1. Fuerst, Mark L.

Article Content

Early treatment with darolutamide in men with non-metastatic castration-resistant prostate cancer leads to significant improvement in overall survival (OS), with a favorable safety profile, regardless of crossing over from placebo to the drug, according to the final analysis of a Phase III clinical trial.

prostate cancer. pro... - Click to enlarge in new windowprostate cancer. prostate cancer

Darolutamide is a structurally distinct androgen receptor inhibitor approved for the treatment of non-metastatic castration-resistant prostate cancer on the basis of primary results from the double-blind, Phase III ARAMIS trial. Those results showed significantly prolonged metastasis-free survival compared with placebo (median 40.4 vs. 18.4 months) and a favorable safety profile.


Following unblinding at the primary analysis, crossover from placebo to darolutamide was permitted for the subsequent open-label treatment phase. At the 2021 ASCO Genitourinary Cancers Symposium (Abstract 240), Neal D. Shore, MD, FACS, Director of CPI at the Carolina Urologic Research Center in Myrtle Beach, SC, presented the results of sensitivity analyses that were performed to assess the effect of crossover from placebo to darolutamide on OS benefit.


"At the ARAMIS final analysis, darolutamide was associated with significant improvement in OS versus placebo. Sensitivity analyses consistently demonstrated that crossover from placebo to darolutamide (31%, 170 of 154 patients) had only a small impact on the estimated OS benefit," said Shore.

Neal D. Shore, MD, F... - Click to enlarge in new windowNeal D. Shore, MD, FACS. Neal D. Shore, MD, FACS

In the ARAMIS trial, a total of 1,509 patients with non-metastatic castration-resistant prostate cancer receiving androgen deprivation therapy were randomized to darolutamide (955 patients) or placebo (554 patients). In addition to OS, secondary endpoints included times to pain progression, first cytotoxic chemotherapy, first symptomatic skeletal event, and safety. The OS analysis was planned to occur after approximately 240 deaths, and secondary endpoints were evaluated in a hierarchical order.


Iterative parameter estimation (IPE) and rank-preserving structural failure time (RPSFT) analyses were performed as pre-planned sensitivity analyses to adjust for the treatment effect of placebo to darolutamide crossover. The IPE method used a parametric model for the survival times and iteratively determined the model parameter describing the magnitude of the treatment effect, whereas a grid search and non-parametric log-rank test were used for the RPSFT analysis.


"The IPE and RPSFT analyses both generated a Kaplan-Meier curve for the placebo arm that predicts what would have been observed in the absence of placebo-darolutamide crossover," said Shore.


After unblinding, 170 patients (just less than one-third of those randomized to placebo) crossed over to darolutamide. Median treatment duration from unblinding to the final data cut-off was 11 months. Final analysis of the combined double-blind and open-label periods was conducted after 254 deaths, 15.5 percent of darolutamide and 19.1 percent of placebo patients.


The safety profile of darolutamide continued to be favorable at the final analysis, and discontinuation rates at the end of the double-blind period remained unchanged from the primary analysis (8.9% with darolutamide and 8.7% with placebo). Treatment-related adverse event rates were similar in both arms (85.7% darolutamide, 79.2% placebo).


In conclusion, Shore said: "These findings indicate that darolutamide is an effective, well-tolerated androgen receptor inhibitor as an early treatment option for non-metastatic castration-resistant prostate cancer."


Safety With Extended Follow-Up

Adverse events commonly associated with androgen receptor inhibitor therapy, including fatigue, falls, fractures, rash, mental impairment, and hypertension, can impact a patient's daily life. In the final analysis of the ARAMIS trial, darolutamide had a favorable safety profile, and the difference in the incidence of most adverse events of interest was 2 percent less between darolutamide and placebo groups. Fatigue was the only adverse event with more than 10 percent incidence with darolutamide. The incidence of permanent discontinuation due to adverse events remained low and was similar between darolutamide and placebo (8.9 % vs. 8.7%).


At the meeting, Matthew R. Smith, MD, PhD, Director of the Genitourinary Oncology Program at Massachusetts General Hospital Cancer Center, presented safety data for prolonged treatment with darolutamide from the final analysis of the double-blind plus open-label period of the ARAMIS trial (Abstract 239).


Research showed the median treatment duration for patients randomized to darolutamide was extended from 18.5 months for the double-blind period to 25.8 months for the open-label period. About half (48.8%) of patients in the darolutamide open-label group were still receiving drug treatment.

Matthew R. Smith, MD... - Click to enlarge in new windowMatthew R. Smith, MD, PhD. Matthew R. Smith, MD, PhD

"The increase in the incidence of any-grade adverse events (85.7% vs. 89.8%) and serious adverse events (26.1% vs. 32.1%) between the double-blind and open-label period was small," said Smith. Fatigue was the only androgen receptor inhibitor-associated adverse event of interest that exhibited more than 10 percent incidence in the darolutamide arm during the open-label period.


The incidence of permanent discontinuation due to adverse events increased slightly from 8.9 percent during the double-blind period to 10.5 percent during the open-label period. In comparison, the incidence of discontinuation of placebo due to adverse events during the double-blind period was 8.7 percent, he noted.


Smith concluded: "With longer treatment exposure, darolutamide remained well-tolerated. No new safety signals were observed in the open-label period. For adverse events of interest, the expected increases in incidence between the double-blind and open-label periods largely disappeared when adjusted for the longer exposure. These results confirm the favorable safety profile of darolutamide with prolonged treatment."


Mark L. Fuerst is a contributing writer.