MedicalResearch.com Interview with:
Prof. Karim Fizazi, MD, PhD
Head of the Department of Cancer Medicine
Institute Gustave Roussy
MedicalResearch.com: What is the background for this study?
How does darolutamide differ from other medications for prostate cancer?
Response: Despite recent treatment advances, there is still significant unmet need for new therapeutic options for men with non-metastatic castration-resistant prostate cancer (nmCRPC).
In laymen’s terms, nmCRPC is cancer that has not spread beyond the prostate region; PSA levels are elevated, despite treatment with hormone therapy, and men with nmCRPC generally feel well and do not have symptoms. The unmet medical need is for treatments that achieve disease control and delay the spread of the cancer without impacting their daily lives or increasing the burden of disease with treatment side effects.
While the current treatments in this space are effective in delaying onset of metastases, the side effects can be unpleasant and disruptive to men’s lives; particularly cognitive issues, seizures, impact on balance which may lead to falls and bone fractures, rash and hypertension.
Furthermore, new treatment options that have limited interactions with medications typically used in this patient population are also important.
Response: Darolutamide has the potential to be the first novel androgen receptor (AR) antagonist to delay metastases and extend survival, while allowing patients with nmCRPC to continue their day-to-day life without adding any burden.
The phase III ARAMIS trial results showed a significant improvement of 40.4 months of metastasis-free survival (MFS) with darolutamide plus androgen deprivation therapy (ADT), an improvement of 22 months versus ADT in combination with placebo. These results are highly clinically relevant.
In addition to this significant improvement in MFS and a positive trend in overall survival (OS), ARAMIS trial results also showed a marked improvement in time to pain progression with darolutamide plus ADT, a patient-reported secondary endpoint compared to placebo plus ADT. Darolutamide plus ADT did not increase the rate of discontinuation due to adverse events (AEs) compared to placebo plus ADT and did not increase the rate of AEs typically seen with ADT and/or currently available AR antagonist therapies, including seizures, falls, fractures, rash, cognitive disorder, mental impairment and hypertension.
The distinct clinical structure of darolutamide allows for lower blood-brain barrier penetration compared to currently available AR antagonists as demonstrated in preclinical studies. A lower blood-brain barrier penetration may explain the overall low incidence of CNS-related adverse events seen in the ARAMIS Phase III study.
In addition, drug-drug interaction studies have demonstrated that darolutamide can be administered with certain types of medications that are typical in this patient population, such as simvastatin, warfarin and digoxin, whereas the prescribing information for currently available AR antagonist therapies recommends concomitant use with these medications should be avoided.
MedicalResearch.com: What are the main findings?
Response: Results from the pivotal Phase III ARAMIS trial in men with nmCRPC showed a statistically significant improvement in metastasis-free survival (MFS) with darolutamide plus androgen deprivation therapy (ADT) compared to placebo plus ADT (HR=0.41, 95% CI 0.34-0.50; P<0.001). This translates to a 59 percent reduction in the risk of metastasis or death. The median MFS was 40.4 months in the darolutamide arm compared to 18.4 months for the placebo arm – an overall improvement in median MFS of 22 months.
A positive trend in overall survival (OS) was also observed (HR=0.71, 95% CI 0.50-0.99; P=0.045), and all other secondary endpoints demonstrated a benefit in favor of darolutamide. Importantly, the incidence of treatment-emergent adverse events (AEs) with greater than or equal to 5 percent frequency or of grade 3–5 was comparable between darolutamide plus ADT and placebo plus ADT arms; only fatigue occurred in more than 10 percent of patients (darolutamide plus ADT resulted in 12.1 percent versus 8.7 percent in patients with placebo plus ADT). Health related quality of life was maintained with a positive trend favoring darolutamide over placebo.
MedicalResearch.com: What should readers take away from your report?
Response: In addition to a benefit in metastasis-free survival (MFS), a favorable safety profile is critical for these largely asymptomatic men with nmCRPC because treatment decisions can impact their overall well-being, prognosis and compliance with the treatment, as well as with other medications that are typical for this patient population.
These phase III ARAMIS trial data are exciting for the prostate cancer community. They show that darolutamide has the potential to address an important unmet medical need that remains despite recent advances in nmCRPC treatment; they not only demonstrate darolutamide’s significant efficacy in preventing the spread of prostate cancer, but also its favorable safety profile that, if approved by regulatory authorities, may allow men with nmCRPC to continue their day-to-day life without increasing the burden of disease with treatment side effects.
Compared to placebo plus androgen deprivation therapy (ADT), darolutamide plus ADT did not increase rates of critical adverse events including seizures, falls, fractures, rash, cognitive disorder, mental impairment or hypertension. Patients with a history of seizure were not excluded from the study.
MedicalResearch.com: Is there anything else you would like to add?
Response: The importance of providing an nmCRPC treatment with a favourable safety profile cannot be understated. A lot of these men may be on treatment for three or four years, and even low-grade side effects can become problematic over a long period of time. If approved, darolutamide has the potential to fulfill critical treatment goals for men with nmCRPC: to achieve disease control and delay the spread of the cancer without impacting their daily lives or increasing the burden of disease with treatment side effects.
Disclosures Prof. Karim Fizazi: Participation to advisory boards/honorarium for:
Amgen, Astellas, Astrazeneca, AAA, Bayer, Clovis, Curevac, ESSA, Genentech, Janssen, MSD, Orion, Sanofi
Karim Fizazi, M.D., Neal Shore, M.D., Teuvo L. Tammela, M.D., Ph.D., Albertas Ulys, M.D., Egils Vjaters, M.D., Sergey Polyakov, M.D., Mindaugas Jievaltas, M.D., Murilo Luz, M.D., Boris Alekseev, M.D., Iris Kuss, M.D., Christian Kappeler, Ph.D., Amir Snapir, M.D., Ph.D., et al., for the ARAMIS Investigators*
February 14, 2019
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