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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of two drugs, durvalumab and olaparib, can effectively treat prostate cancer with certain genetic traits. Durvalumab, an immunotherapy, may help the immune system attack cancer cells, while olaparib, a PARP inhibitor, could prevent cancer cells from repairing themselves. The study aims to determine if these drugs can work together to kill more cancer cells. Men with prostate cancer who have undergone prior treatments like radiation or surgery, and whose cancer has specific genetic mutations, might be eligible to join. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that olaparib is generally well-tolerated by patients with prostate cancer. In studies, many patients taking olaparib did not experience increased pain. Specifically, after six months, 85% of patients on olaparib reported no increase in pain, compared to 75% in the group not taking it. This suggests that olaparib is effective and has manageable side effects.

Since the trial is in Phase 2, the combination of durvalumab and olaparib has already undergone some safety testing. While side effects may still occur, the treatments are considered safe enough for testing in more patients. Researchers are studying both treatments for their potential to work together in fighting prostate cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of durvalumab and olaparib for prostate cancer because they offer a unique approach compared to standard treatments like hormone therapy or chemotherapy. Durvalumab is an immunotherapy drug that boosts the body's immune system to better attack cancer cells. Olaparib is a PARP inhibitor that specifically targets cancer cells with certain genetic mutations, such as homologous recombination mutations and CDK12 mutations, enhancing the precision of the treatment. This combination therapy could potentially provide a more targeted and effective option for patients with specific genetic profiles, offering hope for improved outcomes.

What evidence suggests that durvalumab and olaparib might be an effective treatment for prostate cancer?

Research has shown that olaparib, a PARP inhibitor, can help treat prostate cancer, particularly in patients with genetic changes like BRCA1, BRCA2, or ATM. Studies found that patients taking olaparib lived an average of 19.1 months, compared to 14.7 months for those on other standard treatments. After 6 months, 85% of patients on olaparib did not experience worsening pain, compared to 75% in the comparison group. Olaparib prevents cancer cells from repairing themselves, potentially slowing or stopping tumor growth. In this trial, combining olaparib with durvalumab, an immunotherapy drug, aims to enhance the body's ability to fight cancer, although specific data on this combination for prostate cancer remains limited. Participants with certain genetic mutations will receive both durvalumab and olaparib, while others will receive durvalumab alone. ^{1 2 3 5 6}

Who Is on the Research Team?

Michael Schweizer

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

Citations

1. lynparza.com lynparza.com/prostate-cancer/results.html

Metastatic Prostate Cancer Treatment Results The median time of survival after the start of LYNPARZA was 19.1 months vs 14.7 months on enzalutamide or abiraterone. FOR ADULTS WITH BRCA1, BRCA2, OR ATM ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1911440

Olaparib for Metastatic Castration-Resistant Prostate Cancer After 6 months, 85% of the patients in the olaparib group were free of pain progression, as compared with 75% in the control group (Figure 3B). The median ...

3. lynparzahcp.com lynparzahcp.com/prostate-cancer/efficacy/monotherapy.html

LYNPARZA PROfound Trial for HRRm mCRPC | Efficacy Data ... Median OS with LYNPARZA was 19.1 months (95% CI: 17.4–23.4) vs 14.7 months with investigator's choice of enza or abi/pred (95% CI: 11.9–18.8).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9520412/

Olaparib outcomes in metastatic castration-resistant prostate ... Olaparib is a highly effective oral PARP that has been approved for the treatment of prostate and other cancer10, 11, 12, 13.

5. sciencedirect.com sciencedirect.com/science/article/pii/S2352396424003244

Articles Assessing olaparib efficacy in US Veterans with ... Olaparib is an effective medication in patients with prostate cancers harboring diverse HRR alterations, albeit slowing of tumor growth with prolongation of ...

6. dukecancerinstitute.org dukecancerinstitute.org/blogs/research-shows-promising-outcomes-prostate-cancer-patients-treated-olaparib

Research Shows Promising Outcomes for Prostate Cancer ... This trial revealed that patients receiving olaparib monotherapy had longer treatment duration, improved progression-free survival, and improved ...