Ultra-low PSA responses are more prevalent with darolutamide plus ADT

Combination treatment with darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) was associated with much lower prostate-specific antigen (PSA) responses compared with ADT alone, according to data from a post hoc analysis of the phase 3 ARANOTE trial (NCT04736199).^1,2

The data were presented at the 2025 American Urological Association Annual Meeting in Las Vegas, Nevada.

Previously reported data from ARANOTE indicated that, “Time to prostate-specific antigen (PSA) progression was longer for patients receiving darolutamide versus placebo (HR 0.31; 95% CI 0.23–0.41), and 3 times as many patients receiving darolutamide achieved undetectable PSA <0.2 ng/mL at any time (62.6%) vs patients on placebo (18.5%).”³ Further, according to a Game Changer presentation at the 40th Annual European Association of Urology Congress, reaching a PSA level of 0.2 ng/mL with darolutamide was found to be correlated with clinical benefit.

Neal D. Shore, MD, FACS

For the study presented at AUA 2025, the investigators, led by, Neal D. Shore, MD, FACS, medical director of the START Center for Cancer Research in Myrtle Beach, South Carolina, reported on post hoc analyses of ultra-low PSA responses (defined as <0.02 ng/mL) as well as their correlation with outcomes both overall and by baseline PSA level from ARANOTE.

In terms of methodology, the investigators explained that serum was collected for testing of PSA levels at screening as well as every 12 weeks. Rates of ultra-low PSA were then evaluated at 24, 36, and 48 weeks and at any time. The proportions of patients who reached an ultra-low PSA level were assessed by baseline PSA group. This was defined as less than first quartile (<Q1: <4.1 ng/mL), between Q1 and median (Q2: 4.1 ng/mL to <21.3 ng/mL), and ≥median (Q3 and Q4: ≥21.3 ng/mL). In addition, “radiological progression-free survival (rPFS), time to metastatic castration-resistant prostate cancer [mCRPC], and time to PSA progression were correlated with PSA responses (<0.02 ng/mL, ≥0.02 to <0.2 ng/mL, and ≥0.2 ng/mL) in patients treated with darolutamide,” the investigators wrote.

The investigators reported that out of the entire ARANOTE population (n = 669), 434 out of 446 patients in the darolutamide group and 218 out of 223 patients in the placebo group had a baseline PSA level of at least 0.02 ng/mL. They also reported that baseline disease characteristics of patients when stratified by baseline PSA subgroups were generally similar, with the exception that fewer patients with a PSA level lower than 4.1 ng/mL had de novo disease compared with groups with a PSA level of at least 4.1 ng/mL.

The investigators reported that ultra-low PSA responses “were associated with prolonged rPFS and delayed progression to mCRPC and PSA progression.” Specifically, patients who received darolutamide and reached an ultra-low PSA response at any time were found to have a lower risk of radiological progression or death vs patients with a PSA level of at least 0.2 ng/mL, with a risk reduction of 91%. Lower risk of radiological progression of death was also seen with patients who had a PSA level between 0.02 ng/mL and 0.2 ng/mL vs patients with a PSA level of at least 0.2 ng/mL, with a risk reduction of 59%.

Additionally, patients who received darolutamide and who attained an ultra-low PSA were found to have a longer time to mCRPC compared with patients with a PSA of at least 0.2 ng/mL, with a risk reduction of 93%. A longer time to mCRPC was also seen in patients who had a PSA level between 0.02 ng/mL and 0.2 ng/ML vs patients with a PSA level of at least 0.2 ng/mL, with a risk reduction of 64%.

Regarding PSA progression, patients who received darolutamide and who attained an ultra-low PSA level were found to have a longer time to PSA progression compared with patients with a PSA level of at least 0.2 ng/mL, with a risk reduction of 98%. Longer time to PSA progression was also observed in patients who had a PSA level between 0.02 ng/mL and 0.2 ng/mL vs patients with a PSA level of at least 0.2 ng/mL, with a risk reduction of 79%.

In terms of PSA response, treatment with darolutamide and ADT was associated with higher rates of PSA levels of less than 0.02 ng/mL vs ADT alone at all time points. In addition, “ultra-low PSA response rates increased with time, regardless of baseline PSA level,” the investigators wrote. In addition, it was reported that less than 2% of patients with a baseline PSA level of at least 4.1 ng/mL who were treated with ADT alone attained a PSA level of less than 0.02 ng/mL at any time, and 30.5% of patients treated with darolutamide plus ADT who had a baseline PSA level of at least 21.3 ng/mL attained PSA levels of less than 0.02 ng/mL at any time.

In terms of safety, the investigators reported, “The safety profile of darolutamide was independent of PSA response, with lower treatment discontinuation rates due to TEAEs [treatment-emergent adverse events] compared with placebo, consistent with the overall population.”

“Regardless of baseline PSA [level], the proportion of patients reaching ultra-low PSA responses of <0.02 ng/mL was higher with darolutamide treatment vs placebo and ultra-low PSA response rates increased with time. Ultra-low PSA responses were associated with improved clinical outcomes for patients treated with darolutamide, prolonging rPFS and delaying times to mCRPC and PSA progression,” the investigators wrote in their conclusion.

In a news release about the data, Christine Roth, Global Head of Product Strategy and Commercialization at Bayer’s Pharmaceuticals Division, said, "At Bayer, we are committed to redefining prostate cancer care and enhancing patient outcomes at various stages of the disease. The growing evidence supporting NUBEQA reinforces its potential to meet the needs of men with prostate cancer. These data add to the meaningful insights from the ARANOTE trial which can be leveraged by physicians to inform clinical decisions, helping them to identify the right treatment options for their patients living with prostate cancer.”²

REFERENCES

1. Shore N, Haresh KP, Vjaters E, et al. Ultra-low prostate-specific antigen response (<0.02 ng/mL) with darolutamide plus androgen-deprivation therapy in ARANOTE correlates with greatly improved clinical outcomes. J Urol. 2025;213(5S):e1359. doi:10.1097/01.JU.0001110200.18879.65.06

2. AUA 2025: New data from post-hoc analyses shared on ultra-low prostate-specific antigen (PSA) response in patients with metastatic hormone-sensitive prostate cancer receiving NUBEQA® (darolutamide) plus androgen deprivation therapy (ADT). News release. Bayer. April 29, 2025. Accessed April 29, 2025. https://www.businesswire.com/news/home/20250428612520/en/AUA-2025-New-Data-from-Post-Hoc-Analyses-Shared-on-Ultra-Low-Prostate-Specific-Antigen-PSA-Response-in-Patients-with-Metastatic-Hormone-Sensitive-Prostate-Cancer-Receiving-NUBEQA-darolutamide-plus-Androgen-Deprivation-Therapy-ADT

3. Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. 2024;42(36):4271-4281. doi:10.1200/JCO-24-01798