Matthew Smith, MD, Professor of Medicine of Harvard Medical School and Director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center Speaks about the ASCO GU 2021 Abstracts Analysis of the effect of crossover from placebo (PBO) to darolutamide (DARO) on overall survival (OS) benefit in the ARAMIS Trial and Safety of darolutamide (DARO) for nonmetastatic castration-resistant prostate cancer (nmCRPC) from extended follow-up in the phase III ARAMIS trial.
Link To The Abstract 239 –
https://meetinglibrary.asco.org/record/195160/abstract
Link To The Abstract 240 –
https://meetinglibrary.asco.org/record/194935/abstract
Abstract 240 –
Analysis of the effect of a placebo (PBO) crossover on the overall survival (OS) value of darolutamide (DARO) in the ARAMIS experiment.
Context:
DARO is a structurally distinct androgen receptor inhibitor approved for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) on the basis of substantially extended metastatic-free survival relative to PBO (median 40.4 vs 18.4 months; hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34"“0.50; P < 0.0001) and a favorable phase III ARAMIS safety profile. The crossover from PBO to DARO for the subsequent open-label treatment process was allowed after unblinding in the primary study. In order to determine the effect of PBO-DARO crossover on OS advantage, sensitivity analyses were performed.
Methodology:
Randomized 2:1 to DARO (n = 955) or PBO (n = 554) for patients (pts) with nmCRPC undergoing androgen deprivation therapy. In addition to OS, secondary endpoints included cycles of development of pain, first cytotoxic chemotherapy, first skeletal symptomatic case, and protection. After about 240 deaths, the OS analysis was scheduled to occur, and secondary endpoints were evaluated in a hierarchical order. In order to compensate for the treatment effect of PBO-DARO crossover, iterative parameter estimation (IPE) and rank-preserving structural failure time (RPSFT) analyses were performed as pre-planned sensitivity analyses. The IPE approach used a survival time parametric model and iteratively calculated a model parameter describing the magnitude of the treatment effect, while the RPSFT study used a grid search and a non-parametric log-rank test. Both the IPE and RPSFT analyses provided a Kaplan-Meier curve for the PBO arm that predicts what would have been observed in the absence of the crossover between PBO and DARO.
Outcomes:
170 pts (30.7 percent of those randomized to PBO) crossed from PBO to DARO after unblinding; the median period of treatment from unblinding to the final data cut-off was 11 months. After 254 deaths (15.5% DARO and 19.1% PBO pts), final analysis of the combined double-blind and open label periods was performed and revealed a statistically significant OS advantage for DARO vs PBO (HR 0.69; 95% CI 0.53"“0.88; P = 0.003). Results from the IPE (HR 0.66; 95 percent CI 0.51-0.84; P < 0.001) and RPSFT (HR 0.68; 95 percent CI 0.51-0.90; P = 0.007) studies were similar to those from the population of intention-to-treat, indicating that the crossover effect of PBO-DARO was minimal. Additional analyses will be provided which account for the impact of the PBO-DARO crossover. In the final study, the safety profile of DARO continued to be favorable and the discontinuation rates remained unchanged from the primary analysis at the end of the double-blind period (8.9 percent with DARO and 8.7 percent with PBO).
Findings:
In males with nmCRPC, early treatment with DARO is associated with a substantial change in OS irrespective of pts crossing from PBO to DARO. At the end of the study, DARO’s safety profile remained favorable. Data on clinical trials: NCT0220061414
Abstract – 239
Safety of darolutamide (DARO) for nonmetastatic castration-resistant prostate cancer (nmCRPC) from extended follow-up in the phase III ARAMIS trial.
Context:
DARO is a structurally distinct inhibitor of the androgen receptor (ARI) licensed for nmCRPC therapy. DARO substantially decreased the risk of death in ARAMIS by 31% (HR = 0.69; 95% CI: 0.53-0.88; p = 0.003) and sustained median survival vs placebo without metastases (PBO; 40.4 months vs 18.4 months; HR = 0.41; 95% CI: 0.34-0.50; p < 0.001). Patient everyday life may be affected by adverse events (AEs) of concern typically associated with ARI treatment, such as exhaustion, falls, fractures, rash, mental disability, and hypertension, as well as interactions between ARIs and simultaneously administered medications. DARO had a favorable safety profile in the final review of the double-blind (DB) duration of the ARAMIS study, showing a ~2 percent difference for most AEs of interest compared to PBO. The only AE with an occurrence of > 10 percent with DARO was fatigue. The incidence of permanent discontinuation due to AEs between DARO and PBO was also similar (8.9 percent vs 8.7 percent ). Here we present safety data from the final review of the DB+ open-label (OL) cycle of ARAMIS for extended treatment with DARO.
Here we present safety data from the final review of the DB+ open-label (OL) cycle of ARAMIS for extended treatment with DARO.
Methodology:
During the continuation of androgen deprivation therapy, patients (pts) with nmCRPC (N = 1509) were randomized 2:1 to DARO or matched PBO. The data cut-off for the DB period’s primary review was September 3, 2018. Research unblinding occurred on November 30, 2018, during which OL DARO continued with pts in the DARO arm still undergoing study treatment. The data cut-off for the final DB+OL time review was November 15, 2019.
Outcomes:
The median treatment duration for randomized DARO pts was 18.5 months for the DB period and 25.8 months for the DB+OL period at the conclusion of the final study. 48.8 percent of patients in the DARO DB+OL group were already seeking DARO treatment at the final cut-off date. There was a slight rise in the occurrence of all-grade AEs (85.7% vs 89.8%) and severe AEs (26.1% vs 32.1%) between the DB and DB+OL eras. Only small numerical changes in ARI-associated AEs were observed between the DB and DB+OL periods. There were minor variations between the DB and DB+OL periods when the incidences were corrected for exposure, e.g., the fracture rate was 3.4 vs 4.0 per 100 patient-years for the DB vs DB+OL periods, respectively. The only ARI-associated AE of concern showing an incidence of > 10% in the DARO arm during the DB+OL era was fatigue. The incidence of permanent DARO discontinuation due to AEs increased marginally from 8.9% during the DB period to 10.5% during the DB+OL period; the incidence of PBO discontinuation due to AEs was 8.7% during the DB period.
Findings:
DARO has been well-tolerated with longer exposure to medication. There were no new safety signals observed in the DB+OL era. The predicted increases in the incidence of AEs between the DB and DB+OL cycles, when adjusted for longer exposure, largely disappeared, confirming the favorable safety profile of DARO with extended treatment. Data on clinical trials: NCT0220061414