Darolutamide vs Enzalutamide for Prostate Cancer

(ARACOG Trial)

Recruiting in Palo Alto (17 mi)

+7 other locations

Overseen by Monica Bertagnolli, MD

Age: 18+

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Alliance Foundation Trials, LLC.

Must be taking: LHRH agonists

Disqualifiers: Non-adenocarcinoma, High testosterone, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This is a prospective, randomized, open-label phase II study comparing cognitive outcomes between men with metastatic and non-metastatic castration resistant prostate cancer (CRPC) or metastatic hormone sensitive prostate cancer (HSPC). Approximately 132 patients will be enrolled. Eligible patients will be randomized in a 1:1 fashion to treatment with enzalutamide 160 mg orally daily or darolutamide 600 mg orally twice daily, in combination with standard LHRH agonist based treatment. Cognitive assessments will be performed using modules from Cambridge Neuropsychological Test Automated Battery (CANTAB) an internationally recognized software for assessing cognitive function and impairment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must continue taking a GnRH agonist or antagonist if you are medically castrated.

What data supports the effectiveness of the drug Darolutamide for prostate cancer?

Darolutamide has been shown to be effective in treating prostate cancer, particularly in men with non-metastatic castration-resistant prostate cancer, by significantly prolonging the time patients live without the cancer spreading. It has also been effective in combination with other treatments for metastatic hormone-sensitive prostate cancer, improving overall survival rates.

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Is Darolutamide safe for humans?

Darolutamide is generally well tolerated and has a manageable safety profile, with fewer central nervous system-related side effects compared to other similar drugs. It does not cross the blood-brain barrier, reducing the risk of seizures, and has been well tolerated in clinical trials for prostate cancer.

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How does the drug darolutamide differ from other treatments for prostate cancer?

Darolutamide is unique because it is a non-steroidal androgen receptor inhibitor with a distinct chemical structure, which may make it effective for patients who are resistant to other similar drugs like enzalutamide. It also has minimal penetration into the brain, potentially reducing certain side effects compared to other treatments.

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Eligibility Criteria

Men with advanced prostate cancer that's resistant to hormone therapy, either spread (metastatic) or not (non-metastatic). They must be able to swallow pills, have low testosterone from treatment, and be in fairly good health. Men who've had certain treatments like enzalutamide or darolutamide before, brain metastasis, seizures, dementia, or are at risk of falls can't join.

Inclusion Criteria

My prostate cancer is growing despite hormone therapy, with increasing PSA levels.

I can swallow pills without any issues.

My prostate cancer is confirmed and does not have neuroendocrine or small cell features.

Exclusion Criteria

I will undergo radiation treatment for more than 21 days during the study.

I had chemotherapy for prostate cancer more than 6 months ago.

Use of investigational agents for the treatment of prostate cancer within 4 weeks of study entry

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either enzalutamide or darolutamide in combination with standard LHRH agonist based treatment

48 weeks

Regular visits for cognitive assessments and treatment monitoring

Crossover

Participants may cross over to the opposite treatment arm at 12 and 24 weeks if criteria are met

Up to 48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Participant Groups

The study is testing the effects of two drugs on thinking skills in men with advanced prostate cancer. Half will take Darolutamide and half Enzalutamide along with standard hormone-blocking injections. Their cognitive functions will be measured using a special computerized test called CANTAB.

Group I: Darolutamide (DARO) Active Control 1 Intervention

Patients will take DARO at a dose of 600 mg (300 mg ×2 tablets) by mouth twice daily beginning on Day 1, of Week 1. Patients will take DARO throughout planned treatment period or withdrawal of consent or progression of disease requiring change in therapy.

Group II: Enzalutamide (ENZ) Active Control 1 Intervention

Patients will take ENZ at a dose of 160 mg PO once daily (QD), beginning on Day 1, of Week 1. Patients will take ENZ throughout planned treatment period or withdrawal of consent or progression of disease requiring change in therapy.

Darolutamide is already approved in United States, European Union, Canada, Australia for the following indications:

🇺🇸 Approved in United States as Nubeqa for:

• Non-metastatic castration-resistant prostate cancer (nmCRPC)
• Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel

🇪🇺 Approved in European Union as Nubeqa for:

• Non-metastatic castration-resistant prostate cancer (nmCRPC)
• Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel

🇨🇦 Approved in Canada as Nubeqa for:

• Non-metastatic castration-resistant prostate cancer (nmCRPC)
• Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel

🇦🇺 Approved in Australia as Nubeqa for:

• Non-metastatic castration-resistant prostate cancer (nmCRPC)
• Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of California - San Diego Moores Cancer Center San Diego, CA

New Hampshire Oncology and Hematology Hooksett, NH

Ohio State University James Cancer Center Columbus, OH

Froedtert and the Medical College of Wisconsin Milwaukee, WI

More Trial Locations

Who Is Running the Clinical Trial?

Alliance Foundation Trials, LLC. Lead Sponsor

Bayer Industry Sponsor

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Darolutamide: First Approval. [2020] Darolutamide (NUBEQA™) is a structurally distinct non-steroidal androgen receptor antagonist being developed by Orion and Bayer as a treatment for prostate cancer. Based on positive results in the phase III ARAMIS trial, darolutamide was recently approved in the USA for the treatment of men with non-metastatic castration-resistant prostate cancer. This article summarizes the milestones in the development of darolutamide leading to this first approval.

2. France pubmed.ncbi.nlm.nih.gov

Darolutamide: A Review in Metastatic Hormone-Sensitive Prostate Cancer. [2023] Darolutamide (NUBEQA®) is an oral androgen receptor inhibitor (ARi) that is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) and docetaxel. In a pivotal trial, darolutamide plus ADT and docetaxel was superior to placebo plus ADT and docetaxel in prolonging the primary endpoint of overall survival, with improvements also reported in most secondary endpoints. Treatment with darolutamide plus ADT and docetaxel was associated with a manageable tolerability profile. Furthermore, the adverse events reported with darolutamide plus ADT and docetaxel were generally consistent with the safety profiles previously reported for ADT and docetaxel. Darolutamide expands the availability of treatment options in mHSPC and may be useful as a treatment for high-volume disease (typically defined as ≥ 4 bone metastases with spread outside of the pelvis and vertebral column).

3. France pubmed.ncbi.nlm.nih.gov

Darolutamide: A Review in Non-Metastatic Castration-Resistant Prostate Cancer. [2022] Oral darolutamide (Nubeqa™) is a novel second-generation, nonsteroidal, selective androgen receptor (AR) inhibitor indicated for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). In the pivotal multinational, phase 3 ARAMIS trial in men with nmCRPC, relative to placebo plus ongoing androgen deprivation therapy (ADT), darolutamide (+ ADT) significantly prolonged metastasis-free survival (MFS) at the time of the primary analysis and overall survival (OS) at the time of the final OS analysis and was generally well tolerated in extended follow-up. Albeit long-term data from the real-world setting are required to fully define the safety profile of darolutamide, current evidence from the final ARAMIS analysis indicates that darolutamide has a low propensity for CNS-related adverse events (AEs) associated with other currently approved second-generation AR inhibitors. Given the efficacy and safety evidence from the final ARAMIS analysis and the key role of second-generation AR inhibitors in the management of nmCRPC, darolutamide + ADT represents an important emerging option for the treatment of men with nmCRPC who are at high risk of developing metastatic prostate cancer.

4. United States pubmed.ncbi.nlm.nih.gov

Sequential therapy with darolutamide in patients with non-metastatic castration-resistant prostate cancer resistant to enzalutamide or apalutamide. [2023] Enzalutamide, apalutamide, and darolutamide are currently recommended for patients with non-metastatic castration-resistant prostate cancer (nmCRPC), but cross-resistance of androgen receptor-axis-targeted therapies (ARAT) occurs. Because darolutamide has a distinct chemical structure to other non-steroidal antiandrogens, it may be effective for nmCRPC patients resistant to enzalutamide or apalutamide. We retrospectively evaluated the efficacy of switching to darolutamide in patients with nmCRPC. We included nine nmCRPC patients who experienced biochemical progression on enzalutamide or apalutamide and were switched over to darolutamide. Five patients (55.5%) had a PSA response >50% decline after starting darolutamide, with an average of 73% PSA decline. Median progression-free survival was 6 months. In conclusion, an ARAT switch from enzalutamide or apalutamide to darolutamide might be effective for nmCRPC. Although the validation in a large-scale cohort is necessary, the switch to darolutamide could be a promising therapeutic option after the progression of 1st line ARAT in nmCRPC patients.

5. Germany pubmed.ncbi.nlm.nih.gov

Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer. [2023] This trial assessed the safety, pharmacokinetics, and efficacy of darolutamide (ODM-201), a new-generation nonsteroidal androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC).

6. United States pubmed.ncbi.nlm.nih.gov

Indirect Comparison of Darolutamide versus Apalutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer. [2021] No published head-to-head randomized trials have compared the safety and efficacy of darolutamide vs apalutamide or enzalutamide in nonmetastatic castration-resistant prostate cancer. This study compares prespecified adverse events and metastasis-free survival associated with darolutamide vs apalutamide, and darolutamide vs enzalutamide, via matching-adjusted indirect comparisons.

7. Netherlands pubmed.ncbi.nlm.nih.gov

Darolutamide as a Second-Generation Androgen Receptor Inhibitor in the Treatment of Prostate Cancer. [2021] Prostate cancer (PC) is known as the most frequent cancer among men in the world. Androgen Deprivation Therapy (ADT) is one of the initial treatment approaches in the PC therapy and various drugs can be used in routine Hormonal therapy for PC therapy. Nevertheless, PC cells can survive and continue their growth via different mechanisms which lead to their resistance to common treatments i.e., Enzalutamide. olutamide (ODM-201) is a second-generation androgen receptor (AR) inhibitor with a new chemical structure and has a high affinity to the AR. Darolutamide does not cross the blood-brain barrier and for this reason, reduces the possibility of seizures. Darolutamide can also inhibit the transcriptional activity of several AR mutant variants (F877L, F877L/T878A, and H875Y/T878A), which are Enzalutamide resistant. In this review, we reviewed the results of different studies: in vitro, animal model and phase 1, 2 and 3 clinical trials (ARADES, ARAFOR and ARAMIS). We shall discuss worldwide phase 2 and 3 clinical trials (ARASENS and ODENZA) that are in progress, in order to demonstrate the advantages of Darolutamide consumption in different groups of patients. Darolutamide has shown high potential in inhibiting the growth of MR49F (Enzalutamide resistant PC cells) and VCaP (Castration-resistant PC cells) cell lines and transcriptional activities of AR. Fewer doses of Darolutamide are needed compared to Enzalutamide. The drug had significant anti-tumor activity and no effect on serum testosterone levels in animal models. Darolutamide demonstrates its safety and efficacy in different studies and was well tolerated nearly in all of the patients.

8. England pubmed.ncbi.nlm.nih.gov

Darolutamide (ODM-201) for the treatment of prostate cancer. [2018] Androgen deprivation therapy (ADT) is a mainstay initial treatment for advanced hormone-sensitive prostate cancer (HSPC), but disease progression to castration-resistant prostate cancer (CRPC) invariably occurs when patients do not succumb to another disease or comorbidity. Recognition that the androgen receptor (AR) axis continues to drive disease progression has led to the development of several AR-directed approved agents, including abiraterone acetate and enzalutamide. An investigational agent, darolutamide (ODM-201, BAY-1841788), has completed early-phase clinical trials, and two global phase III trials are currently accruing patients. Areas covered: The unmet clinical need, pharmacokinetics, preclinical development, and clinical efficacy and safety of darolutamide for the treatment of advanced prostate cancer are reviewed. The design of two ongoing phase III trials (ARAMIS and ARASENS) of darolutamide in men with non-metastatic CRPC and metastatic HSPC, respectively, are also discussed. Expert opinion: Darolutamide is an oral, investigational, high-affinity AR antagonist which has activity against known AR mutants that confer resistance to other second-generation antiandrogens, has minimal blood-brain barrier penetration, and does not significantly increase serum testosterone. These features may offer potential advantages over the second-generation antiandrogens. In the phase I/II ARADES trial, darolutamide demonstrated promising antitumor activity and a favorable safety profile in men with metastatic CRPC.