Darolutamide Delays The Spread Of Some Prostate Cancers
The androgen receptor in cells is a key driver of castrate-resistant prostate cancer. Drugs like darolutamide work by blocking the AR’s activity in cancer cells.
On July 30, 2019, the Food and Drug Administration approved darolutamide for the treatment of men with castration-resistant prostate cancer that has not metastasized. The approval was based on the results from the ARAMIS clinical trial. Under the approval, men being treated with darolutamide should also receive hormone-blocking therapies known as GnRH agonists or have undergone a bilateral orchiectomy.
The investigational drug darolutamide can help delay the spread of prostate cancer to other parts of the body in men with nonmetastaticcastration-resistant disease, according to results from a large clinical trial. In addition, the drug appears to lack some of the side effects seen with similar drugs used to treat men with this form of prostate cancer, the trial results showed.
Until recently, there had been no effective treatment options for patients with nonmetastatic castration-resistant prostate cancer. These men have prostate tumors that continue to grow even after receiving androgen deprivation therapy to keep androgen levels in the body extremely low or undetectable.
But over the last 2 years, two drugs have been approved by the Food and Drug Administration to treat this form of the disease and some researchers expect that, based on the results of this new trial, darolutamide may be next.
Darolutamide In Metastatic Castrate
Karim Fizazi, MD, PhD: Enzalutamide, apalutamide, and darolutamide are all approved for use in nonmetastatic castration-resistant prostate cancer, with similar outcomes for efficacy, including overall survival, and seemingly different safety profiles, with no marked difference between darolutamide and its placebo regarding adverse effects. In regard to metastatic castration-sensitive disease, we have data for apalutamide, enzalutamide, and abiraterone all 3 drugs show overall survival improvement in sometimes different spaces like high risk or low risk, but these 3 drugs work.
We dont have data with darolutamide in the metastatic castration-sensitive space. We are waiting for the ARASENS large phase 3 trial, which is comparing androgen deprivation therapy plus docetaxel with or without darolutamide. This is eagerly awaited because we recently reported the PEACE-1 data indicating that the triplet treatment with abiraterone improves overall survival. I hope that this is also the case with darolutamide, and data will tell, hopefully soon.
Now, regarding men with metastatic castration-resistant prostate cancer, enzalutamide and abiraterone are approved, while apalutamide and darolutamide are not because we dont have phase 3 data in this space for these 2 agents.
Transcript edited for clarity.
Current Treatment Landscape Of Recurrent And Advanced Prostate Cancer
As previously discussed, the treatment options for CRPC have expanded in the last decade and new and more active therapies are currently available. Figure 1 depicts the FDA approved life-prolonging or metastasis-prolonging therapies for advanced prostate cancer, including the recently approved drugs for nmCRPC . Notably, while enzalutamide also has an FDA label for mCRPC, apalutamide and darolutamide will only have labels for nmCRPC initially. This schematic also includes pembrolizumab, an anti-programed cell death-1 receptor inhibitor, for patients with MMR-deficient or microsatellite-high tumors. It is important to emphasize that several clinical trials are ongoing in the different prostate cancer clinical states, testing novel agents and/or combinations, which may further modify the treatment landscape of this disease in the near future and lead to improved outcomes for patients with advanced prostate cancer.
Prostate cancer clinical states model.
Notes: Data created to include the corresponding agents that are FDA approved in each state. Data from Scher et al.35 Green boxes refer to the castration-sensitive state whereas the orange boxes refer to castration-resistant state. Green texts refer to castration-sensitive state whereas orange texts refer to castration-resistant state.
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A Unique Chemical Structure
Darolutamide has a different chemical structure than apalutamide and enzalutamide, which the study authors believe may explain why it has fewer side effects.
Darolutamide basically does not penetrate the bloodbrain barrier, whereas apalutamide and enzalutamide do, said Dr. Fizazi. Most of what is known about darolutamide and the bloodbrain barrier comes from studies in rodents rather than in humans, he added.
The low incidence of central nervous system-related side effects seen in the trial was consistent with the rodent studies. Side effects likely to be related to the drug reaching the central nervous system include fatigue, dizziness, cognitive impairment, and seizures, according to Dr. Fizazi.
There was no detectable difference in the incidence of these side effects between patients treated with darolutamide and those who received a placebo, he added, noting that patients with a history of seizures were not excluded from the trial.
In the trial, fatigue was the only side effect that occurred in more than 10% of participants in either group.
A low incidence of side effects is particularly important for men who do not have symptoms of the disease, Dr. Fizazi noted. The percentage of participants who stopped taking either the drug or the placebo because of side effects was similar: about 9%.
In the coming years, researchers and patients hope to learn more about patient preferences for darolutamide, enzalutamide, and apalutamide.
An Evolving Standard Of Care
Hormone-sensitive prostate cancer means a patients tumors are still largely being fueled by male sex hormones called androgens. For many years, metastatic hormone-sensitive prostate cancer was treated with ADT alone, which blocks the production of androgens by the testicles.
In 2014, a large clinical trial showed that adding the chemotherapy drug docetaxel to ADT improved survival in men with metastatic hormone-sensitive prostate cancer. Since then, this combination has become the standard of care for this group of patients.
More recently, studies have shown that adding other drugs that block the production or binding of androgensincluding abiraterone , enzalutamide , and apalutamide to ADT also helps people with metastatic hormone-sensitive prostate cancer live longer. In a trial combining apalutamide with ADT, for example, approximately 82% of men were still alive after 2 years compared with 74% of men treated with ADT alone.
Several clinical trials were then launched to see if combining any of these drugs with ADT and docetaxel could build on those survival gains. Results of those studies, however, have been mixed, with one showing an improvement in survival without the disease progressing and another finding no increase in overall survival.
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Darolutamide Combo Significantly Increased Overall Survival In Metastatic Hormone
The phase 3 ARASENS trial, which assessed the use of darolutamide and docetaxel in patients with metastatic hormone-sensitive prostate cancer, met its primary end point of significantly improved overall survival.
A combination of the oral androgen receptor inhibitor darolutamide , docetaxel, and androgen deprivation therapy was found to significantly improve overall survival in a population of patients with metastatic hormone-sensitive prostate cancer , according to findings from the phase 3 ARASENS study .1
The trial’s primary end point of improved OS with the addition of darolutamide was met, according to investigators. Moreover, it was reported that the incidence of adverse effects was similar between the 2 treatment arms. Findings from the study are expected to be presented at an upcoming scientific congress.
Drug developer Bayer intends to discuss findings from the study with global health authorities in order to submit a marketing authorization for darolutamide in this indication.
The goal of the randomized, multicenter, double-blind study was to evaluate the safety and efficacy of combining an androgen receptor inhibitor with docetaxel and ADT vs docetaxel and ADT alone.
A total of 1306 patients with newly diagnosed disease were randomized 1:1 to be treated with either 600 mg of darolutamide plus standard docetaxel and ADT or the docetaxel ADT backbone alone.
Adding Darolutamide: New Soc For Metastatic Prostate Cancer
Roxanne Nelson, RN, BSN
New data suggest that adding darolutamide onto androgen deprivation therapy and docetaxel should become a new standard of care for men with metastatic hormone-sensitive prostate cancer , say investigators reporting results from the phase 3 ARASENS study.
The three drug combination significantly reduced the risk of death by 32.5% vs ADT plus docetaxel. After 4 years, 62.7% of the darolutamide group vs 50.4% of the placebo were still alive.
The addition of darolutamide also led to improvement in key secondary endpoints, including the time to reach castration-resistant prostate cancer, when the disease becomes more difficult to treat.
The new results were presented here at the 2022 Genitourinary Cancers Symposium, and simultaneously published in The New England Journal of Medicine to coincide with the meeting.
“Based on these findings, darolutamide in combination with ADT and docetaxel should become a new standard of care for treatment of mHSPC,” said lead author Matthew Smith, MD, PhD, director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center, Boston.
Discussant for the study, Elisabeth Heath, MD, associate center director of Translational Sciences and leader of the Genitourinary Oncology Multidisciplinary Team at Karmanos Cancer Institute, Detroit, agreed.
The ARASENS study has “provided us with a new standard of care, a triplet, for the right patients,” she commented.
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Fda Launches Priority Review Of Darolutamide For Metastatic Hormone
The FDA has granted a priority review designation to darolutamide plus docetaxel for patients with metastatic hormone-sensitive prostate cancer.
Following the submission of new drug application , the FDA will conduct a priority review of darolutamide plus docetaxel for patients with metastatic hormone-sensitive prostate cancer .1
The application is supported by findings from the phase 3 ARASENS trial , in which the combination of darolutamide, docetaxel, and androgen deprivation therapy resulted in a 32.5% reduction in the risk of death compared with docetaxel/ADT .2 The 4-year overall survival rate in the darolutamide arm was 62.7% vs 50.4% in the control arm.
Bayer remains dedicated to addressing unmet needs in prostate cancer treatment for various stages of the disease, Christine Roth, member of the executive committee of the Pharmaceutical Division and head of the Oncology SBU at Bayer, stated in a press release. Todays sNDA acceptance, confirmation of priority review and participation in Project Orbis, bring us closer to adding a new indication for in combination with docetaxel to benefit men with mHSPC.
Patients who had regional lymph-node involvement only or who received ADT more than 12 weeks before randomization were excluded. Patients also could not have received androgen-receptor pathway inhibitors, chemotherapy, or immunotherapy for their disease before randomization, nor could they have received radiotherapy within 2 weeks before randomization.
Details Of The Arasens Study
The ARASENS study included 1306 patients with mHSPC who were randomly assigned to receive darolutamide at 600 mg twice daily or placebo , combined with ADT and docetaxel.
All patients had metastatic disease at baseline 79.5% had bone metastases and 17.5% had visceral metastases . Additionally, most patients had metastatic disease at their time of initial diagnosis.
At the time of data cutoff, darolutamide had significantly decreased the risk of death and improved overall survival , and the survival benefit of darolutamide was observed across most subgroups.
“This significant improvement in overall survival was observed despite a high percentage of patients who received subsequent life-prolonging systemic therapies,” said Smith.
Darolutamide also significantly delayed the development CRPC and time to pain progression. The median time to CRPC was 19.1 months for placebo vs not reached for the darolutamide arm , and the median time to pain progression was 27.5 vs not reached .
Treatment-related adverse events were similar in the two groups, and the incidences of the most common events were highest during the overlapping docetaxel treatment period for both arms. Grade 3/4 events occurred in 66.1% of patients in the darolutamide arm and 63.5% in the placebo group. The most common adverse event was neutropenia .
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Fda Approves Darolutamide For Metastatic Prostate Cancer Subset
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The FDA approved darolutamide tablets in combination with docetaxel for men with metastatic hormone-sensitive prostate cancer.
Darolutamide is an androgen receptor inhibitor designed to inhibit androgen binding, AR nuclear translocation and AR-mediated transcription.
The FDA based the approval on results of the randomized phase 3 ARASENS trial, which included 1,306 men with newly diagnosed metastatic hormone-sensitive prostate cancer.
Researchers assigned men to androgen deprivation therapy and docetaxel plus either 600 mg darolutamide twice daily or placebo.
OS served as the primary endpoint.
As Healio previously reported, results presented at ASCO Genitourinary Cancers Symposium and published in The New England Journal of Medicine showed the addition of darolutamide to ADT and docetaxel significantly extended OS . Darolutamide-treated men also achieved prolonged time to pain progression .
The most common adverse events reported among men treated with darolutamide included constipation, decreased appetite, rash, hemorrhage, increased weight and hypertension. Laboratory test abnormalities that occurred among at least 30% of darolutamide-treated men included anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased aspartate aminotransferase and alanine aminotransferase levels, and hypocalcemia.
Inhibiting The Androgen Receptor
Darolutamide belongs to a class of drugs called androgen receptor inhibitors. In the body, these agents compete with androgens for binding to the androgen receptor, which reduces the ability of androgens to promote the growth of prostate cancer cells.
In 2018, the Food and Drug Administration approved both apalutamide and enzalutamide for men with nonmetastatic castration-resistant prostate cancer.
In the clinical trials that led to the approvals, the drugs were shown to improve the median time from random assignment until the tumor spread or the patient diedknown as metastasis-free survivalin men with this form of prostate cancer.
Treatment with both drugs, however, was associated with side effects related to the central nervous system, including fatigue, falls, and cognitive changes.
In both trials, treatment with the respective drugs more than doubled metastasis-free survival compared with men who received a placebo: 40 versus 16 months in the apalutamide trial and 36.6 versus 14.7 in the enzalutamide trial.
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Darolutamide Plus Adt And Docetaxel Improves Survival In Men With Metastatic Hormone
Treatment with the androgen receptor inhibitor darolutamide, in combination with androgen-deprivation therapy and docetaxel, significantly improved overall survival compared with ADT and docetaxel alone in patients with metastatic hormone-sensitive prostate cancer , according to recent results from the phase 3 ARASENS clinical trial, which were simultaneously published in the New England Journal of Medicine.1
Lead investigator Matthew R. Smith, MD, PhD, Director, Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center, Boston, presented the data at the 2022 ASCO GU Cancers Symposium. Darolutamide is approved by the FDA for the treatment of patients with nonmetastatic castration-resistant prostate cancer who are at high risk for metastatic disease.
ARASENS was a global, randomized, multicenter, double-blind, placebo-controlled clinical trial of 1306 newly diagnosed patients with metastatic HSPC who were randomized to oral darolutamide in combination with ADT and 6 cycles of docetaxel or to placebo, ADT, and docetaxel.
The patients had an ECOG performance score 0 or 1 and had adequate bone marrow, liver, and renal function. Approximately 78% of patients in both arms had a Gleason score of 8 at initial diagnosis, 79% had bone metastases, and 18% had visceral metastases with or without bone metastases.
Clinical Development And Early
The initial clinical development of darolutamide included two important early-phase studies that assessed the safety and preliminary efficacy of the drug in patients with mCRPC: i) the ARADES study: activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer: an open-label phase 1 dose-escalation and randomized phase 2 dose expansion trial38 and ii) the ARAFOR study: pharmacokinetics, antitumor activity, and safety of ODM-201 in patients with chemotherapy-naive metastatic castration-resistant prostate cancer: an open-label phase 1 study.39 These will be discussed in turn.
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Fda Approves Darolutamide Plus Docetaxel For Metastatic Hormone
The FDA has approved darolutamide tablets in combination with docetaxel for adult patients with metastatic hormone-sensitive prostate cancer.
The FDA has approved darolutamide tablets in combination with docetaxel for adult patients with metastatic hormone-sensitive prostate cancer .
The regulatory decision was supported by findings from the phase 3 ARASENS trial , in which darolutamide plus docetaxel improved median overall survival compared with docetaxel alone. The median OS with darolutamide/docetaxel was not yet reached vs 48.9 months with docetaxel alone .
Moreover, treatment with darolutamide plus docetaxel significantly delayed time-to-pain progression .
More Options Lead To More Questions
Elisabeth Heath, M.D., director of prostate cancer research at Karmanos Cancer Institute in Detroit, agreed that the ARASENS results should have an immediate impact on how this form of the disease is treated.
Speaking at the ASCO symposium, Dr. Heath, who was not involved in the study, highlighted an important difference between ARASENS and other trials that tested androgen receptorblocking drugs in men with this form of prostate cancer. In those other trials, she explained, some participants received docetaxel prior to treatment with the androgen receptorblocking drugs rather than at the same time.
Based on the ARASENS results, Dr. Heath said, giving all three treatments simultaneously looks to be the preferred option for some patients.
Dr. Karzai noted that despite there being multiple options to treat metastatic hormone-sensitive prostate cancer, many questions remain. We don’t have guidelines on who should start with what drug and whether one drug is better than another for a patient, she said.
She also pointed out that more research is needed on how the order in which the drugs are given impact their effectiveness and the frequency of side effects.
Additionally, she said, the survival improvement in the ARASENS trial was seen in patients whose cancer had spread in multiple areas beyond the prostate .
We dont know if people with lower-volume benefit from as much as the patients with higher-volume disease do, she said.
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What Does Treatment Involve
Darolutamide is usually taken as two 300mg tablets, twice a day. This means a total dose of 1,200mg per day. Swallow the tablets whole with food.
You will keep having your original hormone therapy alongside darolutamide. This will help to keep the amount of testosterone in your body low and may help the darolutamide to work.