Olaparib for Bladder Cancer

Recruiting at 17 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors/inducers

Disqualifiers: Brain metastases, Liver disease, Stroke, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 28 days per cycle, ongoing

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a medication called olaparib to evaluate its effectiveness against advanced bladder cancer and similar cancers that have spread and resist standard treatments. Olaparib, a PARP inhibitor, prevents cancer cells from repairing themselves, potentially slowing their growth. The trial seeks patients with advanced bladder cancer who have specific genetic mutations related to DNA repair, such as BRCA1 or BRCA2, and who have not responded to other treatments. As a Phase 2 trial, this research measures 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 2 weeks for chemotherapy and 4 weeks for monoclonal antibodies before starting the study. Additionally, if you are taking strong or moderate CYP3A inhibitors or inducers, you will need a washout period of 5 half-lives or 3 weeks, whichever is shorter. Please consult with your doctor about your specific medications.

Is there any evidence suggesting that olaparib is likely to be safe for humans?

Studies have shown that olaparib is generally well-tolerated by patients with various types of cancer, including bladder cancer with DNA repair issues. In one study involving patients with bladder cancer, olaparib combined with another drug proved safe to manage, allowing most patients to continue treatment without major problems.

Another study found that patients with ovarian cancer who took olaparib experienced it as safe, with most side effects being mild, such as fatigue or nausea. Serious side effects occurred less frequently.

Overall, research has demonstrated that olaparib is safe for most patients in different situations. However, discussing potential risks and side effects with healthcare providers before joining a trial is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Olaparib is unique because it targets cancer-associated DNA-repair gene mutations, which sets it apart from the standard chemotherapy and immunotherapy treatments typically used for bladder cancer. Most treatments for this condition focus on destroying cancer cells directly, but olaparib works differently by inhibiting the PARP enzyme. This enzyme plays a crucial role in repairing DNA damage in cells, so by blocking it, olaparib makes it harder for cancer cells to repair themselves, potentially leading to their death. Researchers are excited about olaparib because it offers a more targeted approach, potentially reducing side effects and improving effectiveness for patients with specific genetic profiles.

What evidence suggests that olaparib might be an effective treatment for bladder cancer?

Studies have shown that olaparib, a PARP inhibitor, can treat certain cancers by blocking proteins that repair DNA in cancer cells. This blockage can prevent cancer cells from repairing themselves, potentially stopping their growth. While olaparib has improved survival in ovarian cancer, its effects on bladder cancer remain under investigation. In this trial, participants in Cohort I will receive olaparib to evaluate its effectiveness for bladder cancer. Early results are promising, but further research is needed to understand its impact on this specific cancer type. ^{5 6 7 8 9}

Who Is on the Research Team?

Andrea B Apolo

Principal Investigator

National Cancer Institute LAO

Are You a Good Fit for This Trial?

Adults with advanced bladder cancer or genitourinary tumors that have DNA-repair defects and can't be cured by standard treatments. Participants must have specific genetic changes, provide a tumor sample, not be pregnant or fathering children, and meet certain health criteria like good organ function and blood counts.

Inclusion Criteria

I can understand and am willing to sign the consent form, or I have someone legally authorized to do so on my behalf.

My genetic test shows benign or uncertain results.

My tests show a genetic change linked to cancer.

Exclusion Criteria

You have had allergic reactions to drugs similar to olaparib.

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

I have lasting side effects from cancer treatment, except for hair loss.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive olaparib orally twice daily on days 1-28 of each cycle, with cycles repeating every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle, ongoing

Regular visits for blood sample collection, imaging, and optional biopsies

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 4 weeks, every 2 months for 1 year, then every 3 months thereafter.

Up to 5 years

Follow-up visits every 2 months for 1 year, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib

Trial Overview The trial is testing Olaparib, a PARP inhibitor designed to prevent cancer cells from repairing their DNA, potentially stopping their growth. It's for patients whose cancer has spread and involves collecting biospecimens to study the treatment's effectiveness.

How Is the Trial Designed?

Group I: Cohort II (biospecimen collection) Experimental Treatment 7 Interventions

Patients that do not have cancer-associated DNA-repair gene mutations undergo blood sample collection at baseline. Additionally, patients undergo CT, MRI, PET/CT, or bone scan and optional tumor biopsy and bone marrow biopsy on study.

Group II: Cohort I (olaparib) Experimental Treatment 8 Interventions

Patients that have cancer-associated DNA-repair gene mutations receive olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT, MRI, PET/CT, or bone scan and optional tumor biopsy and bone marrow biopsy on study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Olaparib is an effective treatment for patients with platinum-sensitive, relapsed BRCA-mutated high-grade serous ovarian cancer, showing significant improvement in progression-free survival compared to placebo in a study of 265 patients.

The treatment is generally well tolerated, with most side effects being mild to moderate, although fatigue, anemia, and neutropenia were noted as more severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. Frampton, JE.[2016]

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]

The combination of olaparib, a PARP inhibitor, and metformin significantly enhances the inhibition of bladder cancer cell growth, migration, and invasion compared to using either drug alone.

Metformin appears to boost the antitumor effects of olaparib by downregulating proteins in the STAT3/C-MYC signaling pathway, suggesting a potential new strategy for bladder cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin Can Enhance the Inhibitory Effect of Olaparib in Bladder Cancer Cells. Chi, BJ., Sun, Y., Quan, LL., et al.[2022]

Olaparib is an effective first-line maintenance treatment for adults with advanced ovarian cancer who have responded to platinum-based chemotherapy, significantly improving progression-free survival compared to placebo in phase III trials.

When combined with bevacizumab, olaparib further enhances treatment efficacy in patients with homologous recombination deficiency (HRD), but does not show benefits in HRD-negative tumors, indicating its targeted effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: A Review as First-Line Maintenance Therapy in Advanced Ovarian Cancer. Paik, J.[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]

Olaparib, approved by the FDA for patients with advanced ovarian cancer carrying BRCA mutations, showed a 34% objective response rate in a trial of 137 patients who had undergone three or more prior chemotherapy treatments, with a median response duration of 7.9 months.

Common side effects included anemia, nausea, and fatigue, with a small risk (2%) of developing myelodysplastic syndrome or acute myeloid leukemia, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy. Kim, G., Ison, G., McKee, AE., et al.[2022]

Olaparib is a powerful inhibitor of PARP-1 and PARP-2, showing effectiveness in treating ovarian cancer, particularly in patients with germline BRCA mutations.

Phase III trials are currently evaluating olaparib's efficacy as a maintenance therapy after initial treatment in patients with BRCA mutations, highlighting its potential role in long-term cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Gunderson, CC., Moore, KN.[2016]

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]

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]

Olaparib significantly improves overall survival in patients with recurrent platinum-sensitive ovarian cancer, with a hazard ratio of 1.24 based on a meta-analysis of 7 randomized controlled trials involving 2406 patients.

However, the treatment is associated with a higher incidence of adverse events, particularly for grades 3 or higher, indicating that while olaparib is effective, it also carries a risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of Olaparib in the Treatment of Recurrent Platinum Sensitive Ovarian Cancer. Chen, Q., Li, X., Zhang, Z., et al.[2022]

Citations

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Personalized treatment with PARP inhibitors in advanced ... The outcome for these advanced cases is often poor and treatment options are limited. One type of treatment, called PARP inhibitors, has shown ...

2. clinicaltrials.ucsd.edu clinicaltrials.ucsd.edu/trial/NCT03375307

UCSD Bladder Cancer Trial → Testing Olaparib in Patients ... This phase II trial studies how well olaparib works in treating patients with bladder cancer and other genitourinary tumors with deoxyribonucleic acid ...

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The NEODURVARIB Trial - PMC - PubMed Central Conclusions: The combination of neoadjuvant durvalumab and olaparib shows therapeutic activity in bladder cancer. Resistance mechanisms seem to ...

4. merck.com merck.com/news/lynparza-olaparib-improved-median-progression-free-survival-to-over-four-and-a-half-years-compared-to-13-8-months-with-placebo-for-patients-with-brca-mutated-advanced-ovarian-cancer/

LYNPARZA® (olaparib) Improved Median Progression ... LYNPARZA improved progression-free survival to over four and half years versus 13.8 months with placebo following response to first-line platinum-based ...

5. ascopubs.org ascopubs.org/doi/10.1200/PO.18.00264

Clinical Activity of Olaparib in Urothelial Bladder Cancer ... However, there are no reported data on the clinical activity of this molecularly targeted therapy in urothelial bladder cancer.

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Durvalumab Plus Olaparib in Previously Untreated, ... Anecdotal case reports have provided evidence for olaparib activity in previously treated patients with mUC and BRCA1/2 mutations, and the results from the ...

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Study of Olaparib (AZD2281) in Patients With Metastatic/ ... This phase II trial studies how well olaparib works in treating patients with bladder cancer and other genitourinary tumors with deoxyribonucleic acid (DNA)- ...

8. lynparzahcp.com lynparzahcp.com/ovarian-cancer/efficacy/paola-1.html

PAOLA-1 Phase 3 Trial - LYNPARZA® (olaparib) PARP Inhibitor Learn about the PAOLA-1 phase 3 trial and the results of LYNPARZA® (olaparib) + bevacizumab as a first-line maintenance treatment for HRD-positive advanced ...

9. urotoday.com urotoday.com/recent-abstracts/urologic-oncology/bladder-cancer/161271-neoadjuvant-durvalumab-and-olaparib-in-resectable-urothelial-bladder-cancer-expert-commentary.html

Neoadjuvant Durvalumab and Olaparib in Resectable ... The trial showed a pathologic complete response rate of 44.8% (13/29 patients), with manageable safety, and 90% (26/29) of patients proceeded to ...