PSMA PET and RLT 2024: The Role of PSMA PET in CRPC Patients

(UroToday.com) The 2024 PSMA conference featured a presentation by Dr. Wolfgang Fendler discussing the role of PSMA PET in CRPC patients.

Dr. Fendler started his presentation by emphasizing that there are waves of progression during a patient’s prostate cancer journey: from local disease to metastatic hormone sensitive prostate cancer, to non metastatic prostate cancer, to metastatic castration resistant prostate cancer, and finally to advanced/terminal disease. These disease states are associated with varying PSA or prostate cancer tumor load:
Previous work from Dr. Fendler’s group suggests that identification of PCWG3 target populations is more accurate and reproducible with PSMA PET than with conventional imaging.¹ Among 67 CRPC patients undergoing conventional imaging and ⁶⁸Ga-PSMA-11 PET/CT, PSMA PET CT resulted in 67% upstaging among nmCRPC patients, 25% upstaging in nodal disease patients, and 47% downstaging among visceral disease patients:

In another study from Dr. Fendler’s group, they conducted a retrospective analysis from six centers of 200 patients with nmCRPC, PSA >2 ng/ml, and high risk for metastatic disease (PSA doubling time ≤ 10 months and/or Gleason Score ≥8).² PSMA PET/CTs were centrally reviewed to assess PSMA-PET detection rate for pelvic disease and distant metastasis. PSMA PET/CT was positive in 196 of 200 patients. Overall, 44% had pelvic diseases, including 24% with local prostate bed recurrence, and 55% had M1 disease despite negative conventional imaging. Significant predictors of M1 disease included: PSA ≥ 5.5 ng/mL, locoregional nodal involvement determined by pathology (pN1), prior primary radiation, and prior salvage radiotherapy. The interobserver agreement was very high (κ= 0.81 – 0.91):
As a follow-up study (which was just accepted to European Urology) they also found that polymetastatic disease, pN1, and high PSMA avidity are associated with shorter overall survival for patients with nmCRPC:

To summarize nmCRPC, (i) PSMA-PET detected lesions in 98% of high-risk nmCRPC patients, (ii) the PSMA PET detection of M1 disease was 55%, and (iii) PSMA PET polymetastatic disease (>= 5 metastases) and PSMA avidity (SUVmax) are prognostic factors:
With regards to the impact of PSMA-PET on volume of disease for patients with mHSPC, Barbato, and colleagues have proposed a compatible quantitative PSMA-PET framework for disease volume assessment in mHSPC.³ Among 85 CT-based CHAARTED-low volume disease patients, and 20 CT-based CHAARTED-high volume disease patients, a PSMA tumor volume of ~40 ml was the optimal cutoff between CT-based CHAARTED-low volume disease (non-unifocal) and high volume disease (non-M1c) (AUC 0.86):
Dr. Fendler then presented a case of a patient with initial high risk prostate cancer (Gleason score 8, PSA 18 ng/ml) who had pelvic nodes and bone metastasis (low volume) on conventional imaging, who then had pelvic + retroperitoneal nodes + mediastinal nodes + bone metastasis (high volume) on PSMA PET/CT:
Dr. Fendler summarized the mHSPC section of his talk with the following points:

• The addition of PSMA PET/CT leads to considerable upshift for stage and volume of mHSPC
• PSMA PET/CT accurately stratifies subgroups of uni-, oligo-, or disseminated mHSPC
• PSMA PET/CT allows for quantification of total PSMA tumor volume
• Combining PSMA PET stage and quantitative volume reveals volume of disease assessment similar to CHAARTED/STAMPEDE

In 2021, Gafita and colleagues published in Lancet Oncology a nomogram of baseline characteristics for prediction of overall survival following ¹⁷⁷Lu-PSMA-617. Among 270 patients, predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline hemoglobin, and ⁶⁸Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0.71 (95% CI 0.69-0.73):³
which was similar to the C-index of the PSA-progression-free survival model (0.70, 95% CI 0.68-0.72). Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24.9 months vs 7.4 months; p<0.0001):
and PSA-progression-free survival (6.6 months vs 2.5 months; p=0.022). To summarize PSMA PET/CT for PSMA radioligand therapy, Dr. Fendler notes:

• A nomogram was constructed and validated using data routinely collected in mCRPC patients treated with ¹⁷⁷Lu-PSMA-617
• PSMA PET/CT derived parameters are important baseline prognostic markers for progression free and overall survival
• These models have potential clinical utility for individual and trial-level survival

With regards to PSMA PET/CT for response assessment using ¹⁷⁷Lu-PSMA-617, Gafita and colleagues developed version 1.0 of a novel framework for response evaluation criteria in PSMA PET/CT and a composite response classification that combines responses by PSA measurements and by RECIP 1.0 (PSA + RECIP). RECIP is defined as follows:⁴

• PSMA PET Partial Response: >30% decrease in PSMA volume without appearance of new lesions
• PSMA PET Progressive Disease: >20% increase in PSMA volume with appearance of new lesions
• PSMA PET Stable Disease: all other

Overall, patients with RECIP progressive disease (n = 39; 8.3 months) had a shorter overall survival than patients with RECIP stable disease (n = 47; 13.1 months; p < 0.001) or RECIP partial response (n = 38; 21.7 months; p < 0.001):

To summarize PSMA PET/CT for response assessment, Dr. Fendler noted the following: (i) PSMA PET/CT is a baseline prognostic biomarker and monitors response to ¹⁷⁷Lu-PSMA-617 and potentially other mCRPC treatments, (ii) novel RECIP criteria were developed based on a multicenter ¹⁷⁷Lu-PSMA-617 patient cohort, and (iii) validation of RECIP in a prospective setting is needed.

Dr. Fendler concluded his presentation discussing the role of PSMA PET in CRPC patients with the following take-home points:

• PSMA PET/CT detects metastases in more than half of conventional nmCRPC patients, however current therapy labels should not be affected. PSMA PET/CT is prognostic for overall survival
• The addition of PSMA PET/CT leads to considerable upshift for the stage and disease volume of metastatic prostate cancer
• PSMA PET/CT is the gatekeeper of PSMA radioligand therapy, and baseline SUV/extent/liver involvement is predictive of overall survival
• PSMA PET/CT response assessment by novel RECIP was proposed for ¹⁷⁷Lu-PSMA therapy and needs further prospective validation

Presented by: Wolfgang Fendler, MD, University of Duisburg-Essen and German Cancer Consortium, University Hospital Essen, Germany

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 PSMA Conference, San Francisco, CA, Thurs, Jan 18 – Fri, Jan 19, 2024.

Related content: Role of PSMA PET in CRPC Patients "Presentation" - Wolfgang Fendler

References:

1. Farolfi A, Hirmas N, Gafita A, et al. Identification of PCWG3 target populations is more accurate and reproducible with PSMA PET than with conventional imaging: A multicenter retrospective study. J Nucl Med. 2021 May 10;62(5):675-678.
2. 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.
3. Gafita A, Calais J, Grogan TR, et al. Nomograms to predict outcomes after ¹⁷⁷Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: An international, multi-centre, retrospective study. Lancet Oncol. 2021 Aug;22(8):1115-1125.
4. Gafita A, Rauscher I, Weber M, et al. Novel framework for treatment response evaluation using PSMA PET/CT in patients with metastatic castration-resistant prostate cancer (RECIP 1.0): An International multicenter study. J Nucl Med. 2022 Nov;63(11):1651-1658.