Abemaciclib +/− Atezolizumab for Prostate Cancer

Overseen By Atish Choudhury, MD, PhD

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must be taking: LHRH agonist or antagonist

Must not be taking: CYP3A4 inducers or inhibitors

Disqualifiers: CNS disease, Active malignancy, Autoimmune, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 22

Duration: up to 2 years

75 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing whether a molecularly targeted chemotherapy drug called abemaciclib and an immunotherapy drug called atezolizumab, alone or in combination, are effective in shrinking or preventing the growth of metastatic prostate cancer. The trial is also testing the safety of the combination of abemaciclib with atezolizumab.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting, such as chemotherapy or radiotherapy within 4 weeks and oral anti-cancer drugs within 14 days. If you're on a CYP3A4 inducer or inhibitor, it must be stopped at least five half-lives before starting the trial.

What data supports the effectiveness of the drug Abemaciclib +/− Atezolizumab for prostate cancer?

Some studies suggest that atezolizumab, when combined with other treatments, may benefit certain patients with prostate cancer, especially those with specific immune markers. However, the overall effectiveness of atezolizumab in improving survival for prostate cancer patients has not been consistently demonstrated, indicating that more research is needed to identify which patients might benefit the most. ^{1 2 3 4 5}

How is the drug combination of Abemaciclib and Atezolizumab unique for prostate cancer treatment?

The combination of Abemaciclib, a cell cycle inhibitor, and Atezolizumab, an immune checkpoint inhibitor, is unique because it targets both cancer cell growth and the immune system, offering a novel approach for treating prostate cancer, especially in cases resistant to standard hormone therapies. ^{1 2 4 5 6}

Research Team

Atish D. Choudhury

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adult males with metastatic castration-resistant prostate cancer (mCRPC) who have progressive disease and are not candidates for certain chemotherapies. They must have tried at least one antiandrogen therapy, maintain low testosterone levels, and be in good enough health to participate. Men with untreated brain metastases or active autoimmune diseases treated recently are excluded.

Inclusion Criteria

creatinine clearance ≥30 mL/min/1.73 m2

My tumor has not been tested with NGS; I can join the unselected study groups.

My doctor thinks taxane treatment isn't right for me.

Exclusion Criteria

Any of the following abnormalities on pre-treatment pulmonary function testing:

I have had radiation therapy to my chest area before.

Active smoking or a history of smoking greater than 20 pack-years (i.e. # packs of cigarettes smoked per day × # of years patient has smoked > 20)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive abemaciclib and atezolizumab alone or in combination, with treatment cycles every 21 days

up to 2 years

Every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 24 months

Regular follow-up visits

Treatment Details

Interventions

• Abemaciclib
• Atezolizumab

Trial Overview The trial examines the effectiveness of abemaciclib alone or combined with atezolizumab in treating mCRPC. It also assesses the safety of this combination therapy. Participants will receive molecularly targeted chemotherapy and immunotherapy drugs to see if they can shrink or halt tumor growth.

Participant Groups

Group I: CDK12 Mutation Atezolizumab Monotherapy (Non-Randomized) Experimental Treatment 1 Intervention

Participants in the CDK12 Mutation Cohort defined as those whose tumors are known to have mutations in the CDK12 gene are not randomized but are assigned to receive either Atezolizumab monotherapy or in combination with Abemaciclib based on how many participants in this cohort previously received study treatment. Atezolizumab monotherapy will be given to participants 1-5, these participants will receive Atezolizumab intravenously Day 1 of each 21-Day cycle

Group II: CDK12 Mutation Abemaciclib + Atezolizumab (Non-Randomized) Experimental Treatment 2 Interventions

Participants in the CDK12 Mutation Cohort defined as those whose tumors are known to have mutations in the CDK12 gene are not randomized but are assigned to receive either Atezolizumab monotherapy or in combination with Abemaciclib based on how many participants in this cohort previously received study treatment. Combination Therapy will be given to participants 6-21, these participants will receive Abemaciclib orally 2x daily and Atezolizumab intravenously Day 1 of each 21-Day cycle

Group III: Biomarker-Unselected Abemaciclib Monotherapy (Randomized) Experimental Treatment 1 Intervention

Participants in the Biomarker-Unselected Cohort, defined as those whose tumors are not known to have mutations in the CDK12 gene will be randomized to either receive Abemaciclib as monotherapy or in combination with Atezolizumab * Monotherapy : Participants will receive Abemaciclib orally 2x daily

Group IV: Biomarker-Unselected Abemaciclib + Atezolizumab (Randomized) Experimental Treatment 2 Interventions

Participants in the Biomarker-Unselected Cohort, defined as those whose tumors are not known to have mutations in the CDK12 gene will be randomized to either receive Abemaciclib as monotherapy or in combination with Atezolizumab * Combination Therapy: Participants will receive Abemaciclib orally 2x daily and Atezolizumab intravenously Day 1 of each 21-Day cycle

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?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

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

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

Atezolizumab, an anti-PD-L1 therapy, was generally well tolerated in 35 patients with metastatic castration-resistant prostate cancer (mCRPC), showing a safety profile similar to that observed in other cancers, with no treatment-related deaths.

While there was some evidence of disease control, with a median overall survival of 14.7 months, the efficacy was limited, indicating that atezolizumab may be more effective when used in combination with other treatments rather than as a monotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of Atezolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase I Study. Petrylak, DP., Loriot, Y., Shaffer, DR., et al.[2022]

Combining atezolizumab, an anti-PD-L1 immunotherapy, with enzalutamide, an androgen receptor antagonist, did not improve survival rates in patients with metastatic prostate cancer.

Further research is needed to understand the mechanisms of resistance to immunotherapy in the prostate tumor microenvironment, which may help improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. Siddiqui, BA., Subudhi, SK., Sharma, P.[2023]

The IMbassador250 trial involving 759 men with metastatic castration-resistant prostate cancer found that adding atezolizumab to enzalutamide did not improve overall survival, although it had an acceptable safety profile.

However, patients with high levels of PD-L1 expression and certain immune gene signatures showed longer progression-free survival, suggesting that careful patient selection could enhance the effectiveness of immune checkpoint inhibitors in this cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Powles, T., Yuen, KC., Gillessen, S., et al.[2023]

Cabozantinib, which inhibits multiple receptor tyrosine kinases, is being evaluated in combination with the PD-L1 inhibitor atezolizumab for its potential to enhance treatment responses in men with metastatic castration-resistant prostate cancer (mCRPC).

A phase III trial (NCT04446117) is being designed to compare the efficacy of cabozantinib plus atezolizumab against a second novel hormone therapy in patients with mCRPC who have previously received hormone treatments, addressing a significant need for effective options in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer. Agarwal, N., Azad, A., Carles, J., et al.[2022]

In a study involving 132 patients with metastatic castration-resistant prostate cancer, the combination of cabozantinib and atezolizumab demonstrated an objective response rate of 23%, indicating promising antitumor activity after prior hormonal therapies.

While the treatment showed efficacy, 55% of patients experienced grade 3-4 treatment-related adverse events, with pulmonary embolism and diarrhea being the most common, suggesting that while the combination is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Agarwal, N., McGregor, B., Maughan, BL., et al.[2022]

In a phase I/II trial involving men with androgen-independent prostate cancer, the combination of thalidomide, paclitaxel, and estramustine showed promising efficacy, with 76% of patients experiencing a significant decrease in prostate-specific antigen levels.

The treatment was generally well-tolerated, with minimal dose-limiting toxicity at the lowest thalidomide dose (200 mg daily), and only 13% of patients experiencing significant adverse effects, suggesting a favorable safety profile for further studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thalidomide/estramustine/paclitaxel in metastatic androgen-independent prostate cancer. Mathew, P., Logothetis, CJ., Dieringer, PY., et al.[2016]

References

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

Safety and Clinical Activity of Atezolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase I Study. [2022]

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

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer. [2023]

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

Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. [2023]

4. England pubmed.ncbi.nlm.nih.gov

A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). [2022]

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

Thalidomide/estramustine/paclitaxel in metastatic androgen-independent prostate cancer. [2016]