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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness and safety of two drugs, abemaciclib (a cancer treatment) and atezolizumab (an immunotherapy drug), for treating metastatic prostate cancer that no longer responds to traditional hormone therapy. The trial examines how these drugs work alone or together to shrink or halt the cancer's growth. Men with prostate cancer that has spread and shown resistance or intolerance to other treatments might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, providing an opportunity to access potentially effective therapies early.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that atezolizumab, when used alone, is usually well-tolerated by patients. In studies, patients lived for an average of 14.7 months. However, responses vary, and some people might experience side effects.

Abemaciclib, another treatment under study, targets specific proteins that aid cancer cell growth and has shown potential in shrinking tumors. It is generally well-tolerated, but some individuals might experience side effects.

The combination of abemaciclib and atezolizumab is still undergoing safety testing for prostate cancer. Since this combination is new, some side effects might not yet be fully understood.

Both treatments have been used in other cancer types, providing some insight into their safety. However, using them together for prostate cancer is new. By joining the trial, participants help researchers learn more about the safety and effectiveness of this combination for this condition. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Abemaciclib and Atezolizumab for prostate cancer due to their unique mechanisms. Unlike traditional hormone therapies, Abemaciclib targets CDK4 and CDK6, proteins that help cancer cells grow, offering a new way to slow down tumor growth. Atezolizumab, on the other hand, is an immunotherapy that helps the immune system recognize and attack cancer cells, a fresh approach compared to standard chemotherapy. Together, they may provide a more comprehensive attack on prostate cancer by combining targeted therapy with the body's natural defenses.

What evidence suggests that this trial's treatments could be effective for prostate cancer?

Studies have shown that atezolizumab, when used alone, can help some patients with advanced prostate cancer live for about 14.7 months on average. However, it usually works better when combined with other treatments. In this trial, some participants will receive atezolizumab monotherapy, while others will receive a combination of abemaciclib and atezolizumab. Abemaciclib, another treatment, has shown promise by slowing the disease in some cases. Researchers are testing the combination of abemaciclib and atezolizumab because they might work better together, especially in patients with certain genetic traits like CDK12 mutations. Abemaciclib could help stop cancer cells from growing, while atezolizumab helps the immune system fight the cancer. Early research suggests this combination might be more effective than using either drug alone. ^{1 5 6 7 8}

Who Is on the Research Team?

Atish D. Choudhury

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38512117/

A Signal-Finding Study of Abemaciclib in Heavily ... Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04408924

Study Details | NCT04408924 | Abemaciclib (LY2835219) ... The study will evaluate how safe and effective abemaciclib is when given to participants whose metastatic prostate cancer progresses after they had received ...

3. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(25)00475-9/abstract

Abemaciclib plus abiraterone in patients with metastatic ... Abemaciclib, a potent CDK4 and CDK6 inhibitor, has shown antitumour activity in prostate cancer models and in patients with metastatic castration-resistant ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41167216/

Abemaciclib plus abiraterone in patients with metastatic ... Median radiographic progression-free survival was 22·0 months (95% CI 19·3-27·5) for abemaciclib plus abiraterone and 20·3 months (16·5-24·4) for placebo plus ...

5. aacrjournals.org aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-23-3436/3441478/ccr-23-3436.pdf

A Signal-Finding Study of Abemaciclib in Heavily Pretreated ... Results: At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)–only progression ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05288166

NCT05288166 | A Study of Abemaciclib (LY2835219) With ... The purpose of this study is to learn whether adding abemaciclib to abiraterone plus prednisone prolongs the time before prostate cancer gets worse.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1470204525004759

Abemaciclib plus abiraterone in patients with metastatic ... Abemaciclib, a potent CDK4 and CDK6 inhibitor, has shown antitumour activity in prostate cancer models and in patients with metastatic castration-resistant ...

8. urotoday.com urotoday.com/conference-highlights/asco-2024/asco-2024-prostate-cancer/152472-asco-2024-cyclone-2-a-phase-3-study-of-abemaciclib-with-abiraterone-in-patients-with-mcrpc.html

ASCO 2024: CYCLONE 2: A Phase 3 study of Abemaciclib ... The addition of abemaciclib to abiraterone did not significantly improve radiographic progression free survival in patients with mCRPC · Safety ...