Carboplatin vs Olaparib for Prostate Cancer

(COBRA Trial)

Recruiting at 16 trial locations

Overseen By Makayla L DeJong, BA

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must be taking: GnRH analogues

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Other neoplastic disorders, Brain metastasis, Heart disease, 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: 70

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two treatments, carboplatin (a chemotherapy drug) and olaparib (a targeted therapy), for prostate cancer that has spread and resists standard hormone therapy. Participants will first receive one treatment and switch to the other if the cancer progresses. The trial targets patients with specific genetic mutations in their tumors, such as BRCA1 or BRCA2. Men with advanced prostate cancer who have already tried medications like abiraterone or enzalutamide might be suitable for this study. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group, offering participants a chance to contribute to important advancements in prostate cancer treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications. However, you must stop taking strong or moderate CYP3A inhibitors and inducers before starting olaparib. The washout period is 2 weeks for inhibitors and 3-5 weeks for inducers, depending on the specific medication.

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

Research has shown that carboplatin is generally well-tolerated by patients with prostate cancer. Studies suggest it might be a better choice than similar treatments like cisplatin. However, common side effects include low blood cell counts and nausea, which can be managed with supportive care.

Research highlights the safety of olaparib in treating prostate cancer. Most patients experienced fewer issues with worsening pain, which is a positive sign. Common side effects may include tiredness and some changes in blood counts, but these are usually not severe.

Both treatments are already used for other conditions and have established safety records. While both have possible side effects, they are typically manageable with medical support. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard chemotherapy options like docetaxel, carboplatin, and androgen deprivation therapies that are typically used for prostate cancer, olaparib introduces something new by targeting cancer cells differently. Olaparib is a PARP inhibitor, which means it blocks an enzyme that cancer cells use to repair DNA damage, making it harder for them to survive and multiply. Researchers are excited about olaparib because it offers a targeted approach, potentially leading to fewer side effects compared to traditional chemotherapy. Moreover, the combination and sequencing of carboplatin and olaparib might offer a more effective strategy against prostate cancer by leveraging both traditional and targeted therapies.

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

This trial will compare the effectiveness of Carboplatin and Olaparib for prostate cancer. Research has shown that carboplatin can be somewhat effective in treating advanced prostate cancer that no longer responds to hormone therapy. Patients have experienced some reduction in tumor size, and the drug is usually well tolerated. However, its effectiveness can vary depending on its timing in the treatment plan.

In contrast, olaparib, another treatment option in this trial, is a type of targeted therapy that has demonstrated a stronger impact on this cancer. Studies have found that patients taking olaparib lived longer and experienced less pain progression compared to other treatments. Olaparib works especially well for patients with certain genetic mutations, such as BRCA1 or BRCA2. ^{6 7 8 9 10}

Who Is on the Research Team?

Robert B Montgomery, MD

Principal Investigator

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Ryan Burri, MD

Principal Investigator

Bay Pines VA Healthcare System, Pay Pines, FL

Phoebe Tsao, MD MSc

Principal Investigator

VA Ann Arbor Healthcare System, Ann Arbor, MI

Maneesh Jain, MD

Principal Investigator

Washington DC VA Medical Center, Washington, DC

Are You a Good Fit for This Trial?

Men over 18 with advanced prostate cancer that's resistant to hormone therapy and has specific gene mutations (like BRCA1/2). They must have ongoing hormone treatment, measurable disease progression, normal organ/bone marrow function, no brain metastasis or other cancers being treated, and not taken certain drugs before.

Inclusion Criteria

Absolute neutrophil count (ANC) > 1.5 x 109/L

Platelet count > 100 x 109/L

My prostate cancer is resistant to medical or surgical treatments to lower testosterone.

Exclusion Criteria

Any condition(s), medical or otherwise, which, in the opinion of the Investigators, would jeopardize either the patient or the integrity of the data obtained.

I am currently undergoing treatment for another cancer.

Concurrent enrollment in another clinical investigational drug or device study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

First-line Treatment

Participants receive either carboplatin (IV) every 21 days or olaparib (oral) twice daily in 28-day cycles until intolerance, complete response, or progression

Varies until progression or intolerance

Every 21 days for carboplatin, daily for olaparib

Crossover to Second-line Treatment

Participants switch to the opposite study medication (carboplatin or olaparib) after first progression, receiving treatment until intolerance or progression

Varies until progression or intolerance

Every 21 days for carboplatin, daily for olaparib

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

End of treatment visit 28 days after completion or withdrawal

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Olaparib

Trial Overview The trial compares carboplatin chemotherapy to olaparib pills for men with a type of advanced prostate cancer. Patients are randomly chosen to start with one drug and can switch to the other if the first one stops working. The study checks how well each drug controls the cancer.

How Is the Trial Designed?

Group I: Treatment Arm 2 - Olaparib to Carboplatin Active Control 2 Interventions

Participants are prescribed olaparib which is taken orally at home, twice daily, 300 mg in 28 day cycles, as first line therapy. For second line (crossover), carboplatin is administered AUC 5 IV every 21 days thereafter.

Group II: Treatment Arm 1 - Carboplatin to Olaparib Active Control 2 Interventions

Participants are administered carboplatin AUC 5 IV first, which is administered Cycle-1, Day-1, and then every 21 days as first line therapy. For second line (crossover), olaparib is prescribed and taken orally at home, twice daily, 300 mg in 28 day cycles.

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

In a Phase I study involving 28 Japanese patients with advanced solid tumors, olaparib tablets at doses of 200 and 300 mg twice daily were found to be tolerable, with no dose-limiting toxicities reported.

The most common side effects included nausea, decreased appetite, anemia, and constipation, but no confirmed antitumor responses were observed, leading to the selection of 300 mg bid as the recommended dose for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. Yonemori, K., Tamura, K., Kodaira, M., et al.[2022]

In a study involving 77 patients with metastatic or recurrent women's cancer, the combination of olaparib and carboplatin was found to be safe and effective, with a response rate of 46%, particularly higher in BRCA mutation carriers (68% vs. 19%).

The sequence of drug administration matters: giving carboplatin before olaparib increased olaparib clearance and reduced its bioavailability, suggesting that carboplatin should be administered first to optimize treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer. Lee, JM., Peer, CJ., Yu, M., et al.[2019]

Olaparib is an oral medication that inhibits poly (ADP-ribose) polymerase and is primarily developed for treating BRCA mutation-positive ovarian cancer, with its capsule formulation already approved in the EU and USA.

The drug is currently undergoing extensive clinical trials for various cancers, including breast, gastric, and pancreatic cancers, indicating its potential broad application in oncology beyond ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: first global approval. Deeks, ED.[2020]

Olaparib, a PARP inhibitor, showed a 36% objective response rate in women with relapsed ovarian cancer and a germline BRCA1/2 mutation, even after they had undergone multiple lines of chemotherapy, indicating its efficacy in this challenging patient population.

The median duration of response to olaparib was 7.4 months, and the safety profile was consistent across patients who had received three or more lines of prior chemotherapy, with similar rates of serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Matulonis, UA., Penson, RT., Domchek, SM., et al.[2022]

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

The combination of olaparib and radium-223 is safe for patients with metastatic castration-resistant prostate cancer (mCRPC), with a recommended phase II dose of olaparib at 200 mg taken twice daily alongside radium-223.

Early results show promising efficacy, with a 6-month radiographic progression-free survival (rPFS) rate of 58%, particularly in patients with specific HRR gene alterations, indicating potential for further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE). Pan, E., Xie, W., Ajmera, A., et al.[2023]

The OPINION study is evaluating the safety and efficacy of olaparib as a maintenance therapy for women with high-grade serous or endometrioid platinum-sensitive relapsed ovarian cancer who do not have BRCA mutations, involving patients who have undergone at least two prior lines of platinum-based chemotherapy.

The primary goal of the study is to assess progression-free survival, which will help determine how effective olaparib is in delaying cancer progression in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. Poveda, AM., Davidson, R., Blakeley, C., et al.[2020]

Citations

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Carboplatin in Metastatic Castrate Resistant Prostate Cancer Carboplatin therapy has modest response rates in the metastatic castrate-resistant prostate cancer (mCRPC) setting. Carboplatin is relatively well tolerated.

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1619P Efficacy of carboplatin in patients with metastatic ... Limited randomised data in metastatic castration-resistant prostate cancer (mCRPC) have demonstrated moderate effects of platinum-based chemotherapy.

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Study Details | NCT03652493 | Trial Evaluating the Efficacy ... The investigators propose a phase II study to evaluate the efficacy of carboplatin monotherapy in the tumor subgroup of metastatic castration-resistant ...

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Advancements in platinum chemotherapy for metastatic ... Carboplatin is a better candidate for future use rather than cisplatin and oxaliplatin. Although prostate cancer has a cold immune ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT02311764

Carboplatin in Castration-resistant Prostate Cancer ... In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical ...

10. sciencedirect.com sciencedirect.com/science/article/abs/pii/S155876731930179X

Efficacy and Safety of Carboplatin Plus Paclitaxel as the ... Carboplatin and paclitaxel (CP) had shown moderate efficacy in treating castration-resistant prostate cancer (CRPC) before standard first-line docetaxel ...