Leuprolide Acetate Alone versus in Combination with 177Lu-PSMA-617, with or without Abiraterone Acetate and Prednisone, for the treatment of Recurrent or De Novo Low Volume Metastatic Hormone-Sensitive Prostate Cancer

Status: approved

This phase II trial tests leuprolide acetate alone versus in combination with 177Lu-PSMA-617, with or without abiraterone acetate and prednisone, for the treatment of hormone-sensitive prostate cancer has spread to a limited number of anatomic sites at the time of initial diagnosis (de novo low volume metastasis) or that has come back after a period of improvement (recurrent). Standard of care treatment for prostate cancer usually includes androgen deprivation therapy, with or without abiraterone acetate and prednisone. Leuprolide acetate is a form of androgen deprivation therapy. It blocks the body from making testosterone (a male hormone) and estradiol (a female hormone). It may stop the growth of prostate cancer cells that need testosterone to grow. 177Lu-PSMA-617 is a type of radioconjugate drug. Upon administration, vipivotide tetraxetan targets and binds to prostate specific membrane antigen (PSMA)-expressing tumor cells. Upon binding, PSMA-expressing tumor cells are destroyed by 177Lu through the specific delivery of radiation. PSMA, a tumor-associated antigen and type II transmembrane protein, is overexpressed on prostate tumor cells. Abiraterone acetate is a type of anti-androgen drug. It blocks tissues from making androgens (male hormones), such as testosterone. This may cause the death of cancer cells that need androgens to grow. Prednisone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving 177Lu-PSMA-617 in combination with leuprolide acetate, with or without abiraterone acetate and prednisone, may be more effective at treating patients with recurrent or de novo low volume metastatic hormone-sensitive prostate cancer than giving leuprolide acetate alone.

Inclusion Criteria

Male patients aged 18 years or older
Signed informed consent must be obtained prior to participation in the study
Histologically confirmed adenocarcinoma of the prostate
Prior treatment with radical prostatectomy or radiation therapy for localized disease is required
Prior treatment with ADT or androgen receptor pathway inhibitor (ARPI) or cytotoxic chemotherapy is permitted if: * The last treatment > 12 months from enrollment on the trial * The duration of treatment is less than 3 months and no evidence of disease progression on treatment
Disease detected on PSMA PET/CT scan (PSMA-avid low volume metastasis [LVM]). Patients with standardized uptake value maximum (SUVMax) lesion/liver >1 (molecular imaging PSMA [miPSMA] score of 2) or lesion/parotid > 1 (miPSMA score of 3) would be included. PET scanners used in the study will comply with current guidelines established by the European Association of Nuclear Medicine (EANM) Research Limited (Ltd) (EARL) for harmonizing PET/CT image acquisition and reconstruction
Patients with hormone sensitive low volume metastatic disease (LVM); either de novo metastatic or recurrent disease. LVM, as assessed on PSMA PET/CT is defined as: * =< 10 total metastatic spots ** Lymph nodes with short axis of =< 2.5 cm ** Total tumor volume (TTV) < 200 mL * =< 4 bone metastases * No brain or liver metastases
Eastern Cooperative Oncology Group (ECOG) performance 0 – 2
Hemoglobin >= 9 g/dL
Platelet count >= 100,000/mm^3
Absolute neutrophil count >= 1,500/mm^3
Serum bilirubin =< 1.5 x upper limit of normal (ULN)
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 x ULN
Serum creatinine =< 1.5 x ULN or an estimated glomerular filtration rate (eGFR) >= 50 mL/min/1.73m^2
Able to start therapy within 28 days of screening
Expected life expectancy > 6 months

Exclusion Criteria

PSMA-undetectable disease defined as rising PSA with absence of PSMA-positive lesions in PSMA PET/CT imaging
PSMA-negative disease defined as lesions detected on imaging that are deemed concerning for active cancer metastasis with PSMA SUVmax less than liver and meeting specific size criteria: lymph nodes with short axis of >= 2.5 cm, visceral lesions with a solid appearance (soft tissue density) >= 1 cm, and bone metastases with a measurable soft tissue component >= 1 cm
Patient with in-field failure (disease recurrence in prostate bed after primary definitive prostatectomy or radiotherapy)
Patient with spinal metastatic disease-causing cord compression
Patient with prior disease progression on ADT (castration resistance prostate cancer [CRPC])
Prior treatment with ADT or cytotoxic chemotherapy or ARPI within less than 12 months from enrollment on the trial
Prior treatment with ADT or ARPI or cytotoxic chemotherapy is permitted only if more than 3 months treatment duration and no evidence of disease progression on treatment
Patients with severe (Common Terminology Criteria for Adverse Events [CTCAE] grade > 2) xerostomia
Patients with well documented history of myelosuppression or renal disease that might impair their participation in the trial per medical advice
Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated non-melanoma skin cancer, superficial bladder cancer are eligible
Estimated life expectancy < 6 months
Concurrent serious medical co-morbidities as determined by study investigator and expected to impair participation in the study * Subjects with female partners of reproductive potential are required to use effective, medically acceptable methods of birth control (e.g., spermicide in conjunction with a barrier such as a condom or sexual abstinence) while on this study, and for 14 weeks after the last dose of 177Lu-PSMA-617

PRIMARY OBJECTIVES:

I. If lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617) + intermittent androgen deprivation therapy (iADT) can demonstrate lower rates of 18-month radiographic progression based on prostate specific membrane antigen (PSMA) positron emission tomography (PET) progression criteria (PPP) compared to iADT alone. (Cohort A)

II. If 177Lu-PSMA-617 + iADT + (intermittent abiraterone acetate [iAA] + prednisone [P]) can demonstrate lower rates of 18-month radiographic progression based on PSMA PET progression criteria (PPP) compared to iADT + (iAA+P) alone. (Cohort B)

SECONDARY OBJECTIVES:

I. If 177Lu-PSMA-617 + iADT can extend the prostate specific antigen (PSA) progression free survival compared to iADT alone. (Cohort A)

II. If 177Lu-PSMA-617 + iADT can extend the treatment free interval compared to iADT alone. (Cohort A)

III. If 177Lu-PSMA-617 + iADT can demonstrate non-inferior 3-year overall survival compared to iADT alone. (Cohort A)

IV. 12-months health related quality of life (HRQoL) assessment. (Cohort A)

V. Safety of 177Lu-PSMA-617 + iADT compared to iADT alone in patients with low-volume metastatic hormone sensitive prostate cancer (mHSPC). (Cohort A)

VI. If 177Lu-PSMA-617 + iADT + (iAA+P) can extend the PSA progression free survival compared to iADT + (iAA+P) alone. (Cohort B)

VII. If 177Lu-PSMA-617 + iADT + (iAA+P) can extend the treatment free interval compared to iADT + (iAA+P) alone. (Cohort B)

VIII. If 177Lu-PSMA-617 + iADT + (iAA+P) can demonstrate non-inferior 3-year overall survival compared to iADT + (iAA+P) alone. (Cohort B)

IX. 12-months HRQoL assessment. (Cohort B)

X. Safety of 177Lu-PSMA-617 + iADT + (iAA+P) compared to iADT + (iAA+P) alone in patients with low-volume mHSPC. (Cohort B)

EXPLORATORY OBJECTIVES:

I. Compare treatment outcomes (18-month radiographic progression free survival [rPFS], 12-month biochemical recurrence free survival [BCRFS], 18-month treatment free interval) based on volume of disease as a continuous and categorical variable in exploratory analyses.

II. Evaluate PSMA-based extracellular vesicles (EVs) and its role in predicting response to 177Lu-PSMA-617

III. Measure tumor mutational burden (TMB) before treatment, and after every 2 cycles of therapy and at progression of all treatment lines using Guardant360 which test patients for 83 genes including and not limited to FGFR, CDNE, and CKD.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients are randomized to 1 of 2 arms.

ARM A1: Patients receive 177Lu-PSMA-617 intravenously (IV) once every 6 weeks and leuprolide acetate subcutaneously (SC) once every 3 months (Q3M). Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo PSMA PET/computed tomography (CT) and collection of blood samples throughout the trial and undergo single photon emission computed tomography (SPECT) on study.

ARM A2: Patients receive leuprolide acetate SC Q3M for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo PSMA PET/CT and collection of blood samples throughout the trial.

COHORT B: Patients are randomized to 1 of 2 arms.

ARM B1: Patients receive 177Lu-PSMA-617 IV every 6 weeks, leuprolide acetate SC Q3M, abiraterone acetate orally (PO) once daily (QD) and prednisone PO twice daily (BID). Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo PSMA PET/CT and collection of blood samples throughout the trial and undergo SPECT on study.

ARM B2: Patients receive leuprolide acetate SC Q3M, abiraterone acetate PO QD and prednisone PO BID. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo PSMA PET/CT and collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 3-6 months in years 2 and 3.

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Leuprolide Acetate Alone versus in Combination with 177Lu-PSMA-617, with or without Abiraterone Acetate and Prednisone, for the treatment of Recurrent or De Novo Low Volume Metastatic Hormone-Sensitive Prostate Cancer

Inclusion Criteria

Exclusion Criteria

United States

Minnesota

Rochester

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Leuprolide Acetate Alone versus in Combination with 177Lu-PSMA-617, with or without Abiraterone Acetate and Prednisone, for the treatment of Recurrent or De Novo Low Volume Metastatic Hormone-Sensitive Prostate Cancer

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