Ultra-Low PSA Response With Darolutamide/ADT Correlates With Better Outcomes in mHSPC

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Ultra-low prostate-specific antigen (PSA) responses were linked with improved clinical outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC) who received darolutamide (Nubeqa) plus androgen deprivation therapy (ADT), according to data from post hoc analyses of the phase 3 ARANOTE study (NCT04736199) presented during the 2025 AUA Annual Meeting.1

Those with ultra-low PSA under .02 ng/mL at any time were found to have lower risk of radiological progression or death vs those with a PSA of 0.2 ng/mL (HR, 0.09; 95% CI, 0.05-0.16); these patients experienced a 91% risk reduction. The same was true for patients who received darolutamide and reached PSA between 0.02 and 0.2 ng/mL vs those with a PSA of 0.2 ng/mL or higher, with a 59% risk reduction (HR, 0.41; 95% CI, 0.27-0.63).

The radiological progression-free survival (rPFS) in those with a PSA below .02 ng/mL was not reached (NR-NR). In those with a PSA of .02 ng/mL but under 0.2 ng/mL, the rPFS was also NR (27-NR), and in those with a PSA of 0.2 ng/mL or higher, the rPFS was 17 months (14-23).

Additionally, those who received darolutamide who reached ultra-low PSA under .02 ng/mL experienced a longer median time to metastatic castration-resistant prostate cancer (mCRPC) than those with a PSA of 0.2 ng/mL or higher, with a 93% risk reduction (HR, 0.07; 95% CI, 0.04-0.11); this was also true for patients who had a PSA between .02 ng/mL and 0.2 ng/mL vs those with a PSA of 0.2 ng/mL or greater, with a 64% risk reduction (HR, 0.36; 95% CI, 0.25-0.53). The time to mCRPC for those with PSA under .02 ng/mL, with PSA of at least .02 ng/mL but under 0.2 ng/mL, and 0.2 ng/mL or higher was NR (NR-NR), 28 months (24-NR), and 11 months (8.5-14).

“Regardless of baseline PSA, the proportion of patients reaching ultra-low PSA responses of [less than] 0.02 ng/mL was higher with darolutamide treatment vs placebo and ultra-low PSA response rates increased over time,” Neal Shore, MD, FACS, of Carolina Urologic Research Center and AUC Urology Specialists, in Myrtle Beach, SC, and colleagues, wrote in a poster. “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.”

Analyzing ARANOTE: What Came Before and Current Analyses

The double-blind, placebo-controlled, global, randomized trial enrolled patients with histologically or cytologically confirmed adenocarcinoma of the prostate and metastatic disease who were at least 18 years of age and had an ECOG performance status ranging from 0 to 2.2 Patients needed to have acceptable bone marrow, liver, and renal function.

Study participants were assigned 2:1 to receive 600 mg of darolutamide twice daily (n = 446) or placebo (n = 223) with concomitant ADT. The primary end point of the study was rPFS, which was met. At the primary data cutoff date of June 7, 2024, the rPFS was NR in the darolutamide arm vs 25.0 months in the placebo arm (HR, 0.54; 95% CI, 0.41-0.71; P < .0001). Moreover, the time to PSA progression was longer for those in the darolutamide arm vs the placebo arm (HR, 0.31; 95% CI, 0.23-0.41). Moreover, a higher percentage of patients receiving darolutamide achieved undetectable PSA under 0.2 ng/mL at any time vs those who received placebo, at 62.6% and 18.5%, respectively.

For the post-hoc analyses, investigators collected serum for centralized PSA level testing at the time of screening and every 12 weeks.1 They evaluated ultra-low PSA rates at the following time points: 24 weeks, 36 weeks, 48 weeks, and at any time. Proportion of patients who achieved PSA under .02 ng/mL were also examined by PSA baseline group, which included: under first quartile (<Q1; <4.1 ng/mL), between Q1 and median (Q2: 4.1 to <21.3 ng/mL), and median or higher (Q3 and Q4: ≥21.3 ng/mL).

Moreover, rPFS, time to mCRPC, and time to PSA progression were correlated with PSA responses in those who received darolutamide. In a 36-week landmark analysis, they examined the risk of survival bias leveraging an unstratified Cox regression model.

The median PSA at baseline in the darolutamide arm was 21.4 ng/mL vs 21.2 ng/mL in the placebo arm. Across baseline PSA subgroups, disease characteristics of patients were generally comparable, according to the study authors, although there were fewer patients with PSA under 4.1 ng/mL who had de novo disease vs groups with PSA of at least 4.1 ng/mL.

Additional Insights

Treatment with darolutamide plus ADT resulted in higher rates of PSA response of under .02 ng/mL vs those who received placebo plus ADT at all time points. Moreover, ultra-low PSA rates climbed over time, irrespective of PSA levels at baseline.

Specifically, in those with baseline PSA under 4.1 ng/mL (<Q1), rates of ultra-low PSA under .02 ng/mL at 12 weeks with darolutamide vs placebo were 32.1% and 11.3%, respectively; these rates were 50.9% and 15.1% at 24 weeks, 56.6% and 20.8% at 36 weeks, 62.3% and 24.5% at 48 weeks, and 68.9% and 26.4% at any time. In those with baseline PSA between 4.1 ng/mL and no higher than 21.3 ng/mL (Q1 to <median), rates of ultra-low PSA under .02 ng/mL at 12 weeks with darolutamide vs placebo were 10.2% and 0%, respectively; these rates were 16.7% and 0% at 24 weeks, 28.7% and 1.8% at 36 weeks, 33.3% and 1.8% at 48 weeks, and 41.7% and 1.8% at any time. In those with baseline PSA of 21.3 ng/mL or higher (≥median), rates of ultra-low PSA under .02 ng/mL at 12 weeks were 3.2% and 0% with darolutamide and placebo, respectively; these rates were 12.3% and 0% at 24 weeks, 16.4% and 0% at 36 weeks, 20.0% and 0.9% at 48 weeks, and 30.5% and 1.9% at any time.

“In landmark analyses, [the aforementioned] associations [with regard to rPFS, time to mCRPC, and PSA progression] held up in an assessment of the effect between PSA response levels at a 36-week landmark and subsequent time-to-event outcomes for darolutamide-treated patients,” study authors wrote.

In those with a PSA under .02 ng/mL vs those with a PSA greater than 0.2 ng/mL, the HR for rPFS was 0.20 (95% CI, 0.10-0.40), the HR for time to mCRPC was 0.22 (95% CI, 0.11-0.41), and the HR for time to PSA progression was 0.10 (95% CI, 0.04-0.29).

Safety Spotlight

“The safety profile of darolutamide was independent of PSA response, with lower treatment discontinuation rates due to treatment-emergent adverse effects [TEAEs] compared with placebo, consistent with the overall population,” the study authors wrote.

In those who experienced a PSA response under .02 ng/mL at any time who received darolutamide (n = 185), TEAEs occurred in 94.1% of patients and they were grade 3 or 4 for 29.7% of patients. Serious effects occurred in 17.3% of these patients, and TEAEs led to drug discontinuation for 4.3% of patients. In those who experienced a PSA response under .02 ng/mL at any time and received placebo (n = 17), the respective rates were 94.1%, 35.3%, 29.4%, and 17.6%.

In those who did not experience a PSA response under .02 ng/mL at any time who received darolutamide (n = 247), TEAEs occurred in 88.3% of patients and they were grade 3 or 4 for 30.8% of patients; they led to discontinuation of study treatment for 6.9% of patients. Serious effects were reported in 27.1% of patients. In those who did not experience a PSA response under .02 ng/mL at any time and were given placebo (n = 200), these respective rates were 89.5%, 29.5%, 8.5%, and 23.5%.

Disclosures: Dr Shore disclosed serving in a consulting or advisory role for Bayer, Janssen Scientific Affairs, Dendreon, Tolmar, Ferring, Medivation/Astellas, Amgen, Pfizer, AstraZeneca, Myovant Sciences, Astellas Pharma, Abbvie, Merck, Bristol-Myers Squibb/Sanofi, Clovis Oncology, Exact Imaging, FerGene, Foundation Medicine, CG Oncology, InVitae, MDxHealth, Myriad Genetics, Nymox, Propella Therapeutics, Genzyme, Sanofi, Sesen Bio, CG Oncology, Exact Sciences, Genesis Cancer Care, Pacific Edge Biotechnology, Phosphorus, Urogen pharma, Speciality Networks, Peerview, Clarity Pharmaceuticals, Lantheus Medical Imaging, Lilly, Photocure, Sema4, Telix Pharmaceuticals, Tempus, Vaxiion.

He serves on the Speakers’ Bureau for Janssen, Bayer, Dendreon, Astellas Pharma, AstraZeneca, Clovis Oncology, Pfizer, Guardant Health, Merck, Foundation Medicine; Expert Testimony: Ferring. Other Relationship: Photocure, Alessa Therapeutics. Abbvie received Research Funding; Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer,Boston Scientific, Clovis Oncology, Dendreon, Exact Imaging, Ferring, Foundation Medicine, InVitae, Janssen, MDxHealth, Merck, Myovant Sciences, Myriad Genetics, Nymox, Pfizer, Sanofi, Sesen Bio, Tolmar, CG Oncology, DisperSol, FORMA Therapeutics, Guardant Health, Jiangsu Yahong Meditech, Novartis, pacific edge, POINT Biopharma, Propella Therapeutics, Seattle Genetics, MT Group, Theralase, Veru, Zenflow, Advantagene, Aragon Pharmaceuticals, Endocyte, Exelixis, FKD Therapies, Genentech, ISTARI Oncology, Medivation, OncoCellMDx, ORIC Pharmaceuticals, Palette Life Sciences, Plexxikon, RhoVac, Steba Biotech, Urogen pharma, Urotronic, US Biotest, and Vaxiion.

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. Presented at: 2025 AUA Annual Meeting; April 26-29, 2025; Las Vegas, NV. Abstract IP26-07.
2. 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