Darolutamide Associated With Lower Rates of Treatment Discontinuation and Disease Progression in nmCRPC

Neal Shore, MD, FACS

Treatment with darolutamide (Nubeqa) was associated with lower rates of discontinuation and progression to metastatic disease compared with enzalutamide (Xtandi) and apalutamide (Erleada) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), according to data from the retrospective DEAR study (NCT05362149) presented at the 2023 American Urological Association Annual Meeting.1

Findings showed that at a median follow-up of approximately 2 years for all patients, 30% of patients treated with darolutamide (n = 362) discontinued treatment, vs 41% of those administered enzalutamide (n = 382) and 46% for those given apalutamide (n = 126). The median time to discontinuation for the darolutamide arm was not reached (NR; 95% CI, 35.2 months–not applicable [NA]), compared with NR (95% CI, 27.0-NA) in the enzalutamide arm and 28.7 months (95% CI, 18.5-NA) in the apalutamide arm.

Additionally, the 12-month estimated probability of discontinuation was 17.0% (95% CI, 13.5%-21.3%) for darolutamide, 25.9% (95% CI, 21.8%-30.6%) for enzalutamide, and 34.0% (95% CI, 26.4%-43.1%) for apalutamide. The 24-month estimated probability of discontinuation for darolutamide, enzalutamide, and apalutamide was 32.8% (95% CI, 27.7%-38.5%), 43.2% (95% CI, 38.0%-48.9%), and 45.2% (95% CI, 36.4%-55.2%), respectively.

Furthermore, 18% of patients treated with darolutamide progressed to mCRPC, compared with 28% of patients given enzalutamide and 28% of patients administered apalutamide. The median time to progression was NR (95% CI, NA-NA) in the darolutamide arm vs NR (95% CI, NA-NA) for the enzalutamide arm and NR (95% CI, 30.3-NA) in the apalutamide arm.

The 12-month estimated progression rate was 10.7% (95% CI, 7.9%-14.5%) for darolutamide, compared with 16.9% (95% CI, 13.4%-21.1%) for enzalutamide and 13.4% (95% CI, 8.4%-20.9%) for apalutamide. The 24-month estimated progression rates for darolutamide, enzalutamide, and apalutamide were 17.8% (95% CI, 13.8%-22.7%), 28.3% (95% CI, 23.7%-33.7%), and 30.2% (95% CI, 21.9%-40.8%), respectively.

"I wouldn't make the case that any one of these drugs is less efficacious than the other. They're all very potent AR inhibitors with very similar mechanisms of action, but there are differences that have been described in tolerability,” lead study author Neal Shore, MD, FACS, said in a presentation of the data. Shore is the US chief medical officer of Surgery and Oncology at GenesisCare USA, and the medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

The 3 androgen receptor (AR) inhibitors have all been FDA approved for the treatment of patients with nmCRPC. Darolutamide was approved by the regulatory agency in July 2019, enzalutamide was green lit in July 2018, and apalutamide was approved in February 2018.^2-4

Although the 3 agents are considered standard of care for patients with nmCRPC, limited real-world evidence is available on rates of discontinuation for the 3 agents. The DEAR study aimed to compare the utility and outcomes of patients treated with the 3 AR inhibitors in a real-world setting.¹

"This is looking at the real-world experience, as opposed to a prospective, direct-comparative study. That caveat needs to be stated," Shore said.

Investigators accessed patient electronic medical records from the Precision Point Specialty network of United States oncology practices, and they identified patients treated with 1 of the 3 agents between August 1, 2019, and March 31, 2022. The index date referred to the date of initiation of treatment for nmCRPC.

The study included patients at least 18 years of age at the index date who were diagnosed with nmCRPC prior to any treatment with an AR inhibitor. Patients needed to have a baseline period of at least 6 months and 6 months of follow-up, unless the patient died.

Key exclusion criteria included evidence of metastatic disease before or 30 days after the index date; prior history of cancer, except for non-melanoma skin cancer, in the 5 years prior to the index date; prior treatment with darolutamide, enzalutamide, apalutamide, or abiraterone acetate (Zytiga); initiation of multiple AR inhibitors on the same date; or evidence of inclusion in clinical trials during the study period.

"These were patients primarily who [had] nmCRPC, all consistent with the data that came from [the phase 3] PROSPER [NCT02003924], SPARTAN [NCT01946204] and ARAMIS [NCT02200614] trials,” Shore said.

DEAR’s statistical analysis examined the proportion of patients in each AR inhibitor arm who discontinued treatment and who progressed to mCRPC during the study. Reasons for discontinuation were also analyzed for each cohort. Kaplan-Meier estimates were used for time to discontinuation and time to progression.

Shore and colleagues noted that baseline characteristics were similar across all 3 treatment arms. However, the time from diagnosis of prostate cancer to the index date and time from CRPC diagnosis to index date varied slightly across the 3 cohorts.

Additional data showed that a lower proportion of patients in the darolutamide arm (10%) discontinued treatment due to adverse effects compared with the enzalutamide arm (14%) and the apalutamide arm (15%).

Other reasons for discontinuation included disease progression or death (darolutamide, 8%; enzalutamide, 12%; apalutamide, 13%), a switch to another AR inhibitor (1%; 2%; 3%), cost/reimbursement factors (1%; 1%; 2%), other (5%; 7%; 6%), and unknown (4%; 4%; 7%).

Shore noted that the DEAR study was limited since the descriptive analyses did not adjust for small differences in baseline characteristics between the 3 cohorts. Other limitations included potential selection bias from a lack of randomization and the inability to generalize results to other patient populations. Study authors added that limitations related to the mismeasuring or missing study variables would only affect results to the extent that cohorts were impacted differently.

“[We] now have a real-world, evidence-based retrospective analysis trying to demonstrate what's going on [with these 3 AR inhibitors] in the community. Further studies are indicated to further assess this [in patients with nmCRPC,” Shore concluded.

References

1. Shore ND, Khan N, Constantinovici N, et al. Real-world study on darolutamide, enzalutamide, and apalutamide for nonmetastatic castration-resistant prostate cancer patients using a urology network in the United States (DEAR study). Presented at: 2023 American Urological Association Annual Meeting; April 28-May 1, 2023; Chicago, IL. Abstract MP29-13.
2. FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. News release. FDA. July 30, 2019. Accessed April 29, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide
3. FDA approves enzalutamide for castration-resistant prostate cancer. News release. FDA. July 13, 2018. Accessed April 29, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide
4. FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. News release. FDA. February 14, 2018. Accessed April 29, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-apalutamide