Talazoparib + ADT + Abiraterone for Prostate Cancer

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must be taking: LHRH therapy

Must not be taking: Ketoconazole, Enzalutamide

Disqualifiers: Brain metastases, Heart failure, 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

Compensation: Varies

Number of Visits: 1

Duration: Up to 2 years

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of talazoparib with androgen deprivation therapy and abiraterone in treating castration sensitive prostate cancer patients. Talazoparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Androgen can cause the growth of prostate tumor cells. Degarelix, leuprolide acetate, bicalutamide, goserelin acetate, and abiraterone lowers the amount of androgen made by the body. This may help stop the growth of tumor cells that need androgen to grow. Giving talazoparib with androgen deprivation therapy and abiraterone may improve cancer control for patients with castration sensitive prostate cancer.

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

The trial requires that you stop taking bicalutamide at registration. Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Talazoparib + ADT + Abiraterone for prostate cancer?

Research shows that Abiraterone acetate, when used with prednisone, significantly extends survival and delays disease progression in patients with metastatic castration-resistant prostate cancer. This suggests that Abiraterone is effective in treating advanced prostate cancer. ^{1 2 3 4 5}

Is the combination of Talazoparib and Abiraterone safe for humans?

Talazoparib has shown a manageable safety profile in men with metastatic prostate cancer, and Abiraterone has been used safely in combination with other medications for prostate cancer treatment. ^{2 6 7 8 9}

How is the drug combination of Talazoparib, ADT, and Abiraterone unique for prostate cancer?

This drug combination is unique because it combines Talazoparib, a PARP inhibitor that targets cancer cells with DNA repair issues, with Abiraterone, which blocks hormone production that fuels prostate cancer, and ADT (androgen deprivation therapy) to potentially enhance treatment effectiveness for prostate cancer. ^{2 6 8 10 11}

Research Team

Tanya Dorff, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for men with castration sensitive prostate cancer that has spread, and who have not had certain treatments. They must be able to perform daily activities without significant assistance (Karnofsky performance status of 60-100). Participants need normal liver function tests, a creatinine clearance >=30 mL/min, and agree to use contraception or abstain from intercourse during the study.

Inclusion Criteria

My cancer has spread to other parts of my body, including bones or soft tissues.

Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x institutional ULN, or =< 5 x institutional ULN if liver metastases are present (obtained within 28 days prior to registration)

I am taking or plan to take bone-strengthening drugs that don't affect PSA levels.

Exclusion Criteria

I do not have a history of adrenal insufficiency.

I finished chemotherapy aimed at curing my cancer more than 2 years ago.

I have not had chemotherapy for metastatic prostate cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive talazoparib, abiraterone acetate, and prednisone daily, along with androgen deprivation therapy. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Monthly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks

1 visit (in-person) at 30 days post-treatment

Treatment Details

Interventions

• Abiraterone Acetate
• Talazoparib

Trial Overview The trial is testing talazoparib combined with androgen deprivation therapy (ADT) and abiraterone. Talazoparib blocks an enzyme called PARP which helps repair DNA in tumor cells; ADT lowers body's production of androgens that can promote tumor growth; abiraterone works alongside ADT to further reduce androgen levels.

Participant Groups

Group I: Treatment (talazoparib, androgen deprivation therapy) Experimental Treatment 8 Interventions

Patients receive talazoparib PO QD, abiraterone acetate PO QD, and prednisone PO QD on days 1-28. Patients also receive androgen deprivation therapy consisting of degarelix SC on day 1; leuprolide acetate IM on day 1 and bicalutamide PO QD on days 1-28 of cycle 1 and then leuprolide acetate IM on day 1 of subsequent cycles; leuprolide acetate IM on day 1 and bicalutamide PO QD on days 1-28 of cycle 1 and then leuprolide acetate IM on day 1 of cycles 2, 5, 8, and 11; or goserelin acetate SC monthly or every 3 months. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Abiraterone Acetate is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Zytiga for:

• Metastatic castration-resistant prostate cancer
• Metastatic high-risk castration-sensitive prostate cancer

Approved in European Union as Zytiga for:

• Metastatic castration-resistant prostate cancer
• Newly diagnosed high-risk metastatic hormone-sensitive prostate cancer

Approved in Canada as Zytiga for:

• Metastatic castration-resistant prostate cancer
• Metastatic castration-sensitive prostate cancer

Approved in Japan as Zytiga for:

• Prostate cancer

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

Oral abiraterone acetate (Zytiga®) significantly improves overall survival and progression-free survival in patients with metastatic castration-resistant prostate cancer (CRPC) when used with prednisone, compared to a placebo.

The treatment is specifically effective for patients who have already undergone docetaxel-containing chemotherapy, highlighting its role as a subsequent therapy in advanced prostate cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate: a guide to its use in metastatic castration-resistant prostate cancer. Scott, LJ., Yang, LPH., Lyseng-Williamson, KA.[2021]

In a phase II study of 30 men with metastatic castration-resistant prostate cancer (mCRPC), treatment with abiraterone acetate (AA) led to undetectable testosterone levels in metastatic biopsies after 4 weeks, indicating effective suppression of androgens in the tumor environment.

Low levels of serum dehydroepiandrosterone sulfate (DHEAS) before treatment were linked to rapid disease progression, suggesting that patients with higher DHEAS levels may respond better to AA, while those with low levels might need alternative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer. Mostaghel, EA., Marck, BT., Kolokythas, O., et al.[2022]

In a study of 133 patients with non-metastatic castration-resistant prostate cancer, abiraterone acetate (AA) plus prednisone showed comparable overall survival and cancer-specific survival to enzalutamide (Enz) over a median follow-up of 36 months.

However, patients treated with AA plus prednisone had a significantly higher risk of non-cancer-caused death compared to those treated with Enz, suggesting that while both treatments are effective, AA plus prednisone may pose additional safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world survival outcome comparing abiraterone acetate plus prednisone and enzalutamide for nonmetastatic castration-resistant prostate cancer. Tsujino, T., Tokushige, S., Komura, K., et al.[2023]

Abiraterone acetate (AA) effectively inhibits CYP17, leading to significantly reduced testosterone levels and extending survival for men with metastatic castration-resistant prostate cancer after first-line chemotherapy.

AA is currently being evaluated in a Phase III trial for use before chemotherapy, indicating its potential as an early treatment option for prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate: redefining hormone treatment for advanced prostate cancer. Pezaro, CJ., Mukherji, D., De Bono, JS.[2015]

In the phase II TALAPRO-1 study involving 127 men with metastatic castration-resistant prostate cancer, talazoparib demonstrated a manageable safety profile, with 95.3% of participants experiencing treatment-emergent adverse events, primarily mild to moderate in severity.

The most common adverse events included anemia (48.8%), nausea (33.1%), and decreased appetite (28.3%), but serious complications were rare, with no grade 5 events or treatment-related deaths, indicating that talazoparib can be safely administered with appropriate monitoring and supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talazoparib, a Poly(ADP-ribose) Polymerase Inhibitor, for Metastatic Castration-resistant Prostate Cancer and DNA Damage Response Alterations: TALAPRO-1 Safety Analyses. Mehra, N., Fizazi, K., de Bono, JS., et al.[2023]

In a study of 68 patients with metastatic prostate cancer treated with abiraterone acetate, higher plasma trough concentrations of abiraterone (≥ 20.6 ng/mL) were significantly linked to an increased risk of adverse events (AEs) and treatment withdrawal.

Monitoring abiraterone plasma levels may be beneficial for managing treatment in prostate cancer patients, as high concentrations were identified as independent risk factors for both AEs and the time to discontinue therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate. Takahashi, Y., Narita, S., Shiota, M., et al.[2023]

The TALAPRO-2 trial is an ongoing study involving 1037 men with metastatic castration-resistant prostate cancer, testing the combination of talazoparib and enzalutamide to see if it improves survival without cancer progression compared to enzalutamide plus a placebo.

This trial aims to assess not only the efficacy of the drug combination but also the side effects experienced by participants, while also analyzing tumor DNA for faulty repair genes, which could provide insights into treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plain language summary of the design of the TALAPRO-2 study comparing talazoparib and enzalutamide versus enzalutamide and placebo in men with metastatic castration-resistant prostate cancer. Agarwal, N., Azad, A., Shore, ND., et al.[2022]

In the TALAPRO-1 study involving 97 men with metastatic castration-resistant prostate cancer (mCRPC), talazoparib significantly improved health-related quality of life (HRQoL) and reduced pain levels, particularly in patients with BRCA1/2 mutations.

The study found that 84% of all patients and 83% of those with BRCA1/2 mutations did not experience a deterioration in worst pain after 12 months of treatment, indicating a high probability of maintaining pain relief while receiving talazoparib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Harboring DNA Damage Response Alterations Treated with Talazoparib: Results from TALAPRO-1. Saad, F., de Bono, J., Barthélémy, P., et al.[2023]

The TALAPRO-2 study is a phase III clinical trial designed to evaluate the effectiveness of talazoparib combined with enzalutamide compared to placebo with enzalutamide in treating metastatic castration-resistant prostate cancer (mCRPC).

The study aims to determine if this combination therapy can significantly improve radiographic progression-free survival (rPFS) in patients with or without DNA damage response (DDR) alterations, potentially enhancing treatment outcomes for mCRPC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: TALAPRO-2 phase III study design. Agarwal, N., Azad, A., Shore, ND., et al.[2022]

The TALAPRO-3 study is a phase III clinical trial designed to evaluate the effectiveness of combining talazoparib, a poly(ADP-ribose) polymerase inhibitor, with enzalutamide in patients with metastatic castration-sensitive prostate cancer (mCSPC) who have homologous recombination repair (HRR) gene alterations.

The primary goal of the study is to determine if this combination therapy can improve radiographic progression-free survival (rPFS) compared to enzalutamide alone, potentially offering a new treatment strategy for patients with specific genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TALAPRO-3 clinical trial protocol: phase III study of talazoparib plus enzalutamide in metastatic castration-sensitive prostate cancer. Agarwal, N., Saad, F., Azad, AA., et al.[2023]

References

1. 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]

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

Abiraterone acetate: a guide to its use in metastatic castration-resistant prostate cancer. [2021]

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

Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer. [2022]

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

Real-world survival outcome comparing abiraterone acetate plus prednisone and enzalutamide for nonmetastatic castration-resistant prostate cancer. [2023]

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

Abiraterone acetate: redefining hormone treatment for advanced prostate cancer. [2015]

6. England pubmed.ncbi.nlm.nih.gov

Talazoparib, a Poly(ADP-ribose) Polymerase Inhibitor, for Metastatic Castration-resistant Prostate Cancer and DNA Damage Response Alterations: TALAPRO-1 Safety Analyses. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate. [2023]

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

Plain language summary of the design of the TALAPRO-2 study comparing talazoparib and enzalutamide versus enzalutamide and placebo in men with metastatic castration-resistant prostate cancer. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Patient-reported Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Harboring DNA Damage Response Alterations Treated with Talazoparib: Results from TALAPRO-1. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: TALAPRO-2 phase III study design. [2022]

11. England pubmed.ncbi.nlm.nih.gov

TALAPRO-3 clinical trial protocol: phase III study of talazoparib plus enzalutamide in metastatic castration-sensitive prostate cancer. [2023]