APCCC 2022: Advantages of Using Novel Imaging in nmCRPC

(UroToday.com) The 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting included a session on the management of non-metastatic castrate-resistant prostate cancer (nmCRPC), and a presentation by Dr. Michael Morris discussing the advantages of using novel imaging in this disease space. The state of nmCRPC is (re)defined by imaging, specifically by the inadequacy of standard imaging. Fendler and colleagues¹ retrospectively characterized cancer burden in 200 high-risk patients with nmCRPC using PSMA-PET. Of note, PSMA-PET was positive in 196 of 200 patients, including 44% with pelvic disease, 24% with local prostate bed recurrence, and 55% with M1 disease despite negative conventional imaging:

 Definitionally, Dr. Morris notes that molecular imaging is necessary for (i) accurate understanding of disease volume and distribution, (ii) optimizing prognostication, (iii) testing new treatment paradigms, and (iv) clinical trial design. Additionally, the therapeutic goals of care in nmCRPC are defined by imaging, primarily delaying and preventing the onset of metastases or death (ie. MFS). This is important because (i) patients are asymptomatic from their disease, (ii) this involves prevention of a clinically significant event, (iii) involves prevention of disease related morbidity and mortality, and (iv) involves prevention of more intense and toxic therapy for mCRPC. We have used imaging endpoints as a proxy for these endpoints, and these will need to be recalibrated and reassessed.

Data from the ICECAP study previously demonstrated that MFS and OS are closely associated.² Specifically, these metrics correlated at the patient level with a Kendall’s tau of 0.91, and a R² of 0.83:

Delaying MFS has regulatory recognition for clinical benefit. In a statement by the US FDA in 2021, they stated that “the transition from nmCRPC to radiographically detectable metastatic disease (ie. bone or visceral disease) is a clinically relevant event that can be associated with morbidity and the need for additional medical interventions. Conversely, local progression events may be treated with local therapies, may never progress to distant disease, and may not lead to systemic morbidity. Thus, a large treatment effect on MFS with an acceptable safety profile could demonstrate clinical benefit and support product approval.”

nmCRPC is a disease space with a limited set of clinical options with a goal of delaying MFS defined by standard imaging. The three key trials in nmCRPC demonstrated an MFS benefit for apalutamide (SPARTAN³ – HR 0.28, 95% CI 0.23-0.35), enzalutamide (PROSPER⁴ – HR 0.29, 95% CI 0.24-0.35), and darolutamide (ARAMIS⁵ – HR 0.41, 95% CI 0.34-0.50) for these patients. Dr. Morris emphasized that molecular imaging will redefine MFS, offering new opportunities for intermediate endpoints.

Based on support from PCF and the Movember foundation, Dr. Morris and colleagues are able to perform novel imaging and single cell/organoid studies, such as the following:

 There is evidence to suggest that molecular imaging can play a role in delaying disease progression based on data from the EMPIRE-1 trial [6]. This trial evaluated the role of ¹⁸F-fluciclovine-PET/CT in improving cancer control compared with conventional imaging (bone scan and either CT or MRI) alone for salvage post-prostatectomy radiotherapy. There were 165 patients randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus ¹⁸F-fluciclovine-PET/CT. Importantly, 3-year event-free survival was 63.0% (95% CI 49.2-74.0) in the conventional imaging group versus 75.5% (95% CI 62.5-84.6) for ¹⁸F-fluciclovine-PET/CT (difference 12.5; 95% CI 4.3-20.8; p=0.0028):

Of note, based on the most recent SNMMI consensus meeting, our nuclear medicine colleagues state that molecular imaging should be performed for nmCRPC. 

Dr. Morris concluded his presentation discussing the advantages of using novel imaging in nmCRPC with the following take-home messages:

• For accurate representation of disease extent and distribution, you simply cannot use conventional imaging for this disease state. Molecular imaging will drive new nomenclature, new treatment paradigms, new trial designs, and new biologic and genomic correlates
• This may present new opportunities to delay and prevent key milestones, specifically clinically relevant events such as MFS by standard imaging. Clinical paradigms and endpoints must be developed and you cannot do so without imaging
• These applications are consistent with the limited data we have, regulatory guidance, and clinical common sense

Presented By: Michael Morris, MD, Memorial Sloan Kettering Cancer Center, New York, NY 

Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Annual Hybrid Meeting, Lugano, Switzerland, Thurs, Apr 28 – Sat, Apr 30, 2022.

1. Fendler WP, Weber M, Iravani A, et al. Prostate-Specific Membrane Antigen Ligand Positron Emission Tomography in Men with Nonmetastatic Castration-Resistant Prostate Cancer. Clin Cancer Res. 2019 Dec 15;25(24):7448-7454.
2. Xie W, Regan MM, Buyse M, et al. Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer. J Clin Oncol 2017 Sep 20;35(27):3097-3104.
3. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378(15):1408-1418.
4. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474.
5. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
6. Jani AB, Schreibmann E, Goyal S, et al. 18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): A single centre, open-label, phase 2/3 randomized controlled trial. Lancet. 2021 May 22;397(10288):1895-1904.