In ARAMIS Trial, Crossover Has Minimal Impact on Darolutamide OS Benefit

In patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), crossover from the placebo arm to the darolutamide (Nubeqa) treatment arm appeared have minimal impact on the overall survival (OS) benefit observed with the androgen receptor inhibitor in the pivotal phase 3 ARAMIS trial, according to findings from an analysis of the trial shared during the 2021 Genitourinary Cancers Symposium.¹

Darolutamide was approved by the FDA for the treatment of nmCRPC in July of 2019 based on findings from the ARAMIS trial (NCT02200614).

Presenting the findings at the virtual meeting, Neal D. Shore, MD, explained that in September 2018, the primary analysis of the ARAMIS trial found that darolutamide was associated with a statistically significant improvement in metastasis-free survival (MFS; the study’s primary end point) with a median MFS of 40.4 months versus 18.4 months with placebo (HR, 0.41; P < .001).² The study was unblinded at the primary analysis, and 170 of 554 patients in the placebo arm went on to receive treatment with darolutamide.

The investigators performed 4 sensitivity analyses. Two of the analyses, rank-preserving structural failure time (RPSFT) and iterative parameter estimation (IPE), mimicked the Kaplan-Meier curve that would have been observed if the placebo-to-darolutamide switch had not occurred, according to Shore. The other analyses consisted of censoring at crossover and inverse probability of censoring weighting (IPCW).

“RPSFT and IPE are considered more reliable than the 2 censoring methods, which ignore survival duration after crossover and, in the case of IPCW, depend on the selection of baseline characteristics for inclusion in the model,” said Shore, medical director at Carolina Urologic Research Center in Myrtle Beach, South Carolina.

At the final analysis for both the double-blind and open-label periods, darolutamide was found to have significantly improved OS compared with placebo (HR, 0.69; 95% CI: 053-0.88, P = .003).³ Regarding the sensitivity analyses, Shore said they “showed the crossover likely had only a small dilutive effect on the OS results.”

Additionally, the safety profile of the treatment remained favorable at the final analysis, with no unexpected findings in the crossover group. Rates of adverse events were lower in the crossover group due to that group’s shorter exposure to darolutamide, Shore said.

Shore noted, “The interpretation of the sensitivity analyses is limited by the short duration of darolutamide treatment in the crossover group and by the potential bias in patient selection, as not all patients in the placebo arm received darolutamide on unblinding.

“However, the consistency of findings between the final overall survival analysis and the sensitivity analyses indicates that crossover from placebo to darolutamide has minimal impact on the overall survival benefit of darolutamide over placebo. These findings indicate that darolutamide is an effective and well-tolerated androgen receptor inhibitor as an early treatment option for patients with nonmetastatic castration-resistant prostate cancer,” Shore concluded.

_References

_{1. Shore ND, Fizazi K, Tammela T, et al. Analysis of the effect of crossover from placebo (PBO) to darolutamide (DARO) on overall survival (OS) benefit in the ARAMIS Trial. J Clin Oncol 39, 2021 (suppl 6; abstr 240). doi: 10.1200/JCO.2021.39.6_suppl.240}

_{2. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistance prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671}

_{3. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342}