Pembrolizumab + Olaparib for Endometrial Cancer

Not currently recruiting at 6 trial locations

Overseen By Vicky Makker, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: PARP inhibitors, VEGF TKIs, CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Autoimmune disease, Pneumonitis, Liver 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: Unknown

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of two drugs, pembrolizumab (an immunotherapy drug) and olaparib (a PARP inhibitor), can effectively treat endometrial cancer that recurs or persists. Researchers aim to determine the efficacy of the drug combination and assess the severity of any side effects. Individuals previously treated for endometrial cancer, particularly those with specific types, might be suitable candidates. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop any hormonal therapy for endometrial cancer at least one week before starting. If you are taking strong or moderate inhibitors or inducers of CYP3A4, you will need to stop them for a washout period of 2 to 5 weeks before starting the study. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

Is there any evidence suggesting that the combination of pembrolizumab and olaparib is likely to be safe for humans?

Research shows that using pembrolizumab and olaparib together has yielded promising results in earlier studies. Importantly, these studies did not identify any new safety issues, indicating the combination did not cause unexpected side effects.

Pembrolizumab has FDA approval for other uses, which suggests some confidence in its safety. Olaparib, a drug that prevents cancer cells from repairing themselves, has also been used in other treatments.

Overall, the research suggests that this combination is generally well-tolerated. Participants in past trials experienced side effects that were manageable and not considered severe or unusual. While every treatment can have side effects, this combination appears promising in terms of safety based on current data. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining pembrolizumab with olaparib for endometrial cancer because it offers a novel approach compared to standard treatments like chemotherapy or hormonal therapy. Pembrolizumab is an immunotherapy that boosts the immune system to recognize and attack cancer cells, while olaparib is a PARP inhibitor that prevents cancer cells from repairing their DNA, leading to their death. This combination targets cancer cells in two different ways, potentially enhancing effectiveness and offering new hope for patients who might not respond to existing therapies.

What evidence suggests that the combination of pembrolizumab and olaparib could be an effective treatment for endometrial cancer?

Research shows that combining pembrolizumab and olaparib may help treat endometrial cancer. In earlier studies, this combination allowed patients to live about 4.8 months without cancer progression. On average, patients lived for 21.2 months, suggesting the treatment may extend life. This combination has also demonstrated the ability to shrink or slow tumor growth. Importantly, no new safety issues have emerged with this treatment. This evidence suggests the combination could be effective for individuals with persistent or recurrent endometrial cancer. ^{1 2 3 4 6}

Who Is on the Research Team?

Maria Rubinstein, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with certain types of endometrial cancer who've had no more than three prior treatments (excluding hormonal therapy). They must have measurable disease, be in good physical condition, and not be pregnant or breastfeeding. People with severe allergies to the drugs being tested, active autoimmune diseases, recent immunosuppressive therapies, or uncontrolled illnesses cannot participate.

Inclusion Criteria

I stopped my hormonal therapy for endometrial cancer at least a week ago.

My endometrial cancer has come back or did not go away after treatment.

My endometrial cancer is either serous, carcinosarcoma, grade 3 endometrioid, or undifferentiated.

Exclusion Criteria

I have a significant liver condition.

I have been diagnosed with MDS, AML, or have symptoms suggesting these conditions.

I have been treated with drugs targeting PD-1, PD-L1, or CTLA-4.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive olaparib orally at 300 mg every 12 hours and pembrolizumab intravenously at 200 mg every 3 weeks

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Pembrolizumab

Trial Overview Researchers are testing a combination of two drugs—Pembrolizumab and Olaparib—to treat persistent or recurrent endometrial cancer. The study aims to determine the effectiveness and safety of this drug duo while monitoring for mild side effects in participants.

How Is the Trial Designed?

Group I: Pembrolizumab with Olaparib Experimental Treatment 2 Interventions

Eligible patients will receive olaparib in combination with pembrolizumab. Olaparib will be administered orally at 300 mg every 12 hours. Pembrolizumab will be administered intravenously (IV) at 200mg every 3 weeks.

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

Published Research Related to This Trial

In the KEYNOTE-158 study, pembrolizumab showed a clinically meaningful objective response rate in patients with advanced MSI-H/dMMR endometrial cancer, with 84 out of 90 patients completing health-related quality of life (HRQoL) assessments.

Patients receiving pembrolizumab experienced significant improvements in their quality of life, with mean scores on the QLQ-C30 and EQ-5D-3L questionnaires increasing notably, especially among those who achieved a complete or partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. O'Malley, DM., Bariani, GM., Cassier, PA., et al.[2022]

In a phase II study involving 46 patients with advanced endometrial cancer, the combination of pembrolizumab with carboplatin and paclitaxel resulted in a high objective response rate (ORR) of 74.4%, significantly exceeding the historical control rate of 50%.

The treatment was generally well-tolerated, with common mild side effects like anemia and fatigue, while immune profiling indicated that responders had enriched CD8+ and CD4+ T cell populations, suggesting a potential mechanism of action related to immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium. Barber, EL., Chen, S., Pineda, MJ., et al.[2023]

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]

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]

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 of 44 women with advanced or recurrent MMRd/MSI-H endometrial adenocarcinomas treated with pembrolizumab, obesity (BMI≥30) was linked to a higher disease control rate (85.2%) compared to those with a BMI<30 (59.8%).

Patients with obesity also experienced significantly longer progression-free survival (PFS) while overall survival (OS) rates remained similar regardless of BMI, suggesting that body weight may influence treatment outcomes with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obesity is associated with improved progression-free survival in Microsatellite-Instability-High endometrial cancer treated with pembrolizumab. Bernard, L., How, JA., Patel, S., et al.[2023]

A 32-year-old woman with recurrent ovarian clear cell carcinoma (OCCC) showed a partial response to a novel treatment combining olaparib (a PARP inhibitor), pembrolizumab (a PD-1 inhibitor), and bevacizumab (an antiangiogenic agent), which was sustained for 12 months.

This case highlights the potential effectiveness of this triplet therapy for patients with platinum-resistant, recurrent OCCC, especially in the context of identified genomic mutations like ARID1A and homologous recombination deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remarkable Response to the Triplet Combination of Olaparib with Pembrolizumab and Bevacizumab in the Third-Line Treatment of an Ovarian Clear Cell Carcinoma Patient with an ARID1A Mutation: A Case Report. Zhao, Y., Jiang, Y.[2022]

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]

In a study of 48 patients with recurrent endometrial cancer treated with pembrolizumab and lenvatinib, the best objective response rate was 23.8%, indicating a lower effectiveness compared to clinical trial results.

The treatment was associated with notable side effects, with 56.2% of patients requiring a dose reduction of lenvatinib and 16.7% discontinuing treatment due to adverse events, highlighting the importance of monitoring for safety in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea. Kim, J., Noh, JJ., Lee, TK., 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]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

Citations

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A phase II trial of pembrolizumab plus olaparib for the ... Median progression-free survival (PFS) was 4.8 months (80% CI: 3.6-5.9), and median overall survival (OS) was 21.2 months (80% CI: 9.4-NE). 50% ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05156268

NCT05156268 | A Study of Pembrolizumab and Olaparib in ... The purpose of this study is to find out whether the combination of pembrolizumab and olaparib is an effective treatment for people with persistent or ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2302312

Pembrolizumab plus Chemotherapy in Advanced ... In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P ...

4. mdanderson.org mdanderson.org/newsroom/aacr-olaparib-and-pembrolizumab-combination-shows-early-promise-in-molecularly-selected-tumor-agnostic-trial.h00-159775656.html

AACR: Olaparib and pembrolizumab combination shows ... The combination of the PARP inhibitor olaparib and the PD-1 inhibitor pembrolizumab showed initial antitumor activity with no new safety signals.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12215578/

Drug discovery in advanced and recurrent endometrial cancer Results of the dMMR group demonstrated a 70% reduction in the risk of disease progression or death in patients who received pembrolizumab compared to placebo ( ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0959804925001108

Immunotherapy and PARP inhibitors as first-line treatment ... Progression-free survival outcomes in patients with advanced or recurrent endometrial cancer by treatment arm. (A) In the MMRP population and (B) ...