Pembrolizumab + Olaparib for Pancreatic Cancer

Recruiting at 9 trial locations

Overseen By Eileen M O'Reilly, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: PARP inhibitors, Anti-PD-1 agents

Disqualifiers: Disease progression, Second primary cancer, 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: 6 months

63 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for strong or moderate CYP3A inhibitors and inducers before starting. You may need to stop these medications 2 to 5 weeks prior to the trial, depending on the specific drug. The protocol does not specify other medication restrictions, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Pembrolizumab and Olaparib for pancreatic cancer?

Research shows that olaparib significantly extends progression-free survival in patients with BRCA-mutated metastatic pancreatic cancer who responded to platinum-based chemotherapy. However, pembrolizumab alone has shown minimal benefit for most patients with pancreatic cancer. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and Olaparib safe for humans?

Olaparib has been used safely in patients with certain types of breast and pancreatic cancer, showing benefits in quality of life and survival without significant symptoms. Pembrolizumab has been used in patients with pancreatic cancer, but it offers minimal benefit and may increase treatment burden near the end of life. ^{1 2 6 7 8}

What makes the drug combination of Pembrolizumab and Olaparib unique for pancreatic cancer?

The combination of Pembrolizumab and Olaparib is unique for pancreatic cancer because it combines an immune checkpoint inhibitor (Pembrolizumab) with a PARP inhibitor (Olaparib), potentially offering a novel approach by targeting both the immune system and DNA repair mechanisms, which is different from standard chemotherapy treatments. ^{1 2 5 6 7}

What is the purpose of this trial?

This trial is testing a combination of two drugs, pembrolizumab and olaparib, to treat a specific type of cancer. Pembrolizumab helps the immune system fight cancer, while olaparib prevents cancer cells from fixing themselves. Researchers believe this combination might be more effective than using just one drug.

Research Team

Wungki Park, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with metastatic pancreatic cancer who have specific genetic changes or a good response to platinum-based therapy. They must be currently stable or improving on platinum treatment, not have other active cancers, and can't have had certain treatments like anti-PD-1 drugs before. Participants need normal organ function and no serious heart conditions.

Inclusion Criteria

Cohort B eligibility

Cohort C eligibility

You are currently receiving platinum-based therapy as part of your first or second-line treatment plan.

Exclusion Criteria

You have an autoimmune disease that has required treatment in the past two years.

You have received radiation therapy for symptom relief within the last two weeks before the start of the trial.

You have had a bone marrow transplant using cells from a donor.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab and olaparib (POLAR) to evaluate safety and antitumor activity

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Olaparib
• Pembrolizumab

Trial Overview Researchers are testing if combining Pembrolizumab (boosts immune system against cancer) with Olaparib (stops cancer cells from repairing DNA damage) works better than just Olaparib alone for treating this type of pancreatic cancer.

Participant Groups

Group I: Cohort C: Platinum sensitive Experimental Treatment 2 Interventions

Patients without any of the above HR-gene alterations included in Cohort A and B who have platinum-sensitivity, which is defined as a partial response (PR) or complete response (CR) for the best overall response (BOR) during at least 4 months on platinumbased therapy. Variants of unknown significance of candidate HR-genes from Cohort A or B will be eligible for Cohort C if they meet the partial response to platinum criterion.

Group II: Cohort B: Non core HRD Experimental Treatment 2 Interventions

Patients with either pathogenic somatic or germline non-core 14 HR-gene alterations (ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, RTEL1) who have stable or responding disease on first-line or second-line platinum therapy in two consecutive imaging assessments over at least 4 months are eligible for inclusion in Cohort B.

Group III: Cohort A: Core HRD Experimental Treatment 2 Interventions

Patients with either pathogenic germline or somatic alterations of 3 core homologous recombination-genes (HR-genes) - (BRCA1/2, or PALB2) who have stable or responding disease on first-line or second-line platinum therapy in two consecutive imaging assessments over at least 4 months are eligible for inclusion in Cohort A.

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

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

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]

In a study of 41 pancreas cancer patients treated with pembrolizumab, the median overall survival was 7.2 months, which is considered favorable compared to the benchmark of over 4 months.

Patients with specific genetic markers (dMMR, MSI-H, TMB-H, or Lynch syndrome) had a significantly lower risk of death, indicating that these biomarkers may help identify patients who could benefit more from pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab near the end of life in patients with metastatic pancreatic cancer: a multi-site consecutive series to examine survival and patient treatment burden. Storandt, MH., Tran, N., Martin, N., 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]

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]

In a phase 1 trial involving 18 patients with unresectable pancreatic ductal adenocarcinoma (PDAC), the maximum tolerated dose of olaparib combined with irinotecan and cisplatin was determined to be 100 mg twice daily, but the addition of mitomycin C was not tolerated due to high toxicity.

Despite significant toxicity, including a high rate of grade ≥3 adverse events in 89% of patients, one patient with a BRCA2 mutation experienced a durable response lasting over four years, suggesting that further investigation into PARP inhibitors for PDAC may be warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. Yarchoan, M., Myzak, MC., Johnson, BA., et al.[2022]

In a phase 3 study involving 154 patients with metastatic pancreatic cancer and a germline BRCA mutation, maintenance treatment with olaparib significantly increased the time without significant symptoms of disease progression or toxicity (TWiST) compared to placebo (14.6 months vs 7.1 months).

While olaparib improved progression-free survival (PFS) without compromising health-related quality of life (HRQOL), there was no significant difference in quality-adjusted TWiST (Q-TWiST) between olaparib and placebo, indicating that while olaparib is effective, it may not enhance overall quality-adjusted survival time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-centered outcomes in the POLO study of active maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. Kindler, HL., Yoo, HK., Hettle, R., et al.[2023]

References

1. 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]

2. Germany pubmed.ncbi.nlm.nih.gov

Pembrolizumab near the end of life in patients with metastatic pancreatic cancer: a multi-site consecutive series to examine survival and patient treatment burden. [2023]

3. 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]

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

Maintenance Olaparib New Standard in Pancreatic Cancer? [2020]

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

Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer. [2023]

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

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

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

Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. [2022]

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

Patient-centered outcomes in the POLO study of active maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. [2023]