Neoadjuvant Androgen Deprivation, Darolutamide, and Ipatasertib in Men With Localized, High Risk Prostate Cancer (ADDItion)

  • End date
    Dec 21, 2024
  • participants needed
  • sponsor
    David VanderWeele
Updated on 21 July 2022


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 PI3K pathway activation 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 on21 July 2022


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. Next generation sequencing is
Measurable PSA
also acceptable to be eligible regardless of IHC result, but there must also be
sufficient tissue to evaluate for PTEN by IHC
-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
Able to swallow pills
Must have evidence of PI3K pathway activation. This can be by demonstrating PTEN loss
per local institution evaluation, defined as 50% or more of tumor tissue being
negative for PTEN expression on Ventana SP218 immunohistochemistry assay
Alternatively, qualifying alteration in PTEN, PIK3CA, or AKT1 on next generation
sequencing is also acceptable to be eligible, regardless of PTEN expression
-Qualifying mutations include changes in AKT1 at residues E17, L52, or Q79; in PIK3CA
at residues R88, G106, K111, G118, N345, E542, E545, Q546, M1043, H1047, or G1049; or
in PTEN a R130Q/C/H substitution, or a deletion, frameshift, or introduction of early
stop codon. The assay must be a CLIA-certified assay, and a copy of the report must be
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
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

Active infection requiring IV antibiotics
Known additional malignancy that has a life-expectancy < 10 years
hepatitis B (known positive HBV surface antigen (HBsAg) result)
hepatitis C, or
History of type I or type II diabetes mellitus requiring insulin
Congenital long QT syndrome or QTcF > 480 milliseconds
History of or active IBD or active bowel inflammation (diverticulitis)
History of allergic reaction to darolutamide or ipatasertib
Histology of small cell carcinoma prostate cancer. Adenocarcinoma with neuroendocrine
features is allowed
Distant metastatic disease beyond N1 (regional) lymph nodes on conventional baseline
imaging studies within 90 days prior to signing consent
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
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
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
Grade >= 2 uncontrolled or untreated hypercholesterolemia (>300 mg/dL) or
hypertriglyceridemia (>300 mg/dL)
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
Any condition that in the opinion of the investigator would impair the patients'
ability to comply with study procedures
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