Darolutamide + Abemaciclib for Prostate Cancer

Overseen By Praful Ravi, MB BChir, MRCP

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Praful Ravi

Must be taking: Androgen deprivation therapy

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Stroke, Myocardial infarction, Angina, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 13

9 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot take certain drugs that strongly interact with the study drugs. If you are on such medications, they must be stopped or switched at least 5 half-lives before starting the trial. It's important to discuss your current medications with the study team.

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

Darolutamide has shown positive results in delaying metastasis and death in men with nonmetastatic, castration-resistant prostate cancer, as demonstrated in the phase III ARAMIS trial. Additionally, darolutamide has demonstrated antitumor activity and significant decreases in prostate-specific antigen in patients with metastatic castration-resistant prostate cancer in phase I/II trials. ^{1 2 3 4 5}

Is the combination of Darolutamide and Abemaciclib safe for humans?

Darolutamide has been shown to be generally well tolerated in men with non-metastatic castration-resistant prostate cancer, with a low risk of side effects related to the central nervous system (brain and spinal cord). However, long-term safety data from real-world use is still needed to fully understand its safety profile. ^{1 6 7 8 9}

What makes the drug combination of Darolutamide and Abemaciclib unique for prostate cancer?

The combination of Darolutamide and Abemaciclib is unique because Darolutamide is a novel androgen receptor antagonist that effectively delays metastasis in non-metastatic castration-resistant prostate cancer, while Abemaciclib is a CDK4/6 inhibitor that targets cell cycle progression, potentially offering a complementary mechanism of action to enhance treatment efficacy. ^{1 3 4 6 10}

What is the purpose of this trial?

This trial is testing a combination of two oral drugs, abemaciclib and darolutamide, with hormone therapy to treat advanced prostate cancer. It aims to find the safest and most effective dose. The study focuses on men with advanced or high-risk prostate cancer. The treatment works by blocking proteins that help cancer grow and reducing hormone levels that fuel the cancer.

Research Team

Praful Ravi, MB BChir, MRCP

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Men over 18 with confirmed prostate adenocarcinoma, able to swallow pills and follow study rules. They must have a recent biopsy showing significant cancer presence without certain variants, no metastatic disease by specific scans, be candidates for surgical removal of the prostate, and have proper organ function. Contraception is required during and after the trial.

Inclusion Criteria

My organs and bone marrow are working well.

Provision of signed informed consent prior to any study specific procedures, or have a legally authorized representative sign on the participant's behalf

I can take pills and follow study rules.

Exclusion Criteria

I have a history of cancer.

I haven't had cancer in the last 5 years, except for skin cancer.

I have other medical conditions or another active cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive abemaciclib in combination with darolutamide and ADT at different dosages to determine the maximum tolerated dose

6 months

Evaluations every 12 weeks

Phase 2 Treatment

Participants are randomized to receive either abemaciclib, darolutamide, and ADT or darolutamide and ADT

6 months

PSA measured day 1 of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 4.5 years

Treatment Details

Interventions

• Abemaciclib
• Darolutamide
• Goserelin
• Leuprolide Acetate

Trial Overview The trial tests combining two oral drugs (abemaciclib and darolutamide) with standard hormone therapy for various stages of prostate cancer. The first phase will determine safe dosages before expanding into broader testing. About 93 participants will undergo treatment for six months followed by up to four-and-a-half years of monitoring.

Participant Groups

Group I: Phase 2 - Neoadjuvant Darolutamide, Ademaciclib, and ADT prior to Radical Prostatectomy Experimental Treatment 5 Interventions

per protocol, for 6, 28-day cycles

Group II: Phase 2 - Neoadjuvant Darolutamide and ADT prior to Radical Prostatectomy Experimental Treatment 4 Interventions

per protocol, for 6, 28-day cycles

Group III: Phase 1 Lead In in CRPC Experimental Treatment 5 Interventions

Standard 3+3 dose escalation scheme with 3 dose levels of abemaciclib and a constant dose of darolutamide, per protocol, for 6, 28-day cycles

Abemaciclib is already approved in United States, European Union for the following indications:

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Who Is Running the Clinical Trial?

Praful Ravi

Lead Sponsor

Trials

1

Recruited

9+

Praful Ravi, MB BCHir, MRCP

Lead Sponsor

Trials

1

Recruited

9+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Bayer

Industry Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

Findings from Research

Darolutamide (NUBEQA™) is a new non-steroidal androgen receptor antagonist approved for treating non-metastatic castration-resistant prostate cancer in men, based on positive results from the phase III ARAMIS trial.

The approval of darolutamide marks a significant milestone in prostate cancer treatment, highlighting its efficacy and safety profile as demonstrated in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darolutamide: First Approval. Markham, A., Duggan, S.[2020]

In a study involving 249 men with metastatic castrate-resistant prostate cancer, patient preference between darolutamide and enzalutamide was balanced, with no significant preference for either treatment (p = 0.92).

Darolutamide was associated with less fatigue and a moderate improvement in episodic memory compared to enzalutamide, suggesting it may offer a better quality of life for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA. Colomba, E., Jonas, SF., Eymard, JC., et al.[2023]

In a phase 3 trial involving 1509 men with nonmetastatic, castration-resistant prostate cancer, darolutamide significantly improved metastasis-free survival, with a median of 40.4 months compared to 18.4 months for placebo (hazard ratio 0.41).

The safety profile of darolutamide was comparable to placebo, with similar rates of adverse events and no increased risk of serious side effects like seizures or cognitive disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. Fizazi, K., Shore, N., Tammela, TL., et al.[2022]

Darolutamide, a novel nonsteroidal androgen receptor antagonist, has shown a favorable safety profile and significant antitumor activity in early trials for patients with metastatic castration-resistant prostate cancer (CRPC).

Ongoing phase III trials, such as ARAMIS and ARASENS, are evaluating darolutamide's effectiveness in improving metastasis-free survival and overall survival when combined with standard androgen deprivation therapy and docetaxel in men with high-risk nonmetastatic and metastatic hormone-sensitive prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer. Fizazi, K., Smith, MR., Tombal, B.[2019]

In a network meta-analysis of four trials involving treatments for castration-resistant, docetaxel-resistant metastatic prostate cancer, no significant differences in overall survival were found among abiraterone acetate, enzalutamide, cabazitaxel, and Radium-223.

However, enzalutamide showed a significant advantage over the other treatments in delaying PSA progression, suggesting it may be more effective in managing disease progression despite similar overall survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Metastatic, Castration-resistant, Docetaxel-resistant Prostate Cancer: A Systematic Review of Literature With a Network Meta-analysis of Randomized Clinical Trials. Tassinari, D., Cherubini, C., Roudnas, B., et al.[2021]

In the phase 3 ARAMIS trial, darolutamide significantly improved metastasis-free survival and overall survival in men with non-metastatic castration-resistant prostate cancer compared to placebo, indicating its efficacy when combined with ongoing androgen deprivation therapy.

Darolutamide was generally well tolerated, showing a low risk of central nervous system-related side effects, which is a common concern with other second-generation androgen receptor inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darolutamide: A Review in Non-Metastatic Castration-Resistant Prostate Cancer. Scott, LJ.[2022]

In a phase 2 study involving 60 patients with metastatic castration-resistant prostate cancer (mCRPC), enzalutamide treatment led to a significant decline in prostate-specific antigen (PSA) levels in 45% of patients, indicating its efficacy in managing this advanced cancer.

The study found that the presence of the androgen receptor variant ARV7 was linked to primary resistance to enzalutamide, suggesting that certain androgen signaling characteristics before treatment can predict patient response to the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. Efstathiou, E., Titus, M., Wen, S., et al.[2022]

The ERA 223 trial found that combining abiraterone with radium-223 did not improve survival free from symptomatic skeletal events in men with chemotherapy-naïve castration-resistant prostate cancer and bone metastases.

The lack of improvement in outcomes may be linked to bone loss caused by the use of prednisone, which was administered alongside the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Risk of Fragility Fractures in Prostate Cancer Patients Treated with Combined Radium-223 and Abiraterone: Prednisone May Be the Culprit. Dalla Volta, A., Formenti, AM., Berruti, A.[2022]

In a study of 60 patients with metastatic castration-resistant prostate cancer, combining radium-223 with either abiraterone or enzalutamide did not improve overall survival compared to radium-223 alone, with median survival times of 12.7 and 12.8 months respectively.

However, the combination treatment did significantly extend progression-free survival (7.6 months vs. 4.9 months), without increasing the risk of serious adverse events, suggesting a potential benefit in delaying disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer. Kim, SI., Szeto, AH., Morgan, KP., et al.[2021]

Darolutamide, an oral androgen receptor inhibitor, significantly improves overall survival in patients with metastatic hormone-sensitive prostate cancer when combined with androgen deprivation therapy and docetaxel, compared to placebo.

The treatment with darolutamide has a manageable safety profile, with adverse events aligning with those typically seen in androgen deprivation therapy and docetaxel, making it a viable option for patients with high-volume disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Darolutamide: A Review in Metastatic Hormone-Sensitive Prostate Cancer. Lee, A.[2023]

References

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

Darolutamide: First Approval. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

A Randomized, Open-label, Cross-over Phase 2 Trial of Darolutamide and Enzalutamide in Men with Asymptomatic or Mildly Symptomatic Metastatic Castrate-resistant Prostate Cancer: Patient Preference and Cognitive Function in ODENZA. [2023]

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

Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. [2022]

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

Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer. [2019]

5. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Treatment of Metastatic, Castration-resistant, Docetaxel-resistant Prostate Cancer: A Systematic Review of Literature With a Network Meta-analysis of Randomized Clinical Trials. [2021]

6. France pubmed.ncbi.nlm.nih.gov

Darolutamide: A Review in Non-Metastatic Castration-Resistant Prostate Cancer. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Higher Risk of Fragility Fractures in Prostate Cancer Patients Treated with Combined Radium-223 and Abiraterone: Prednisone May Be the Culprit. [2022]

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

A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer. [2021]

10. France pubmed.ncbi.nlm.nih.gov

Darolutamide: A Review in Metastatic Hormone-Sensitive Prostate Cancer. [2023]