ATR + PARP Inhibitors for Prostate Cancer

Recruiting at 2 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: University of Michigan Rogel Cancer Center

Must be taking: Androgen deprivation therapy

Must not be taking: PARP inhibitors, CYP3A inhibitors

Disqualifiers: Ataxia telangiectasia, MDS/AML, 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: Unknown

Duration: 1 year

49 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the effectiveness (how well the drugs work), safety, and tolerability of the investigational drug combination of olaparib and AZD6738 for all patients with metastatic castration-resistant prostate cancer.

Will I have to stop taking my current medications?

The trial requires that you stop certain medications before starting the study. You must be off prior therapies for at least 3 weeks, except for prednisone up to 10 mg daily. Some medications, like enzalutamide, require a longer washout period (time without taking the medication) of 5 weeks.

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

Research shows that Olaparib, a drug that blocks a DNA repair pathway, is effective in treating advanced prostate cancer, especially in patients with specific genetic mutations that affect DNA repair. It has been approved by the FDA for use in certain prostate cancer cases and has shown promising results in clinical trials. ^{1 2 3 4 5}

Is the combination of ATR and PARP inhibitors, like Olaparib, safe for humans?

Olaparib, a PARP inhibitor, has been approved for certain prostate cancers and has been studied for safety. Some patients may experience side effects, but it is generally considered safe for use in humans with specific genetic mutations. ^{2 5 6 7 8}

How is the drug combination of Olaparib and AZD6738 unique for prostate cancer treatment?

This treatment is unique because it combines Olaparib, a PARP inhibitor that blocks DNA repair in cancer cells, with AZD6738, an ATR inhibitor that targets a different part of the DNA repair process, potentially enhancing the effectiveness against prostate cancer with DNA repair defects. ^{1 4 5 9 10}

Research Team

Zachery R. Reichert

Principal Investigator

University of Michigan Rogel Cancer Center

Eligibility Criteria

Men over 18 with advanced prostate cancer that's resistant to castration and has spread, showing progression despite hormone therapy. They must have good performance status, adequate organ function, agree to use contraception, and not have had certain treatments or conditions that could interfere with the trial.

Inclusion Criteria

I am on hormone therapy for cancer and my testosterone is very low.

My cancer has grown or spread, as shown by recent scans.

Your PSA levels have been continuously increasing for at least a week and started at a minimum of 1.0 ng/mL.

Exclusion Criteria

I can swallow pills and don't have serious stomach or bowel issues affecting medication absorption.

I don't have active brain cancer, but if I had it before, it's now stable and I've finished all treatments for it over 3 weeks ago.

I have had episodes of fainting or near-fainting not caused by reversible reasons.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the investigational drug combination of olaparib and AZD6738

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Olaparib and AZD6738

Trial Overview The TRAP Trial is testing a combination of two drugs, Olaparib and AZD6738, for their effectiveness in treating metastatic castration-resistant prostate cancer. The study will assess how well these drugs work together and monitor patients' safety and tolerance to this treatment regimen.

Participant Groups

Group I: Cohort 2 (DRDef) Experimental Treatment 2 Interventions

Patients with metastatic castration-resistant prostate cancer (mCRPC) who are DNA repair deficient (DRDef).

Group II: Cohort 1 (DRPro) Experimental Treatment 2 Interventions

Patients with metastatic castration-resistant prostate cancer (mCRPC) who are DNA repair proficient (DRPro).

Who Is Running the Clinical Trial?

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

Findings from Research

In a phase 2 trial involving 50 patients with metastatic, castration-resistant prostate cancer, treatment with the PARP inhibitor olaparib resulted in a 33% response rate, particularly among patients with DNA-repair gene defects, such as BRCA1/2 and ATM.

Among the 16 patients with identified DNA-repair defects, 88% responded to olaparib, highlighting the efficacy of this treatment in a specific subgroup of prostate cancer patients, while the most common side effects were anemia and fatigue, consistent with previous studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. Mateo, J., Carreira, S., Sandhu, S., et al.[2022]

BRCA1 and BRCA2 mutations significantly increase the risk and aggressiveness of prostate cancer, highlighting the importance of genetic testing in prostate oncology.

Olaparib, an oral PARP inhibitor, has shown efficacy and good tolerance in phase II trials for patients with advanced castration-resistant prostate cancer, making it a promising treatment option while awaiting further phase III trial results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defective DNA repair mechanisms in prostate cancer: impact of olaparib. De Felice, F., Tombolini, V., Marampon, F., et al.[2018]

PARP inhibitors, specifically olaparib and rucaparib, have demonstrated effective antitumor activity and are FDA-approved for treating metastatic castrate-resistant prostate cancer with specific DNA repair defects.

Ongoing clinical trials for other PARP inhibitors like talazoparib, veliparib, and niraparib suggest that more treatment options may soon be available for patients with similar conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DNA Repair and Prostate Cancer: A Field Ripe for Harvest. Bryce, AH., Sartor, O., de Bono, J.[2021]

In a phase 2 trial involving 142 patients with metastatic castration-resistant prostate cancer, the combination of olaparib and abiraterone significantly improved radiographic progression-free survival (rPFS) to a median of 13.8 months compared to 8.2 months with placebo and abiraterone, indicating enhanced efficacy of the treatment.

While the combination treatment showed clinical benefits, it also resulted in a higher incidence of serious adverse events, including a treatment-related death, suggesting that while effective, the combination may carry increased risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Clarke, N., Wiechno, P., Alekseev, B., et al.[2019]

Olaparib was found to be effective in treating metastatic castration-resistant prostate cancer (mCRPC) patients with BRCA mutations, showing a high response rate in 89% of these patients, compared to lower response rates in those without such mutations.

While most adverse events (AEs) were manageable, common side effects included fatigue (70%), anemia (65%), and decreased appetite (55%), with some patients experiencing severe AEs, indicating that while Olaparib is effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib outcomes in metastatic castration-resistant prostate cancer: First real-world experience in safety and efficacy from the Chinese mainland. Pan, J., Ye, D., Zhu, Y.[2022]

References

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

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. [2022]

2. England pubmed.ncbi.nlm.nih.gov

PARP inhibitors in castration-resistant prostate cancer. [2021]

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

Emerging Role of PARP Inhibitors in Metastatic Prostate Cancer. [2023]

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

Defective DNA repair mechanisms in prostate cancer: impact of olaparib. [2018]

5. Switzerland pubmed.ncbi.nlm.nih.gov

DNA Repair and Prostate Cancer: A Field Ripe for Harvest. [2021]

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

Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. [2019]

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

Olaparib-Induced Senescence Is Bypassed through G2-M Checkpoint Override in Olaparib-Resistant Prostate Cancer. [2022]

8. Korea (South) pubmed.ncbi.nlm.nih.gov

Olaparib outcomes in metastatic castration-resistant prostate cancer: First real-world experience in safety and efficacy from the Chinese mainland. [2022]

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

Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer. [2023]

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

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. [2023]