Durvalumab + Olaparib for Prostate Cancer

Overseen By Michael Schweizer

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: University of Washington

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Chemotherapy, PD1/PD-L1 inhibitors, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 13

Duration: 24 weeks

6 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well durvalumab and olaparib work in treating prostate cancer in men predicted to have specific genetic mutations (a high neoantigen load). Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Giving durvalumab and olaparib may kill more tumor cells in patients with prostate cancer predicted to have a high neoantigen load.

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

The trial requires a washout period (time without taking certain medications) for specific drugs. You must stop taking strong or moderate CYP3A inhibitors and inducers before starting the study, with a washout period of 2 to 5 weeks depending on the medication. Other medications are not specifically mentioned, so it's best to discuss with the study team.

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

Research shows that Olaparib, when combined with other drugs like abiraterone, significantly improves progression-free survival in patients with metastatic castration-resistant prostate cancer. Additionally, Durvalumab, although not effective alone for prostate cancer, may have improved activity when used with Olaparib, especially in patients with specific genetic mutations. ^{1 2 3 4 5}

Is the combination of Durvalumab and Olaparib safe for humans?

Durvalumab has been studied for safety in various solid tumors and is approved for certain cancers, indicating it is generally safe for human use. Olaparib has been evaluated for safety in prostate cancer and other conditions, showing it is also generally safe. The combination of these drugs has been assessed in breast cancer patients, suggesting it is safe for human use. ^{1 2 6 7 8}

How is the drug combination of Durvalumab and Olaparib unique for prostate cancer?

The combination of Durvalumab and Olaparib is unique for prostate cancer because it pairs a checkpoint inhibitor (Durvalumab) with a PARP inhibitor (Olaparib), potentially enhancing effectiveness in patients with DNA damage repair mutations, a group that may not respond well to single-agent treatments. ^{1 2 4 7 8}

Research Team

Michael Schweizer

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

Men with prostate cancer who've had local therapy, a rising PSA level, and no metastatic disease on scans. They must have specific genetic mutations indicating a high neoantigen load, not received certain prior treatments like chemotherapy or immunotherapy, and can't be immunocompromised. Participants need to be over 18 years old with an ECOG performance status of =<1 (able to carry out light activity), adequate organ function, and willing to use contraception.

Inclusion Criteria

AST/ALT =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN

Patient is willing and able to comply with the protocol for the duration of the study

My PSA is at least 2 ng/ml after radiation, or I've had a prostatectomy. My PSA doubles in 10 months or less.

Exclusion Criteria

I have or had an autoimmune or inflammatory disorder, but it might be an exception.

I am not currently on, nor have I been on cancer treatment in the last 3 weeks.

I have been diagnosed with myelodysplastic syndrome or acute myeloid leukemia.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive durvalumab IV over 1 hour on day 1 of each cycle for 6 cycles. Starting cycle 4, patients with specific mutations also receive olaparib orally twice daily.

24 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up visits at 2 weeks, and then every 12 weeks up to 24 months.

24 months

7 visits (in-person)

Treatment Details

Interventions

• Durvalumab
• Olaparib

Trial Overview The trial is testing the combination of durvalumab (an immune system-boosting monoclonal antibody) and olaparib (a PARP inhibitor that prevents cancer cells from repairing their DNA) in men whose prostate cancer has specific genetic features suggesting they might respond well to these drugs.

Participant Groups

Group I: Treatment (durvalumab, olaparib) Experimental Treatment 4 Interventions

All patients receive durvalumab IV over 1 hour on day 1 of each cycle. Patients with CDK12 mutation and MMRd/MSI-high also receive olaparib PO BID on days 1- 28 of cycles 3-6. Patients with homologous recombination mutation also receive olaparib PO BID on days 1-28 of cycles 1-6. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

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

Findings from Research

In a phase 3 trial involving 256 patients with metastatic castration-resistant prostate cancer and specific genetic alterations, olaparib significantly improved overall survival compared to standard treatments (median 19.1 months vs. 14.7 months) with a hazard ratio of 0.69, indicating a 31% reduction in the risk of death.

Despite a substantial number of patients (66%) in the control group crossing over to olaparib after disease progression, the results still demonstrated that olaparib is an effective treatment option for patients with BRCA1, BRCA2, or ATM alterations, highlighting its potential as a targeted therapy in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. Hussain, M., Mateo, J., Fizazi, K., et al.[2022]

In a phase 2 trial involving 142 patients with metastatic castration-resistant prostate cancer, the combination of olaparib and abiraterone significantly improved progression-free survival compared to placebo plus abiraterone, indicating its potential efficacy in extending patient survival.

However, exploratory analyses showed no significant differences in pain levels or health-related quality of life between the two treatment groups, suggesting that while the combination therapy may improve survival, it does not necessarily enhance the quality of life or reduce pain for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial. Saad, F., Thiery-Vuillemin, A., Wiechno, P., et al.[2022]

A phase II trial indicates that the combination of the antiandrogen abiraterone and the PARP inhibitor olaparib significantly enhances progression-free survival in patients with metastatic castration-resistant prostate cancer.

This benefit occurs regardless of the patients' homologous recombination repair-mutation status, suggesting a broad applicability of this treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone-Olaparib Combo Aids Men with mCRPC. [2019]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

In a study involving 34 patients with BRCA1 or BRCA2 mutated metastatic breast cancer, the combination of olaparib and durvalumab demonstrated promising antitumor activity, with 80% of patients showing disease control at 12 weeks.

The treatment was generally safe, with 32% of patients experiencing grade 3 or worse adverse events, but no treatment-related deaths were reported, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Domchek, SM., Postel-Vinay, S., Im, SA., et al.[2021]

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]

References

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

Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial. [2022]

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

Abiraterone-Olaparib Combo Aids Men with mCRPC. [2019]

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

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

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

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. [2021]

8. 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]