Treating Prostate Cancer That Has Come Back after Surgery with Apalutamide and Targeted Radiation Using PET / CT Imaging

This phase III trial tests two questions by two separate comparisons of therapies. The first question is whether enhanced therapy (apalutamide in combination with abiraterone + prednisone) added to standard of care (prostate radiation therapy and short term androgen deprivation) is more effective compared to standard of care alone in patients with prostate cancer who experience biochemical recurrence (a rise in the blood level of prostate specific antigen [PSA] after surgical removal of the prostate cancer). A second question tests treatment in patients with biochemical recurrence who show prostate cancer spreading outside the pelvis (metastasis) by positron emission tomography / computed tomography (PET / CT) imaging. In these patients, the benefit of adding metastasis-directed radiation to enhanced therapy (apalutamide in combination with abiraterone + prednisone) is tested. Diagnostic procedures, such as positron emission tomography / computed tomography (PET / CT), may help doctors look for cancer that has spread to the pelvis. Androgens are hormones that may cause the growth of prostate cancer cells. Apalutamide may help fight prostate cancer by blocking the use of androgens by the tumor cells. Metastasis-directed targeted radiation therapy uses high energy rays to kill tumor cells and shrink tumors that have spread. This trial may help doctors determine if using PET / CT results to deliver more tailored treatment (i.e., adding apalutamide, with or without targeted radiation therapy, to standard of care treatment) works better than standard of care treatment alone in patients with biochemical recurrence of prostate cancer.

Inclusion Criteria

• STEP 0: REGISTRATION ELIGIBILITY CRITERIA
• Patient must have had a radical prostatectomy (RP) as definitive therapy for histopathologically-proven prostatic adenocarcinoma
• Patient must have biochemical recurrence (BCR) after RP, with rising PSA defined as follows: * If time to BCR, (defined as time to first detectable PSA after RP) is < 12 months, a minimum PSA level of >= 0.2 ng/mL and a confirmatory reading of >= 0.2 ng/mL is required, per the American Urological Association (AUA) definition (this includes patients with a persistent PSA reading of at least 0.2 ng/mL) * If time to BCR, (defined as time to first detectable PSA after RP) is >= 12 months, a minimum absolute PSA of 0.5 ng/mL is required ** NOTE: Qualifying PSA values per above must be collected at least 4 weeks after RP, with confirmatory persistent or elevated PSA collected at any subsequent time point
• Patient must be negative or equivocal for extrapelvic metastatic disease by conventional imaging modalities (CIM) (anatomic imaging with CT and/or MRI and bone scintigraphy, or equivalent), which must be done within 16 weeks prior to Step 0 registration. Extra-pelvic metastases is defined as any osseous metastases and/or any extrapelvic soft tissue, lymph nodes and organ metastases; extra-pelvic is defined as superior to common iliac bifurcation, outside of standard prostate bed + whole pelvis nodal RT fields
• Baseline PET/CT scan (PET1) is eligible for this study if the SOC PET scan (e.g., 18F-fluciclovine) is completed after step 0 registration and prior to step 1 randomization OR up to 16 weeks prior to Step 0 registration. The PET/CT scanners must meet scanner qualifications, and scans must meet the study imaging parameters and have an interpretation (or confirmation of an institutional clinical read) by a nuclear medicine physician or radiologist who has undergone 18F-fluciclovine reader training
• Patient must be a candidate for standard-of-care (SOC) post-prostatectomy radiation therapy (RT) to the prostate bed and pelvic nodes with androgen deprivation therapy (adjuvant)
• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Patient must be able to lie flat and still for approximately 20-30 minutes or otherwise tolerate a PET/CT scan and radiation treatment planning and delivery
• Patient must be at a participating institution, which has agreed to perform the imaging research studies, completed the ECOG-American College of Radiology Imaging Network (ACRIN) defined PET/CT scanner qualification procedures and received ECOG-ACRIN PET/CT scanner approval
• Hemoglobin (Hgb) >= 9.0 g/dL (independent of transfusion and/or growth factors within 3 months prior to Step 0 registration) (obtained within 8 weeks prior to Step 0 registration)
• Leukocytes >= 3,000/mcL (obtained within 8 weeks prior to Step 0 registration)
• Absolute neutrophil count >= 1,500/mcL (obtained within 8 weeks prior to Step 0 registration)
• Platelets >= 100,000/mcL (obtained within 8 weeks prior to Step 0 registration)
• Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (patients with Gilbert’s syndrome, if total bilirubin is > 1.5 x ULN, must have a direct bilirubin of < 1.5 x ULN to be eligible) (obtained within 8 weeks prior to Step 0 registration)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained within 8 weeks prior to Step 0 registration)
• Glomerular filtration rate (GFR) > 30 mL/min estimated by Modification of Diet in Renal Disease (MDRD) formula or measured directly by 24 hour urine creatinine (obtained within 8 weeks prior to Step 0 registration)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class I or II (by patient symptoms) or A or B (by objective assessment)
• STEP 1: RANDOMIZATION ELIGIBILITY CRITERIA
• Patient must have completed a baseline SOC PET scan using 18F-fluciclovine (PET1), with results of extra-pelvic metastases involvement known (positive or negative). The PET1 must have been completed after step 0 registration and prior to step 1 randomization OR up to 12 weeks prior to step 0 registration. In addition, the PET/CT scanners must meet scanner qualifications and scans must meet the study imaging parameters and have an interpretation (or confirmation of an institutional clinical read) by a nuclear medicine physician or radiologist who has undergone 18F-fluciclovine reader training
• For patients with negative extra-pelvic metastases, PET-imaging status of intra-pelvic nodes must be known (positive or negative)
• For patients with positive extra-pelvic metastases (defined as any PET positive lesions outside of standard salvage RT fields [prostate bed +/- typical whole pelvis]), the number of extra-pelvic lesions must be known (1 - 5 or > 5 extra-pelvic lesions)
• Patient must agree not to father children while on study
• Patient must be English or Spanish speaking to be eligible for the QOL component of the study * NOTE: Sites cannot translate the associated QOL forms

Exclusion Criteria

• Patient must not have started androgen deprivation therapy for biochemical recurrence prior to baseline study PET/CT imaging
• Patient must not be enrolled in another therapeutic clinical trial
• Patient must not have any other malignancy within the last 2 years, other than superficial bladder cancer and skin basal cell carcinoma or cutaneous superficial squamous cell carcinoma that has not metastasized
• Patient must not have history of seizures or known condition that may cause predisposal to seizures (e.g., stroke or head trauma resulting in loss of consciousness) within 1 year prior to registration
• Patient must not have history of inflammatory bowel disease as this would increase risk of complication from radiotherapy or any gastrointestinal disorder affecting absorption
• Patient must not have had prior pelvic radiation therapy for any reason

PRIMARY OBJECTIVES:

I. For patients without PET-evidence of extrapelvic metastases, to evaluate whether the addition of enhanced systemic therapy to standard of care (SOC) salvage radiation therapy (RT) could prolong progression-free survival (PFS).

II. For patients with PET-evidence of extrapelvic metastases, to evaluate whether the addition of metastasis-directed RT to enhanced systemic therapy and SOC salvage RT could prolong PFS.

III. To compare overall quality of life, measured by Functional Assessment of Cancer Therapy - Prostate (FACT-P) total score, at 6 months between the two sets of treatment arms (A with B and C with D). (QUALITY OF LIFE [QOL] OBJECTIVE)

SECONDARY OBJECTIVES:

I. To evaluate overall survival in each arm.

II. To evaluate event-free survival in each arm.

III. To evaluate time to prostate-specific antigen (PSA) progression using Prostate Cancer Working Group (PCWG) 3 criteria in each arm.

IV. To assess the incidence of adverse events with the addition of enhanced systemic therapy in patients without PET-evidence of extrapelvic metastases.

V. To assess the incidence of adverse events with local ablative metastasis-directed RT for PET-positive metastatic disease in patients with PET-evidence of extrapelvic metastases.

VI. To estimate the detection rate of PET/CT at the patient and regional level, and to evaluate its concordance with the follow-up Food and Drug Administration (FDA)-approved conventional imaging modalities considered standard-of-care per institution, including CT, bone scintigraphy, magnetic resonance imaging (MRI) and PET imaging performed as PET/CT and/or PET/MR using 11C-choline and/or 18F-sodium fluoride.

VII. To determine the distribution of PET-positive lesions among anatomic sites (prostate fossa, intrapelvic soft tissue/lymph node, extrapelvic soft tissue/lymph node, and bone metastases) in patients with post-radical prostatectomy (RP) biochemical recurrence (BCR), correlated with PSA (level, doubling time, velocity) and other relevant clinical parameters.

VIII. To determine the value of repeat PET at time of second PSA recurrence, or 12 months after completion of enhanced systemic therapy, whichever comes first (PET2) to assess response to therapy (enhanced systemic therapy +/- focal RT and/or androgen deprivation therapy [ADT]) compared to standard response assessments (PSA and conventional imaging modalities [CIM]).

IX. To compare the change in overall QOL, measured by FACT-P total score, from baseline to 6 months between the two sets of treatment arms (A with B and C with D). (QOL OBJECTIVE)

X. To compare patient-reported fatigue (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scores) at 6 months between the two sets of treatment arms (A with B and C with D). (QOL OBJECTIVE)

XI.. To compare patient-reported overall QOL (FACT-P scores), fatigue (FACIT-Fatigue scores) and pain interference (patient reported outcomes measurement information system [PROMIS] Pain Interference Short Form 4a) between the two sets of treatment arms (A with B and C with D) at the time of disease progression. (QOL OBJECTIVE)

EXPLORATORY OBJECTIVES:

I. To compare cognitive function, measured by FACT - cognitive function (Cog) peritoneal cancer index (PCI) and total scores, between the three treatment arms receiving enhanced systemic treatment with ADT and apalutamide (Arms B, C, and D) and antiandrogen therapy (ADT) alone (Arm A) at 6 and 12 month. (QOL OBJECTIVE)

II. To compare the change in cognitive function, measured by change in FACT-Cog PCI and total scores, from baseline to 6 and baseline to 12 months, between the three treatment arms receiving enhanced systemic treatment with ADT and apalutamide (Arms B, C, and D) and ADT alone (Arm A) at 6 and 12 months. (QOL OBJECTIVE)

III. To characterize longitudinal change in cognitive function between baseline and 24 months in patients with prostate cancer receiving treatment for biochemical recurrence (BCR) and define clinical and disease related characteristics associated with greater cognitive change by the FACT-Cog PCI and total scores. (QOL OBJECTIVE)

OUTLINE:

STEP 0: Patients receive fluciclovine F18 intravenously (IV) and undergo SOC PET/CT scan at baseline. NOTE: Patients randomized to Arms C or D below undergo a repeat fluciclovine F18 PET/CT at time of second PSA recurrence or 12 months after completion of enhanced systemic therapy.

STEP 1: Patients are randomized to 1 of 4 arms based on results of fluciclovine F18 PET/CT in Step 0.

ARM A (PET NEGATIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC external beam radiation therapy (EBRT) for 6 months. Patients also receive goserelin acetate subcutaneously (SC) or leuprolide acetate intramuscularly (IM) for 6 months starting up to 3 months prior to EBRT but no later than the first fraction of EBRT. All treatment continues for 6 months in the absence of disease progression or unacceptable toxicity.

ARM B (PET NEGATIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive goserelin acetate SC or leuprolide acetate IM as in Arm A. Patients also receive apalutamide orally (PO) once daily (QD) for 6 months in the absence of disease progression or unacceptable toxicity.

ARM C: (PET POSITIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive goserelin acetate SC or leuprolide acetate IM as in Arm A. Patients also receive apalutamide PO QD as in Arm B.

ARM D (PET POSITIVE FOR EXTRA PELVIC-METASTASES): Patients undergo SOC EBRT and receive goserelin acetate SC or leuprolide acetate IM as in Arm A and apalutamide PO QD as in Arm B. Patients also undergo stereotactic body radiation therapy (SBRT) or 3-dimensional (3D) conformal radiation therapy (CRT), intensity-modulated radiation therapy (IMRT) (including volume modulated arc therapy [VMAT]), and intensity-modulated proton therapy (IMPT) over 3-5 fractions in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for years 1-3, every 6 months for years 4-5, and then annually for years 6-10.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
ECOG-ACRIN Cancer Research Group

Principal Investigator
Neha Vapiwala

• Primary ID EA8191
• Secondary IDs NCI-2020-02686
• Clinicaltrials.gov ID NCT04423211