Radiation + Pembrolizumab + Olaparib for Breast Cancer

Recruiting at 6 trial locations

Overseen By Atif Khan, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Pregnancy, Active infection, Autoimmune 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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

34 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding pembrolizumab (an immunotherapy drug), with or without olaparib (a targeted therapy drug), to standard radiation therapy is safe and effective for treating metastatic breast cancer. It evaluates whether these combinations outperform radiation alone. The study includes different groups: one with triple-negative breast cancer receiving all treatments, another with paused participation, and a third with ER+ breast cancer receiving pembrolizumab, radiation, and olaparib. Women with metastatic or recurrent breast cancer who have previously undergone similar treatments but still have measurable disease might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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

The trial requires a washout period (time without taking certain medications) of at least 2 weeks for all anti-cancer agents and certain other medications before starting the study treatment. If you are taking strong or moderate CYP3A inhibitors or inducers, specific washout periods of 2 to 5 weeks are required. Please consult with the trial team to discuss your specific medications.

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

Research has shown that the combination of pembrolizumab and olaparib with radiation is generally well-tolerated by patients with triple-negative breast cancer (TNBC). One study found that using olaparib with radiation was safe and accepted by most patients. Similarly, combining pembrolizumab with radiation demonstrated an acceptable safety profile, with no unexpected or severe side effects.

For those with ER+ metastatic breast cancer (a type that grows in response to estrogen), researchers are studying the combination of pembrolizumab, olaparib, and a precise form of radiation therapy called stereotactic body radiation therapy (SBRT). While specific safety data for this exact combination in ER+ patients isn't detailed, pembrolizumab and olaparib have been tested separately and are generally safe in other contexts.

Overall, these treatments have shown a manageable safety profile in other studies and conditions. Participants should discuss any concerns with their healthcare providers to understand potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining radiation, pembrolizumab, and olaparib for breast cancer because this approach targets the cancer in multiple ways. Pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells, while olaparib is a PARP inhibitor that disrupts cancer cells' DNA repair mechanisms, making them more vulnerable to damage. This combination has the potential to be more effective than traditional chemotherapy or radiation alone, particularly in treating aggressive types like triple negative breast cancer and metastatic ER+ breast cancer. By using these treatments together, there is hope for improved outcomes and survival rates for patients facing these challenging cancer types.

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

This trial will evaluate different combinations of treatments for breast cancer. In Arm A, participants with triple-negative breast cancer (TNBC) will receive pembrolizumab, radiation therapy, and olaparib. Studies have shown that pembrolizumab, a type of immunotherapy, can help patients with TNBC by enabling the immune system to attack cancer cells more effectively when used with chemotherapy. Research also indicates that olaparib, a drug that disrupts cancer cell repair, can enhance the effects of radiation therapy in TNBC patients.

In Arm B, which is currently paused, participants with TNBC were to receive pembrolizumab and radiation therapy only.

In Arm C, participants with metastatic ER+ breast cancer will receive a combination of pembrolizumab, targeted radiation (SBRT), and olaparib. For ER+ metastatic breast cancer, combining pembrolizumab with SBRT and olaparib may increase the destruction of cancer cells, although the specific benefits are still under study. Early findings suggest these combinations could make treatments more effective than using radiation alone. ^{1 2 6 7 8}

Who Is on the Research Team?

Atif Khan, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for women at least 18 years old with metastatic or recurrent triple-negative or hormone-receptor positive/Her2 negative breast cancer. Participants must not be pregnant, breastfeeding, and should follow contraceptive guidance. They need to have stable organ function and performance status (ECOG) of 0-1. Those with HIV, active TB or hepatitis, severe allergies to study drugs, certain previous treatments or conditions that could affect the study's outcome are excluded.

Inclusion Criteria

My organs are functioning well according to the test results.

I can swallow and keep down pills.

Participant must agree not to breastfeed during the study or for 180 days after the last dose of study treatment

Exclusion Criteria

Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements

Previous enrollment in the present study

I am not taking strong or moderate CYP3A inhibitors.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab with or without olaparib in combination with standard radiation therapy

8 weeks

Regular visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Pembrolizumab
• Radiation

Trial Overview The trial tests if adding pembrolizumab (an immunotherapy drug), with or without olaparib (a targeted therapy drug), to standard radiation therapy is more effective for treating metastatic breast cancer than radiation alone. The safety and effectiveness of these combinations are being compared.

How Is the Trial Designed?

Group I: Arm C (activate new arm) Experimental Treatment 3 Interventions

Participants will have metastatic ER+ breast cancer (ER+ MBC) Treatment will be pembro/SBRT/Olaparib)

Group II: Arm B (the study is amended to pause Arm B) Experimental Treatment 2 Interventions

Participants will have triple negative breast cancer diagnosis Treatment will be pembro + RT only

Group III: Arm A Experimental Treatment 3 Interventions

Participants will have triple negative breast cancer diagnosis Treatment will be pembro + RT + olaparib

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

Approved in European Union as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in United States as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in Canada as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in Japan as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in China as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Approved in Switzerland as Radiation Therapy for:

• Cancer treatment
• HPV-positive throat cancer
• Various types of tumors

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

Radiation therapy not only helps eliminate cancer cells but also modifies the tumor microenvironment, potentially enhancing the body's immune response against tumors.

Combining radiation with immune checkpoint inhibitors has shown promise in early clinical trials for breast cancer, suggesting a synergistic effect that could improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Combining Radiation and Immunotherapy in Breast Cancer. Nguyen, AT., Shiao, SL., McArthur, HL.[2021]

The KEYLYNK-012 study is a phase III clinical trial evaluating the effectiveness of pembrolizumab combined with chemoradiotherapy in patients with stage III non-small-cell lung cancer (NSCLC), involving participants aged 18 and older with unresectable disease.

This study aims to determine if the addition of pembrolizumab, with or without olaparib, improves progression-free survival and overall survival compared to standard concurrent chemoradiotherapy, with enrollment ongoing at around 190 sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. Jabbour, SK., Cho, BC., Bria, E., et al.[2022]

Combining ionizing radiation therapy (RT) with PD-1/PD-L1 inhibitors has shown promise in enhancing the immune response against tumors, making it a compelling treatment strategy for various cancers.

The review discusses both preclinical and clinical data supporting the safety and efficacy of this combination, emphasizing the need for careful clinical trial design to optimize outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. Gong, J., Le, TQ., Massarelli, E., et al.[2023]

A 74-year-old woman with lung adenocarcinoma developed fatal immune thrombocytopenia after receiving pembrolizumab following radiotherapy, highlighting a potential risk of severe immune-related adverse events (irAEs) when combining these treatments.

Flow cytometry analysis showed increased PD-1 and Ki-67 expression in T cells post-radiotherapy, suggesting that radiotherapy may enhance immune activation and contribute to the development of irAEs in patients undergoing anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy. Tamanoi, D., Saruwatari, K., Imamura, K., et al.[2022]

In a pooled analysis of 148 patients with metastatic non-small-cell lung cancer, adding radiotherapy to pembrolizumab significantly improved the best out-of-field response rate (41.7% vs 19.7%) and best disease control rate (65.3% vs 43.4%), indicating enhanced efficacy of the combination treatment.

Patients receiving the combination therapy also experienced longer median progression-free survival (9.0 months vs 4.4 months) and overall survival (19.2 months vs 8.7 months) compared to those receiving pembrolizumab alone, with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Theelen, WSME., Chen, D., Verma, V., et al.[2021]

In a study involving 8 patients with hormone receptor-positive metastatic breast cancer, combining pembrolizumab with palliative radiation therapy did not result in any objective responses, leading to the study's closure.

The median progression-free survival was only 1.4 months and overall survival was 2.9 months, indicating limited efficacy of this treatment combination in heavily pre-treated patients, although the treatment was generally safe with only one significant adverse event reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer. Barroso-Sousa, R., Krop, IE., Trippa, L., et al.[2021]

The combination of localized radiotherapy and immune checkpoint inhibitors, like pembrolizumab, may enhance the immune response against tumors, particularly in metastatic melanoma, but clinical data on this combination is limited.

A case report indicates that pembrolizumab may cause acute skin radiosensitization when used with radiation therapy, suggesting a rapid interaction that warrants caution in prescribing this combination for advanced cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute skin reaction suggestive of pembrolizumab-induced radiosensitization. Sibaud, V., David, I., Lamant, L., et al.[2015]

In a phase 2 clinical trial involving 17 patients with metastatic triple-negative breast cancer, the combination of pembrolizumab and radiotherapy showed an overall response rate of 17.6%, with three patients achieving complete responses that lasted up to 108 weeks.

The treatment was found to be safe, with the most common side effects being mild dermatitis, and no treatment-related deaths or severe adverse events reported, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer. Ho, AY., Barker, CA., Arnold, BB., et al.[2020]

Citations

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NCT04683679 | A Study of Radiation Therapy With ... The purpose of this study is to find out whether adding pembrolizumab, with or without olaparib, to standard radiation therapy is a safe and effective ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9614672/

Concurrent Olaparib and Radiotherapy in Patients With Triple ... In this phase 1 dose-escalation trial, olaparib used as a radiosensitizer in combination with breast radiotherapy in patients with TNBC was well tolerated.

3. redjournal.org redjournal.org/article/S0360-3016(25)00481-X/fulltext

Long-Term Results From the RADIOPARP Phase 1 Trial The RADIOPARP phase 1 trial demonstrates the long-term safety of combining olaparib with breast radiation therapy in patients with TNBC with residual disease, ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS632

OPERETTA: A phase II study evaluating neoadjuvant and ... OPERETTA: A phase II study evaluating neoadjuvant and adjuvant olaparib plus pembrolizumab following platinum-based chemotherapy plus ...

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Maintenance Pembrolizumab/Olaparib Misses Survival ... Pembrolizumab plus olaparib did not improve progression-free or overall survival vs pembrolizumab plus chemotherapy in patients with locally recurrent ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S036030162500481X

Safety and Potential Radiosensitizing Effect of Olaparib in ... Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant systemic therapy face a high risk of locoregional recurrence, ...

7. nature.com nature.com/articles/s41523-025-00814-y

Association of potential biomarkers with clinical outcomes ... In the randomized, phase 3 KEYNOTE-119 study, overall survival (OS) was not significantly improved with pembrolizumab 200 mg Q3W versus ...

8. merck.com merck.com/news/new-and-updated-data-for-mercks-keytruda-pembrolizumab-and-updated-data-on-lynparza-olaparib-in-multiple-breast-cancer-subtypes-to-be-presented-at-the-2017-san-antonio-breast/

New and Updated Data for Merck's KEYTRUDA® ... Data investigating LYNPARZA (olaparib) as monotherapy will also be presented. Findings include additional data from the pivotal phase 3 OlympiAD trial ...