Olaparib + Chemotherapy for Prostate Cancer

Recruiting at 1 trial location

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Uncontrolled infection, Viral hepatitis, Leukemia, 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: 15

119 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to learn if olaparib, when given after treatment with cabazitaxel, carboplatin, and prednisone, can help to control aggressive variant prostate cancer (AVPC). The safety of these drugs will also be studied. This is an investigational study. Cabazitaxel and carboplatin are FDA approved and commercially available for the treatment of certain types of prostate cancer. Prednisone is FDA-approved and commercially available as a corticosteroid. Olaparib is FDA approved and commercially available for the treatment of certain types of ovarian cancer. The combination of cabazitaxel and carboplatin followed by olaparib in this study is investigational. The study doctor can describe how the study drugs are designed to work. Up to 96 participants will be enrolled on this study. All will take part at MD Anderson.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain drugs that interact with olaparib, such as strong or moderate CYP3A4 inhibitors and inducers. If you are on these, a washout period (time without taking these medications) of 3 to 5 weeks is required before starting the trial.

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

Research shows that Cabazitaxel, when used with prednisone, improves survival in men with advanced prostate cancer that no longer responds to hormone therapy. Additionally, Olaparib, a PARP inhibitor, may be effective in prostate cancer with specific genetic mutations, like BRCA2, suggesting potential benefits when combined with other treatments. ^{1 2 3 4 5}

Is the combination of Olaparib and chemotherapy safe for humans?

Research shows that Olaparib, when combined with chemotherapy drugs like carboplatin, is generally safe for humans, though it can cause side effects like nausea, vomiting, anemia (low red blood cell count), and rarely, interstitial pneumonia (lung inflammation). ^{6 7 8 9 10}

What makes the drug combination of Olaparib, Cabazitaxel, Carboplatin, and Prednisone unique for prostate cancer treatment?

This drug combination is unique because it includes Olaparib, a PARP inhibitor that targets DNA repair mechanisms, particularly effective in prostate cancers with BRCA mutations. The inclusion of platinum-based chemotherapy like Carboplatin may enhance the effectiveness of Olaparib, especially in patients with specific genetic mutations, offering a targeted approach compared to standard treatments. ^{5 11 12 13 14}

Research Team

Ana M. Aparicio, MD

Principal Investigator

UT MD Anderson Cancer Center

Eligibility Criteria

This trial is for men over 18 with aggressive variant prostate cancer (AVPC) that's resistant to castration and has spread. They must have normal organ function, be able to swallow pills, consent to genetic research, and use birth control if needed. Excluded are those with certain medical conditions or who've had specific treatments for CRPC.

Inclusion Criteria

I am a man aged 18 or older.

My prostate cancer diagnosis was confirmed through lab tests.

I can perform daily activities with minimal assistance.

Exclusion Criteria

I have been treated for prostate cancer with specific drugs.

I am allergic to olaparib, carboplatin, or cabazitaxel.

Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Participants receive cabazitaxel and carboplatin intravenously on Day 1 of Cycles 1-6, and prednisone by mouth twice daily on Days 1-21 of Cycles 1-6

18 weeks

6 visits (in-person)

Maintenance Treatment

Participants in Group 1 receive olaparib by mouth twice daily starting on Day 1 of Cycle 7

As long as beneficial

Every 3 cycles after Cycle 10

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to one year from randomization

Every 6 months

Treatment Details

Interventions

• Cabazitaxel
• Carboplatin
• Olaparib
• Prednisone 5Mg

Trial Overview The study tests if olaparib can control AVPC after treatment with cabazitaxel, carboplatin, and prednisone. It's an investigational study of these drugs' combination; up to 96 participants at MD Anderson will receive this regimen following informed consent.

Participant Groups

Group I: Olaparib Maintenance Experimental Treatment 1 Intervention

Participants randomized to receive Olaparib by mouth twice daily on Day 1 of cycle 7.

Group II: Cabazitaxel + Carboplatin Experimental Treatment 3 Interventions

Cabazitaxel, Cabazitaxel and Carboplatin intravenously on day 1 of cycles 1-6. Prednisone by mouth twice daily on days 1-21 of cycles 1-6.

Group III: Observation Only Active Control 1 Intervention

Participants randomized to observation only beginning cycle 7.

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

Approved in European Union as Jevtana for:

• Hormone refractory metastatic prostate cancer

Approved in United States as Jevtana for:

• Metastatic castration-resistant prostate cancer

Approved in Canada as Jevtana for:

• Hormone-refractory metastatic prostate cancer

Approved in Japan as Jevtana for:

• Prostate cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

Cabazitaxel is an effective second-line treatment for men with metastatic castration-resistant prostate cancer (mCRPC), showing a median survival of 15.1 months compared to 12.7 months with mitoxantrone in a randomized trial.

While cabazitaxel has demonstrated efficacy, it is associated with significant adverse effects, including myelosuppression and febrile neutropenia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabazitaxel (jevtana): a novel agent for metastatic castration-resistant prostate cancer. Nightingale, G., Ryu, J.[2023]

Cabazitaxel, when combined with prednisone, significantly improves overall survival in patients with hormone-refractory metastatic prostate cancer who have previously been treated with docetaxel, as shown in the pivotal TROPIC trial.

The treatment also enhances progression-free survival and response rates for tumor and PSA levels, while maintaining an acceptable safety profile, with common side effects including hematological issues and diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabazitaxel: a guide to its use in hormone-refractory metastatic prostate cancer. Keating, GM.[2021]

Cabazitaxel, a new chemotherapy drug, has been shown to improve overall survival by 2.4 months in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment, compared to the older drug mitoxantrone.

While cabazitaxel is effective, it carries a risk of significant hematologic toxicity, including febrile neutropenia, necessitating the use of hematopoietic growth factors in cases of severe neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cabazitaxel after docetaxel: a new option in metastatic castration-resistant prostate cancer]. Lheureux, S., Joly, F.[2018]

The combination of olaparib and carboplatin was found to be safe and effective in treating breast and ovarian cancer in patients with germline BRCA1 or BRCA2 mutations, with 50% of patients showing a partial response and one patient achieving a complete response.

Proteomic analysis indicated that high levels of FOXO3a expression before treatment may predict a better response to the therapy, suggesting a potential biomarker for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. Lee, JM., Hays, JL., Annunziata, CM., 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]

In a study of 120 ovarian cancer patients, the combination of olaparib with paclitaxel and carboplatin significantly improved the objective remission rate and disease control rate compared to the standard treatment with paclitaxel and carboplatin alone.

The addition of olaparib also resulted in lower levels of tumor markers and a reduced rate of tumor metastasis after one year, all without increasing the incidence of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and paclitaxel in combination with carboplatin in treatment of ovarian cancer: influence on disease control. Zhang, H., Zhang, Y.[2022]

The combination of olaparib and abiraterone significantly improves radiographic progression-free survival and other key progression metrics in patients with metastatic castration-resistant prostate cancer, based on a meta-analysis of two randomized controlled trials involving 938 patients.

While the combination therapy shows efficacy, it is associated with a higher risk of high-grade anemia compared to monotherapy, indicating a need for careful management of treatment-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a systematic review and meta-analysis of randomized controlled trials. Luo, Z., Zhu, B., Xu, H., et al.[2023]

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]

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]

References

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

Cabazitaxel (jevtana): a novel agent for metastatic castration-resistant prostate cancer. [2023]

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

Cabazitaxel: a guide to its use in hormone-refractory metastatic prostate cancer. [2021]

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

Second-Line Cabazitaxel Treatment in Castration-Resistant Prostate Cancer Clinical Trials Compared to Standard of Care in CAPRI: Observational Study in the Netherlands. [2020]

4. France pubmed.ncbi.nlm.nih.gov

[Cabazitaxel after docetaxel: a new option in metastatic castration-resistant prostate cancer]. [2018]

5. Italy pubmed.ncbi.nlm.nih.gov

Metastatic Castration-Resistant Prostate Cancer with BRCA2 Mutation: The Challenge Incorporating PARP Inhibitors and Platinum in Treatment Sequencing. [2022]

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

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. [2022]

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

Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer. [2019]

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

Olaparib and paclitaxel in combination with carboplatin in treatment of ovarian cancer: influence on disease control. [2022]

9. Greece pubmed.ncbi.nlm.nih.gov

Real-World Data on Olaparib in Relapsed BRCA-mutated Ovarian Cancer: A Multicenter GINECO RETROLA Cohort Study. [2023]

10. Japan pubmed.ncbi.nlm.nih.gov

[Interstitial Pneumonia Caused by Olaparib during Treatment of Breast Cancer-A Case Report]. [2020]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a systematic review and meta-analysis of randomized controlled trials. [2023]

12. Australia pubmed.ncbi.nlm.nih.gov

Two cases of CRPC with BRCA mutation treated by olaparib after favorable response to cisplatin. [2023]

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

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

14. 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]