentially being less toxic to patients.

Building on findings from Phase 1 and 2 studies where darolutamide showed significant anti-tumor activity and a good safety profile, researchers designed ARAMIS to determine whether the treatment could safely delay metastasis in CRPC patients at high risk.

ARAMIS included 1,509 patients with non-metastatic CRPC whose prostate-specific antigen (PSA) levels were rapidly rising while receiving androgen deprivation therapy. During the trial, all participants continued to receive hormone therapy and were randomly either assigned oral darolutamide (955 patients) or a placebo (554 patients) twice daily.

Darolutamide treatment extended the time patients lived without the disease spreading by nearly two years — 40.4 months versus 18.4 months — representing a 59% reduction in the risk of disease spread or death.

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.

Other secondary endpoints were also met, with darolutamide treatment delaying the time to pain worsening — from a median of 25.4 months on placebo to 40.3 months — and lowering the risk of needing a chemotherapeutic medication by 57%. The time to first skeletal event — deemed as radiation therapy to the bone, bone fractures, spinal cord compression, or bone surgery — was also longer with darolutamide.

Overall, adverse events of any grade were similar in the two groups. Darolutamide treatment did not increase critical adverse events such as seizures, falls, fractures, cognitive disorder, or high blood pressure. It also did not increase the number of patients discontinuing treatment compared to ADT only.

“These data are exciting for the prostate cancer community; they not only show darolutamide’s significant efficacy in preventing the spread of prostate cancer, but also its favorable tolerability profile that, once approved, may allow patients to continue their day-to-day life without adding any burden,” Fizazi said.

Darolutamide has already received Fast Track designation by the U.S. Food and Drug Administration for the treatment of non-metastatic CRPC patients. Bayer is now planning to discuss ARAMIS’ data with regulatory authorities for approval of the medication.

“Prostate cancer patients are still in need of treatments that are not only effective but also safe without adverse events that would compromise their quality of life,” said Christer Nordstedt, PhD, MD, senior vice president, research and development, for Orion. “With the positive results of [the] ARAMIS trial, we together with Bayer are one step closer [to] bringing darolutamide to patients and their treating physicians.”