ASCO GU 2023: Phase III Study of Local or Systemic Therapy Intensification Directed by PET in Prostate Cancer Patients with Post-Prostatectomy Biochemical Recurrence (INDICATE): ECOG-ACRIN EA8191

(UroToday.com) The 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 16^th and 18^th was host to a prostate cancer trials in progress poster session. Dr. Neha Vapiwala presented the framework for INDICATE, a phase III study of local or systemic therapy intensification directed by positron emission tomography (PET) in prostate cancer patients with post-prostatectomy biochemical recurrence.

Standard of care therapy for biochemical recurrence post-radical prostatectomy has long been salvage radiotherapy to the prostate bed and pelvic nodes, with evidence for concurrent short-term (6 months) androgen deprivation therapy.¹ This long-standing paradigm has been challenged with the emergence/increased utilization of PET/CT in the biochemical recurrence disease space, with currently three tracers FDA approved in this setting (¹⁸F-Fluciclovine, ¹⁸F-DCFPyL and ⁶⁸Ga-PSMA-11). The increased sensitivity of PET/CT, compared to conventional imaging with CT and/or bone scan,² has been associated with a stage migration with its findings being increasingly, yet variably, applied to justify modification or omission of standard of care therapies without high-level evidence for clinical benefit. Metastasis-directed therapy (MDT), in the form of metastatectomy or stereotactic body radiation therapy (SBRT), has emerged as increasingly popular treatment option to avoid or delay the use of systemic therapy in patients with oligometastatic disease.³

Apalutamide, an androgen receptor inhibitor, has demonstrated overall survival benefits when utilized in combination with ADT in patients with metastatic hormone sensitive prostate cancer (mHSPC) detected on conventional imaging.⁴ Whether early treatment intensification with apalutamide in patients with PET-detected mHSPC remains unknown. INDICATE aimed to evaluate whether:

1. Patients without PET-detected lesions outside the pelvis benefit from the addition of apalutamide to standard salvage radiotherapy + short-term ADT
2. Patients with PET-detected lesions outside the pelvis benefit from the addition of MDT to treatment intensification with salvage radiotherapy, short-term ADT, and apalutamide

INDICATE will include prostate cancer patients with biochemical recurrence post-radical prostatectomy, defined as PSA >0.5 ng/ml or >0.2 ng/ml if detected within 12 months of the radical prostatectomy, and no evidence of extra-pelvic metastases on conventional imaging who are candidates for standard of care salvage therapy (salvage radiotherapy to the prostate bed and pelvic node with concurrent short-term ADT). Of note, if a patient has a detectable PSA(>=0.01ng/ml) at any time after radical prostatectomy and has a baseline PET that is positive for at least one lesion in any location, there is no minimum PSA requirement.

All patients will undergo baseline PET using one of the three FDA-approved tracers, following which patients will be assigned to either Cohort 1 (PET negative for extra-pelvic metastases) or Cohort 2 (PET positive for extra-pelvic metastases).

Patients in cohort 1 (PET negative) will be randomized to either:

• Arm A: Salvage EBRT + short-term ADT (leuprolide or goserelin) OR
• Arm B: Salvage EBRT + short-term ADT + apalutamide

Patients in cohort 2 (PET positive for extra-pelvic mets) will be randomize to either:

• Arm C: Salvage EBRT + short-term ADT + apalutamide OR
• Arm D: Salvage EBRT + short-term ADT + apalutamide + MDT (RT)

The primary endpoint in both cohorts is progression-free survival, defined as time from randomization to radiographic progression on conventional imaging, symptomatic disease progression or death, whichever occurs first. Secondary endpoints include overall and event-free survival, toxicity, PET progression and quality of life.

For cohort 1, 480 patients will be randomized with 85% power and a one-sided stratified log-rank type I error of 0.025 to detect a 5-year progression-free survival improvement from 80% in the standard of care arm to 90% with addition of apalutamide. For Cohort 2, 324 patients will be randomized with 85% power to detect a clinically meaningful improvement in 5-year progression-free survival from 61.5% in the control arm to 76.5% in the experimental arm with addition of MDT.

INDICATE is currently recruiting with a reported accrual start date of October 8, 2022, and an estimated primary completion date of December 31, 2027 (NCT04423211). 

Presented by: Neha Vapiwala, MD, FACR, Professor and Vice Chair of Education in the Department of Radiation Oncology, University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA

Written By: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, February 16th – February 18th, 2023 

References:

1. Carrie C, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol 2016;17(6):747-756.
2. Hofman MS, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet 2020;395(10231):1208-1216.
3. Deek MP, et al. Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic castration-sensitive prostate cancer: A pooled analysis of the STOMP and ORIOLE trials. J Clin Oncol;40(29):3377-3382.
4. Chi KN, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2019;381:13-24.