Neoadjuvant Androgen Deprivation Darolutamide and Ipatasertib in Men With Localized High Risk Prostate Cancer

  • End date
    Feb 3, 2025
  • participants needed
  • sponsor
    David VanderWeele
Updated on 3 November 2021


This multicenter Phase I/II trial consists of two stages: a phase I stage in patients with castration resistant prostate cancer in which the recommended phase II dose will be determined for ipatasertib administered in combination with darolutamide; and a phase II neoadjuvant stage in which patients with high risk prostate cancer and loss of PTEN expression in the tumor tissue planning on undergoing prostatectomy receive ADT, darolutamide, and ipatasertib for 24 weeks prior to planned surgery.


The proposed trial is a single arm, two stage trial looking for an efficacy signal in the neoadjuvant setting in patients with PTEN-null tumors. The active therapy is a combination of androgen deprivation therapy, darolutamide, and ipatasertib. Patients will be treated for 6 months prior to prostatectomy, since previous studies have shown that pCR+MRD rate is higher with 6 months of ADT + abiraterone (24%) than 3 months (4%) (Taplan ME et al. J Clin Oncol. 2014;32(33):3705-15). Since the combination has not been evaluated before, a lead-in cohort in patients with castration resistant prostate cancer will be performed to evaluate safety and drug-drug interaction.

The lead-in cohort will enroll 6 patients to assess the safety of ipatasertib and darolutamide. Ipatasertib has already been evaluated in combination with the AR pathway inhibitors abiraterone and enzalutamide, where 400 mg was found to be safe. Therefore patients will receive the expected final dose of darolutamide 600 mg BID and ipatasertib 400 mg daily. Toxicities will be monitored for 28 days, and blood samples will be drawn for pharmacokinetic (PK) studies. If one or fewer patients experience a DLT the trial will advance to the neoadjuvant setting. If two or more patients experience a DLT at 400 mg, the dose will be reduced for already enrolled patients and another 6 patients will be enrolled to evaluate darolutamide 600 mg BID and ipatasertib 200 mg daily.

PK evaluations will continue for a total of 6 months. Enrollment in the neoadjuvant cohort can proceed before PK studies are complete.

Patients will have response evaluated at 12 weeks, including PSA response and radiographic response per modified PCWG3. If there is progression on bone scan alone, patients should have confirmatory bone scan in at least 6 weeks later. Patients will continue on therapy until the time of progression.

Condition Castrate Resistant Prostate Cancer
Treatment Androgen Deprivation Therapy, Ipatasertib, Darolutamide
Clinical Study IdentifierNCT04737109
SponsorDavid VanderWeele
Last Modified on3 November 2021


Yes No Not Sure

Inclusion Criteria

Histologically-confirmed diagnosis of localized, untreated prostate cancer with high-risk features. High-risk features is defined as
Two or more cores from prostate biopsy that are grade group 4 (Gleason score 4+4=8) or higher, OR
Stage T3-4 (by clinical exam or MRI), M0, and at least 2 cores from prostate biopsy that are grade group 3 (Gleason score 4+3=7) or higher
NOTE: Pathology confirmation of malignancy must be performed by the
participating site (i.e. reports should be issued by the participating site
if a subject's pathology report was not issued by the participating site
archival tissue should be requested by the participating site for internal
pathology review.)
Sufficient archival tissue (at least 2 cores) available for targeted sequencing and immunohistochemistry to evaluate for PTEN loss using the Ventana SP218 immunohistochemistry assay at the local institution
\--The tumor evaluated for PTEN expression should be selected based on
containing both high grade and high volume of tumor content. The slide
evaluated for PTEN expression should be saved for confirmatory central review
Eligibility is based on local review
Measurable PSA
Must have PTEN loss per local institution evaluation, defined as 50% or more of tumor tissue being negative for PTEN expression on Ventana SP218 immunohistochemistry assay
Disease must be untreated and subject must be eligible for (per PI discretion) and planning to undergo radical prostatectomy
Male and 18 years of age
ECOG performance status of 1 within 14 days prior to signing consent
CT or MRI of abdomen and pelvis and bone scan within 90 days prior to starting study drug
Able to swallow pills
Must have ability to understand and the willingness to sign a written informed consent prior to starting study drug
Sexually active patients, unless surgically sterile, must agree to use effective barrier method and refrain from sperm donation during the study treatment and for 3 months after the end of study treatment
As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
Demonstrate adequate organ function as defined in the protocol; all screening labs to be obtained within 14 days prior to registration

Exclusion Criteria

Histology of small cell carcinoma prostate cancer. Adenocarcinoma with neuroendocrine features is allowed
Active infection requiring IV antibiotics
Distant metastatic disease beyond N1 (regional) lymph nodes on conventional baseline imaging studies within 90 days prior to signing consent
Known additional malignancy that has a life-expectancy < 10 years
Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy including
tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and TB testing in line with local practice)
hepatitis B (known positive HBV surface antigen (HBsAg) result)
hepatitis C, or
human immunodeficiency virus (positive HIV 1/2 antibodies). NOTES: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects with HIV/AIDS with adequate antiviral therapy to control viral load would be allowed if they are stable and have been on treatment for 4 weeks prior to first dose of study drug(s). Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy. Testing not required
Prior treatment of prostate cancer with: second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors or CYP17 enzyme inhibitor, radiation therapy, surgery, or chemotherapy. First generation antiandrogen (e.g. bicalutamide) for 28 days or fewer is allowed
Receipt of an investigational agent within <= 28 days prior to registration; or herbal medications and marijuana products within <= 1 day prior to registration
Receipt of medications (e.g. finasteride, dutasteride) or agents that are likely to alter serum PSA levels within <= 42 days or 5 half-lives prior to registration, whichever is shorter
History of type I or type II diabetes mellitus requiring insulin
Any of the following within 6 months before registration: stroke, myocardial infarction, severe/unstable anginal pectoris, coronary/peripheral artery bypass graft, congestive heart failure New York Heart Association (NYHA) class III or IV
Congenital long QT syndrome or QTcF > 480 milliseconds
Grade >= 2 uncontrolled or untreated hypercholesterolemia (>300 mg/dL) or hypertriglyceridemia (>300 mg/dL)
History of or active IBD or active bowel inflammation (diverticulitis)
Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia)
Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug
History of allergic reaction to darolutamide or ipatasertib
Any condition that in the opinion of the investigator would impair the patients' ability to comply with study procedures
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