Bertrand Tombal, MD, PhD, professor of Physiology, chair of the Division of Urology, the Université catholique de Louvain, the Cliniques universitaires Saint-Luc, in Brussels, Belgium, discusses the pharmacokinetics of darolutamide (Nubeqa) plus docetaxel in metastatic hormone-sensitive prostate cancer (mHSPC).

The phase 3 ARASENS trial (NCT02799602) evaluated the efficacy and safety of darolutamide in combination with androgen-deprivation therapy (ADT) and docetaxel vs ADT and docetaxel alone in patients with mHSPC. Findings showed that darolutamide plus ADT/docetaxel reduced the risk of death by 32.5% vs ADT and docetaxel alone (HR, 0.68; 95% CI, 0.57-0.80; 

 < .0001). In updated data presented at the 2023 Genitourinary Cancers Symposium, investigators reported overall survival data observed in subgroups of patients by disease volume and disease risk showed that the combination reduced the risk of death by about 30% across all subgroups.

Investigators have been attempting to combine docetaxel various agents for the treatment of castration-resistant prostate cancer setting for years; however, none of these trials were positive, Tombal notes. One of the reasons prior combination failed to demonstrate benefit was the additional agent would interfere with the pharmacokinetics of docetaxel, resulting in a decrease of efficacy of either docetaxel or the drug that is being tested, Tombal adds. Since darolutamide has a favorable drug interaction profile, it was a logical choice to test in combination with docetaxel in this setting, and these updated data from ARASENS confirm that hypothesis, Tombal expands.

Investigators showed that darolutamide does not impact the pharmacokinetics of docetaxel, and docetaxel does not impact those of darolutamide, Tombal continues, noting that no added toxicity or inferior efficacy were observed with the combination of the drugs. Although these data only add additional confirmation to the efficacy previously reported from the trial, it was important to report this information, Tombal concludes.

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Bertrand Tombal, MD, PhD, discusses the pharmacokinetics of darolutamide plus docetaxel in metastatic hormone-sensitive prostate cancer.

Dr Tombal on the Pharmacokinetics of Darolutamide Plus Docetaxel in mHSPC

Bertrand Tombal, MD, PhD, professor of physiology, chair of the Division of Urology, the Université catholique de Louvain, the Cliniques universitaires Saint-Luc, in Brussels, Belgium, discusses the rationale for conducting a phase 2 study (NCT02972060) of darolutamide (Nubeqa) monotherapy in newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC).

The open-label EORTC-GUCG 1532 study was designed to investigate the efficacy of darolutamide, as well as the treatment’s ability to achieve prostate-specific antigen (PSA) suppression and lower testosterone in the absence of androgen-deprivation therapy (ADT) for patients with hormone-naïve, histologically confirmed prostate cancer. Patients across all stages were enrolled in the trial and were required to have a maximum of 4 metastatic lesions, be eligible for hormonal treatment, have an ECOG performance status of 0, and a life expectancy greater than 1 year, Tombal says. The primary end point of the trial was the proportion of patients achieving PSA response at 6 months relative to baseline. Moreover, PSA response was defined as PSA decline greater than 80%, Tombal explains.

Results showed that darolutamide monotherapy was associated with a significant PSA response in this patient population, Tombal continues. At week 24, the PSA response rate was 100% in the monotherapy arm, with a median range decrease of 99.6%. Moreover, this response was comparable with responses with darolutamide plus ADT, Tombal details. Serum testosterone levels in the darolutamide monotherapy arm also increased by a median range of 43.4%. In terms of safety data, 45.2% of patients reported primarily grade 1/2 treatment-related adverse events (TRAEs).

Additional quality-of-life (QoL) data was assessed using the standard EORTC QLQ-PR25 questionnaire, as well as the Aging Male Symptoms scale for male hypergonadism, Tombal adds. Darolutamide alone elicited a lower mean change score according to the EORTC and a lower AMS questionnaire score. This indicates that the regimen elicits lesser less severe hypogonadism-related AEs, respectively. 

Editor’s Note: Dr. Tombal reports serving as a consultant or in an advisory role for Astellas Pharma, Bayer, Ferring, Janssen, Myovant Sciences, Pfizer, Sanofi, Steba Biotech, Takeda; he reports institutional research funding from Ferring; he has served on the Speakers' Bureau for Amgen, Astellas Pharma, Janssen; he received honoraria from Amgen, Astellas Pharma, Bayer, Ferring, Janssen, Myovant Sciences, Pfizer, Sanofi.

Bertrand Tombal, MD, PhD,  discusses the rationale for conducting a phase 2 study of darolutamide monotherapy in newly diagnosed metastatic hormone-sensitive prostate cancer.

Dr. Tombal on Darolutamide Monotherapy in Newly Diagnosed mHSPC

Bertrand Tombal, MD, PhD, professor of Physiology, chair of the Division of Urology, the Université catholique de Louvain, the Cliniques universitaires Saint-Luc, in Brussels, Belgium, discusses the overall survival (OS) benefit associated with androgen-deprivation therapy plus darolutamide (Nubeqa) in metastatic hormone-sensitive prostate cancer (mHSPC).

The phase 3 ARASENS trial (NCT02799602) evaluated the efficacy and safety of the triplet vs ADT and docetaxel alone in patients with mHSPC. Previously reported data from the study showed that the addition of darolutamide to ADT and docetaxel reduced the risk of death by 32.5% (HR, 0.68; 95% CI, 0.57-0.80; 

In updated data presented at the 2023 Genitourinary Cancers Symposium

, investigators reported OS data observed in subgroups of patients by disease volume and disease risk. Findings showed that darolutamide plus ADT/docetaxel reduced the risk of death by about 30% across all volume and risk subgroups. The median OS was not reached (NR) for those with high-volume disease (HR, 0.69; 95% CI, 0.57-0.82) or low-volume disease (HR, 0.68; 95% CI, 0.41-1.13). The median OS was also not NR in both the high-risk disease subgroup (HR, 0.71; 95% CI, 0.58-0.86) and the low-risk disease subgroup (HR, 0.62; 95% CI, 0.42-0.90).

These data led investigators to conclude that darolutamide plus ADT/docetaxel should be considered a new standard of care for patients with mHSPC.

Although the addition of darolutamide significantly increased OS in the overall population, investigators aimed to identify if that benefit was consistent across the volume and risk subgroups, Tombal says. As expected, less death and progression were observed in patients with low-risk or low-volume disease; however, the benefit of darolutamide remained consistent across each subgroup, Tombal adds.

These data reassure the assessment that if a physician believes that a patient needs treatment with ADT plus docetaxel, they will benefit from the addition of darolutamide, irrespective of disease volume or risk, Tombal concludes.

Bertrand Tombal, MD, PhD, discusses the overall survival benefit associated with androgen-deprivation therapy plus darolutamide in metastatic hormone-sensitive prostate cancer.

Bertrand Tombal, MD, PhD, Cliniques Universitaires Saint-Luc

Articles

Dr Tombal on the Pharmacokinetics of Darolutamide Plus Docetaxel in mHSPC

Dr. Tombal on Darolutamide Monotherapy in Newly Diagnosed mHSPC

Dr. Tombal on the OS Benefit of Darolutamide Plus ADT/Docetaxel in mHSPC