ATR + PARP Inhibitors for Prostate Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs, olaparib (a PARP inhibitor) and AZD6738 (an ATR inhibitor), to evaluate their effectiveness and safety in treating metastatic castration-resistant prostate cancer. Researchers focus on patients whose prostate cancer has spread and no longer responds to hormone treatments. The study includes two groups: one with patients whose DNA can repair itself normally and another with patients whose DNA repair is faulty. Men with prostate cancer that has spread and progressed despite previous treatments might be suitable for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that olaparib, one of the drugs under study, has been tested in patients with metastatic prostate cancer. It was generally well-tolerated, with most patients not experiencing serious problems, though some did have side effects. The most common side effects were nausea and tiredness, which were usually manageable.

In other studies, AZD6738, another drug being tested, was used in patients with advanced solid tumors. Side effects like tiredness and nausea occurred but were not severe for most patients.

Both drugs are currently being tested together to assess their safety and effectiveness. This trial is in its second phase, building on earlier safety data. This indicates that the treatments have shown enough promise and safety in previous studies to warrant further research. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for prostate cancer?

Researchers are excited about using Olaparib and AZD6738 for prostate cancer because they target specific weaknesses in cancer cells. Most current treatments for metastatic castration-resistant prostate cancer (mCRPC) focus on hormone therapy, but Olaparib is a PARP inhibitor that exploits the cancer cells' reliance on DNA repair mechanisms, leading to their destruction. AZD6738, on the other hand, is an ATR inhibitor that prevents cancer cells from repairing DNA damage, making them more vulnerable to treatment. This dual-target approach could offer a new, more effective way to tackle mCRPC, especially in patients with DNA repair deficiencies.

What evidence suggests that this treatment might be an effective treatment for prostate cancer?

Research has shown that combining olaparib and AZD6738 may offer promise for treating advanced prostate cancer that no longer responds to hormone therapy. In this trial, participants will be divided into two cohorts: Cohort 1 includes patients with DNA repair proficient (DRPro) metastatic castration-resistant prostate cancer, and Cohort 2 includes those with DNA repair deficient (DRDef) cancer. Olaparib blocks a protein called PARP and has been effective in about 33% of patients, regardless of certain DNA repair mutations. Early results suggest that adding AZD6738, which blocks another protein called ATR, could extend the time patients live without their cancer worsening compared to using just one drug. This combination impairs cancer cells' ability to repair damaged DNA, potentially slowing or stopping their growth. ^{1 3 5 6 7}

Who Is on the Research Team?

Zachery R. Reichert

Principal Investigator

University of Michigan Rogel Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

Citations

1. cancertreatmentreviews.com cancertreatmentreviews.com/article/S0305-7372(23)00116-0/fulltext

Efficacy and safety of PARP inhibitors in metastatic ... We conducted a systematic review and meta-analysis to comprehensively evaluate the efficacy and safety of PARPi in patients with metastatic prostate cancer.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8450162/

Clinical Utility of Olaparib in the Treatment of Metastatic ... Treatment with olaparib resulted in a composite response rate of 33% (95% CI 20–48) for patients with and without DDR mutations combined. Of ...

3. withpower.com withpower.com/trial/phase-3-prostatic-neoplasms-9-2019-14adc

ATR + PARP Inhibitors for Prostate Cancer Olaparib, an oral PARP inhibitor, has shown efficacy and good tolerance in phase II trials for patients with advanced castration-resistant prostate cancer, ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0093775423000623

PARP inhibitors for prostate cancer Preliminary results show a markedly improved rPFS with a median rPFS not reached in the combination arm versus 11 months in both single-drug arms and 12-month ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03682289

NCT03682289 | Ceralasertib (AZD6738) Alone and in ... This phase II trial studies how well ceralasertib, am Ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor, works alone or in combination with ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10587563/

Efficacy and safety of olaparib combined with abiraterone ... The use of olaparib in combination with abiraterone was significantly associated with improved rPFS in patients with mCRPC (n = 938, p < 0.01), ...

7. dovepress.com dovepress.com/clinical-utility-of-olaparib-in-the-treatment-of-metastatic-castration-peer-reviewed-fulltext-article-OTT

Olaparib for metastatic castration-resistant prostate cancer In cohort A, olaparib resulted in improved objective response (33.3 vs 2%; OR 20.86; 95% CI 4.18–379.18, p < 0.001) and improved PFS (7.4 months ...