Durvalumab (MEDI4736) and Olaparib (AZD2281) for Treatment of Biochemically Recurrent Prostate Cancer in Men Predicted to Have a High Neoantigen Load: A Multicenter Pilot Study
Overview
- Phase
- Phase 2
- Intervention
- Durvalumab
- Conditions
- Biochemically Recurrent Prostate Carcinoma
- Sponsor
- University of Washington
- Enrollment
- 6
- Locations
- 1
- Primary Endpoint
- Undetectable Prostate Specific Antigen (PSA)
- Status
- Terminated
- Last Updated
- 8 months ago
Overview
Brief Summary
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.
Detailed Description
OUTLINE: All patients receive durvalumab IV over 1 hour on day 1 of each cycle, total 6 cycles. Starting cycle 4, patients with CDK12 mutations and mismatch repair deficiency (MMRd)/microsatellite instability (MSI)-high will also receive olaparib orally (PO) twice daily (BID) on days 1- 28 of cycles 4-6. Patients with homologous recombination mutation will 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. After completion of study treatment, patients are followed up at 2 weeks, and then every 12 weeks to complete 24 months (at 9, 12, 15, 18, 21 and 24 months).
Investigators
Michael Schweizer
Associate Professor
University of Washington
Eligibility Criteria
Inclusion Criteria
- •Histologic confirmation of adenocarcinoma of the prostate
- •The patient must have received definitive local therapy for prostate cancer, consisting of either radiation therapy and/or prostatectomy (salvage or adjuvant radiation post-prostatectomy is not exclusionary)
- •PSA must be \>= 2 ng/ml if received only prior definitive radiation (no PSA threshold required if prior prostatectomy was performed) with a PSA doubling time (PSADT) =\< 10 months:
- •PSADT calculation must include all recorded PSA values \> 0.2 ng/ml over the past 6 months prior to randomization, with a minimum of 3 values spaced at least 2 weeks apart, with each included value preferably measured at the same laboratory. PSA values obtained prior to localized therapy will be excluded
- •The calculation of PSADT is based on the natural log of PSA
- •Prior salvage radiation or not a candidate for localized salvage radiation due to subject preference or clinical assessment based upon disease characteristics and/or subject co-morbidities
- •Prior hormonal therapy (i.e. androgen deprivation therapy) when given as neoadjuvant/concurrent/adjuvant therapy along with definitive radiation is allowed, provided this was stopped \>= 6 months prior to starting treatment per protocol AND testosterone is \>= 150 ng/dl
- •No evidence of metastatic disease on imaging by whole body bone scan and computed tomography (CT) or magnetic resonance imaging (MRI) of the chest/abdomen/pelvis within 6 weeks before study therapy start day. PSMA positron emission tomography (PET) or fluciclovine scan within 6 weeks of start day may substitute other imaging studies.
- •Patients with oligometastatic disease (i.e. =\< 3 sites) detectable on advanced imaging only (e.g. PSMA or fluciclovine PET) are eligible
- •Abdominal or pelvic lymph nodes measuring =\< 2 cm in short axis are allowed
Exclusion Criteria
- •Prior chemotherapy for prostate cancer, unless done in the neoadjuvant setting, and if the last dose was \> 6 months prior to enrollment
- •Any prior treatment with a PD1 or PD-L1 inhibitor, including durvalumab
- •Any prior treatment with a PARP inhibitor, including olaparib
- •History of another primary malignancy except for
- •Malignancy treated with curative intent and with no known active disease \>= 3 years before the first dose of durvalumab and of low potential risk for recurrence
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- •Adequately treated carcinoma in situ without evidence of disease
- •History of leptomeningeal carcinomatosis
- •Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the treating physician (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT interval by Fridericia \[QTcF\] prolongation \> 470 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
- •Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade \>= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
Arms & Interventions
Treatment (durvalumab, olaparib)
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.
Intervention: Durvalumab
Treatment (durvalumab, olaparib)
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.
Intervention: Olaparib
Treatment (durvalumab, olaparib)
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.
Intervention: Quality-of-Life Assessment
Treatment (durvalumab, olaparib)
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.
Intervention: Questionnaire Administration
Outcomes
Primary Outcomes
Undetectable Prostate Specific Antigen (PSA)
Time Frame: At 12 months after initiation of therapy
Will assess if patients achieve undetectable PSA for post-prostatectomy patients (including those that also received salvage radiation) or PSA \< 0.5 ng/ml for post-definitive radiation patients.
Secondary Outcomes
- PSA50 Response(At 3 and 6 months)
- Change in Quality of Life: IIEF(At the time of enrollment and then every three months, with the final measurement after 12 months.)
- Change in Quality of Life: RANDSF-36(At the time of enrollment and then every three months, with the last assessment at 12 months.)