Chemotherapy + PARP Inhibitor/Immunotherapy for Prostate Cancer

Overseen By Ana Aparicio

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Anti-PD1, Anti-PDL1

Disqualifiers: MDS/AML, Uncontrolled infection, Autoimmune disorders, 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: 6

120 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of cabazitaxel, carboplatin, and cetrelimab followed by niraparib with or without cetrelimab in treating patients with aggressive variant prostate cancer that has spread to other places in the body (metastatic). Chemotherapy drugs, such as cabazitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as niraparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Immunotherapy with monoclonal antibodies, such as cetrelimab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving niraparib with or without cetrelimab, after treatment with cabazitaxel, carboplatin, and cetrelimab, may help control aggressive variant prostate cancer.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that patients should not have unresolved side effects from previous cancer treatments and should not be on certain immunosuppressive medications. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of chemotherapy and PARP inhibitors for prostate cancer?

Research suggests that PARP inhibitors, like niraparib, can be effective in treating prostate cancer with specific DNA repair gene defects, especially in patients who have already tried other treatments. Additionally, combining PARP inhibitors with chemotherapy has shown promise in stabilizing the disease and improving symptoms in some cases. ^{1 2 3 4 5}

Is the combination of chemotherapy and PARP inhibitors/immunotherapy safe for prostate cancer treatment?

Cabazitaxel, a chemotherapy drug, has been studied for safety in patients with advanced prostate cancer, showing a manageable safety profile. PARP inhibitors like olaparib and rucaparib are approved for certain prostate cancers with specific genetic mutations, indicating they are generally safe for use in humans with these conditions. ^{6 7 8 9 10}

How is the chemotherapy and PARP inhibitor/immunotherapy drug combination unique for prostate cancer?

This treatment combines chemotherapy with PARP inhibitors, which are drugs that target cancer cells with specific DNA repair defects, and immunotherapy, which helps the immune system fight cancer. This combination is unique because it leverages the synthetic lethality of PARP inhibitors in patients with DNA repair gene defects, offering a new approach for those who have developed resistance to standard treatments. ^{2 11 12 13 14}

Research Team

Ana Aparicio

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for men with aggressive variant metastatic prostate cancer who can swallow pills, have documented disease progression, and are willing to undergo treatment and follow-up. They must not have used immunosuppressive medication recently or had more than one chemotherapy line. Participants need functioning major organs and controlled infections, without certain medical conditions like uncontrolled heart issues or autoimmune disorders.

Inclusion Criteria

I am willing and able to follow the study's requirements, including treatments and visits.

Patients must consent to the MD Anderson Immunotherapy Platform laboratory protocol PA13-0291

My prostate cancer diagnosis was confirmed through lab tests.

Exclusion Criteria

I don't have major side effects from past cancer treatments that haven't gone away.

I have recovered from side effects of cancer treatment, except for specific prostate cancer therapies.

I have or had myelodysplastic syndrome or acute myeloid leukemia.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive cabazitaxel and carboplatin intravenously, with cetrelimab starting from cycle 2, repeated for up to 6 cycles

18 weeks

6 visits (in-person)

Maintenance

Patients receive niraparib orally daily, with or without cetrelimab intravenously, repeated every 28 days

Ongoing until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30 to 90 days after last dose, then every 6 months

Treatment Details

Interventions

• Cabazitaxel
• Carboplatin
• Cetrelimab
• Niraparib

Trial Overview The study tests cabazitaxel, carboplatin, and cetrelimab followed by niraparib with or without cetrelimab. It aims to see if this combination can control the spread of aggressive prostate cancer by damaging tumor cells' DNA repair mechanisms and boosting the immune system's ability to fight cancer.

Participant Groups

Group I: Group II (cetrelimab, niraparib) Experimental Treatment 4 Interventions

INDUCTION: Patients receive cabazitaxel IV over 60 minutes and carboplatin IV over 60 minutes on day 1. Beginning cycle 2, patients also receive cetrelimab IV over 30-60 minutes on day 1. Treatment repeats for up to 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive cetrelimab IV over 30 minutes on day 1 and niraparib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Group I (niraparib) Experimental Treatment 4 Interventions

INDUCTION: Patients receive cabazitaxel IV over 60 minutes and carboplatin IV over 60 minutes on day 1. Beginning cycle 2, patients also receive cetrelimab IV over 30-60 minutes on day 1. Treatment repeats for up to 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive niraparib orally PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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+

Janssen Pharmaceutica

Industry Sponsor

Trials

43

Recruited

9,200+

Founded

1953

Headquarters

Beerse, Belgium

Known For

Immunology Treatments

Top Products

Stelara (ustekinumab), Darzalex (daratumumab), Remicade (infliximab), Tremfya (guselkumab)

Findings from Research

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]

Cabazitaxel is a potentially effective treatment for castration-resistant prostate cancer (CRPC) in patients aged 80 years and older, showing similar efficacy in overall survival and PSA response rates compared to younger patients.

The safety profile of cabazitaxel is comparable across age groups, with high rates of adverse drug reactions (ADRs) in both patients aged <80 (77.2%) and ≥80 years (79.6%), primarily involving hematologic toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabazitaxel in patients aged ≥80 years with castration-resistant prostate cancer: Results of a post-marketing surveillance study in Japan. Matsubara, N., Suzuki, K., Kazama, H., et al.[2021]

In a study involving 112 patients with metastatic castration-resistant prostate cancer (mCRPC), cabazitaxel treatment showed a low incidence of serious side effects, such as neutropenic sepsis (6.3%) and severe diarrhea (4.5%), indicating a favorable safety profile.

Patients reported trends towards improved quality of life during treatment, suggesting that cabazitaxel may enhance overall well-being for those whose cancer progressed after docetaxel, although careful patient selection is necessary due to potential toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final quality of life and safety data for patients with metastatic castration-resistant prostate cancer treated with cabazitaxel in the UK Early Access Programme (EAP) (NCT01254279). Bahl, A., Masson, S., Malik, Z., et al.[2022]

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]

References

1. 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]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Treatment and Patient Selection for Patients with Metastatic Castration-resistant Prostate After Progression on Docetaxel and Abiraterone/Enzalutamide: When to Play Your CARD and When to Do Your PARP. [2022]

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

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

4. 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]

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

Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Cabazitaxel in patients aged ≥80 years with castration-resistant prostate cancer: Results of a post-marketing surveillance study in Japan. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Final quality of life and safety data for patients with metastatic castration-resistant prostate cancer treated with cabazitaxel in the UK Early Access Programme (EAP) (NCT01254279). [2022]

8. 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]

9. England pubmed.ncbi.nlm.nih.gov

Cabazitaxel activity in men with metastatic castration-resistant prostate cancer with and without DNA damage repair defects. [2021]

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

PARP Inhibition in Advanced Prostate Cancer. [2022]

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

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

12. England pubmed.ncbi.nlm.nih.gov

The growing role of rucaparib in contemporary treatment of metastatic prostate cancer: a review of efficacy and guidance for side effect management. [2022]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer. [2023]

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

PARP inhibitors on the move in prostate cancer: spotlight on Niraparib & update on PARP inhibitor combination trials. [2022]