Cediranib + Olaparib for Advanced Prostate Cancer

Recruiting at 16 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: LHRH agonists

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Brain metastases, Cardiac arrhythmia, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Varies (up to 5 years)

90 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase II trial studies how well olaparib with or without cediranib works in treating patients with castration-resistant prostate cancer that has spread to other places in the body (metastatic). PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Cediranib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving olaparib and cediranib may help treat patients with castration-resistant prostate cancer.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for specific drugs. If you are taking strong or moderate CYP3A inhibitors or inducers, you will need to stop them for a certain period before starting the trial. Additionally, natural herbal products must be stopped, but multivitamins and certain supplements are allowed.

What data supports the effectiveness of the drug combination Cediranib and Olaparib for advanced prostate cancer?

Research shows that Cediranib can make prostate cancer cells more sensitive to Olaparib, a drug that targets cancer cells with DNA-repair defects. This combination has been studied for improving outcomes in patients with advanced prostate cancer. ^{1 2 3 4 5}

Is the combination of Cediranib and Olaparib safe for humans?

The combination of Cediranib and Olaparib has been studied for safety in various cancers, including ovarian and prostate cancer. It has been generally considered safe, but like all treatments, it may have side effects, which should be discussed with a healthcare provider. ^{1 2 6 7 8}

What makes the drug combination of Cediranib and Olaparib unique for advanced prostate cancer?

The combination of Cediranib and Olaparib is unique because Cediranib enhances the effectiveness of Olaparib by suppressing certain genes involved in DNA repair, making cancer cells more sensitive to treatment. This approach is different from standard treatments as it targets the cancer's ability to repair itself, potentially improving outcomes for patients with advanced prostate cancer. ^{1 2 4 6 7}

Research Team

Joseph W. Kim, MD

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

Men with advanced prostate cancer that has spread and is resistant to castration treatment. Participants must have had at least one prior therapy for metastatic castration-resistant prostate cancer (mCRPC), be able to swallow pills, and not have untreated brain metastases or a history of allergic reactions to similar drugs. They should also meet specific health criteria like controlled blood pressure, adequate organ function, and agree to use contraception.

Inclusion Criteria

Tumor lesion safely accessible for biopsy

Toxicities of prior therapy resolved to =< grade 1 as per NCI-CTCAE v5.0

Platelets >= 100,000/mcL

Exclusion Criteria

History of stroke or transient ischemic attack within 6 months of the randomization

You have experienced a blocked bowel within the month before starting the study.

You have taken any experimental drugs within the last 28 days before the start of the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive olaparib with or without cediranib in 28-day cycles until disease progression or unacceptable toxicity

Varies (up to 5 years)

Monthly visits for treatment cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 6 months

Biannual follow-up visits

Treatment Details

Interventions

• Cediranib
• Olaparib

Trial Overview The trial is testing if combining two oral medications, Cediranib and Olaparib, is more effective than using just Olaparib in men with advanced prostate cancer. The study will randomly assign participants into groups receiving either the combination or the single drug to compare their effects on tumor growth.

Participant Groups

Group I: Arm A (olaparib, cediranib) Experimental Treatment 2 Interventions

Patients receive olaparib PO BID and cediranib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm B (olaparib) Active Control 1 Intervention

Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Olaparib is already approved in European Union, United States for the following indications:

Approved in European Union as Lynparza for:

• Breast cancer
• Ovarian cancer
• Fallopian tube cancer
• Peritoneal cancer
• Pancreatic cancer
• Prostate cancer
• Endometrial cancer

Approved in United States as Lynparza for:

• Ovarian, fallopian tube, and primary peritoneal cancer
• Breast cancer
• Prostate cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Cediranib showed some anti-tumor activity in patients with metastatic castration-resistant prostate cancer (CRPC) who had previously undergone docetaxel treatment, with 43.9% of patients remaining progression-free at 6 months and a median progression-free survival of 3.7 months.

The treatment was generally well tolerated, with common side effects including hypertension and fatigue; however, adding prednisone helped reduce some of these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer. Dahut, WL., Madan, RA., Karakunnel, JJ., et al.[2023]

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]

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]

The combination of niraparib, a PARP inhibitor, with Radium-223 was found to be safe for treating metastatic castrate-resistant prostate cancer (mCRPC) in men without known BRCA mutations, with manageable dose-limiting toxicities (DLTs) primarily related to blood cell counts.

In a study of 30 patients, the maximum tolerated dose (MTD) varied based on prior chemotherapy exposure, indicating that personalized dosing may be necessary; further research is needed to explore biomarkers that could predict treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate-Resistant Prostate Cancer. Quinn, Z., Leiby, B., Sonpavde, G., et al.[2023]

In the BAROCCO trial involving 123 patients with recurrent platinum-sensitive ovarian cancer, the combination of cediranib and olaparib did not show superior progression-free survival (PFS) compared to paclitaxel chemotherapy, with median PFS of 5.6 months for the continuous cediranib-olaparib group and 3.1 months for the control group.

Despite not outperforming chemotherapy, the cediranib-olaparib combination was associated with a lower rate of treatment discontinuation due to adverse events (5% in the intermittent arm) and offers a potential non-chemotherapy treatment option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. Colombo, N., Tomao, F., Benedetti Panici, P., et al.[2022]

In a phase IIb trial involving 60 women with platinum-resistant recurrent ovarian cancer, the combination of cediranib and olaparib showed a modest objective response rate (ORR) of 15.3%, indicating some clinical activity in this heavily pretreated population.

The treatment was associated with significant safety concerns, as 73.3% of patients experienced grade ≥3 adverse events, highlighting the need for careful monitoring and further research into biomarkers that could predict treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. Lee, JM., Moore, RG., Ghamande, S., et al.[2023]

The combination of cediranib and olaparib did not show clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who do not have a known BRCA mutation, as no objective responses were observed in the study of 19 patients.

Despite some patients experiencing stable disease for a median of 3.1 months, the overall survival was only 3.4 months, indicating limited efficacy of this treatment combination in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. Kim, JW., Cardin, DB., Vaishampayan, UN., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer. [2023]

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

Randomized Trial of Olaparib With or Without Cediranib for Metastatic Castration-Resistant Prostate Cancer: The Results From National Cancer Institute 9984. [2023]

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

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

4. 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]

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

Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate-Resistant Prostate Cancer. [2023]

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

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. [2022]

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

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. [2023]

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

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. [2022]