Visual Abstract
Abstract
Our objective was to evaluate the prognostic value of end-of-treatment prostate-specific membrane antigen (PSMA) PET/CT (PSMA-PET) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA radioligand therapy (PSMA-RLT). Methods: This was a single-center retrospective study. mCRPC patients who underwent PSMA-RLT with available baseline PSMA-PET (bPET) and end-of-treatment PSMA-PET (ePET) within 6 mo of the last PSMA-RLT cycle were eligible. Overall survival (OS) and prostate-specific antigen (PSA) progression status at the time of ePET (by Prostate Cancer Clinical Trials Working Group 3 criteria) were collected. PSMA-PET tumor segmentation was performed to obtain whole-body PSMA tumor volume (PSMA-VOL) and define progressive (≥20% increase) versus nonprogressive disease. Pairs of bPET and ePET were interpreted for appearance of new lesions. Response Evaluation Criteria in PSMA-PET/CT (RECIP) 1.0 were also applied to define progressive versus nonprogressive disease. The associations between changes in PSMA-VOL, new lesions, RECIP 1.0, and PSA progression status at the time of ePET with OS were evaluated by Kaplan–Meier analysis. Results: Twenty mCRPC patients were included. The median number of treatment cycles was 3.5 (interquartile range [IQR], 2–4). The median time between bPET and cycle 1 of PSMA-RLT was 1.0 mo (IQR, 0.7–1.8 mo). The median time between the last cycle of PSMA-RLT and ePET was 1.9 mo (IQR, 1.2–3.5 mo). Twelve of 20 patients (60%) had died at the last follow-up. The median follow-up time from ePET for survivors was 31.2 mo (IQR, 6.8–40.7 mo). The median OS from ePET was 11.4 mo (IQR, 6.8–30.7 mo). Patients with new lesions on ePET had shorter OS than those without new lesions (median OS, 10.7 mo [95% CI, 9.2–12.2] vs. not reached; P = 0.002). Patients with progressive PSMA-VOL had shorter OS than those with nonprogressive PSMA-VOL (median OS, 10.7 mo [95% CI: 9.7–11.7 mo] vs. not reached; P = 0.007). Patients with progressive RECIP had shorter OS than those with nonprogressive RECIP (median OS, 10.7 mo [95% CI, 9.7–11.7 mo] vs. not reached; P = 0.007). PSA progression at the time of ePET was associated with shorter OS (median, 10.9 mo [95% CI, 9.4–12.4 mo] vs. not reached; P = 0.028). Conclusion: In this retrospective study of 20 mCRPC patients treated with PSMA-RLT, progression on ePET by the appearance of new lesions, changes in PSMA-VOL, and RECIP 1.0 was prognostic for OS. Validation in larger, prospective multicentric clinical trials is warranted.
- metastatic castration-resistant prostate cancer
- radioligand therapy
- PSMA-PET
- end-of-treatment PET
- 177Lu-PSMA
The small-molecule inhibitor 177Lu-PSMA binds with high affinity to prostate-specific membrane antigen (PSMA) and delivers β-radiation. In the phase III VISION trial, which led to approval by the Food and Drug Administration, 177Lu-PSMA-617 prolonged overall survival (OS) and image-based progression-free survival when added to the standard of care for patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior taxane-based chemotherapy (1).
In metastatic prostate cancer, treatment response is typically evaluated using conventional imaging (CT and bone scanning) according to the Prostate Cancer Clinical Trials Working Group 3 criteria (2). The Food and Drug Administration approved PSMA PET/CT (PSMA-PET) for different clinical settings in men with prostate cancer (3). However, further research is necessary to evaluate the prognostic value of PSMA-PET for OS in mCRPC patients undergoing treatment with 177Lu-PSMA radioligand therapy (PSMA-RLT) (4).
Progression on end-of-treatment PSMA-PET (ePET) by modified PSMA-PET progression criteria was reported to be prognostic for OS in mCRPC patients undergoing treatment with PSMA-RLT (5,6). Increased whole-body PSMA tumor volume (PSMA-VOL) on ePET was also reported to be prognostic for OS, independent of 18F-FDG PET/CT parameters (7). Recently, Response Evaluation Criteria in PSMA-PET/CT (RECIP) 1.0 were introduced. Patients were classified as having progressive disease (PD) if they had at least a 20% increase in PSMA-VOL and the appearance of new lesions on interim PSMA-PET after the first 2 cycles of PSMA-RLT (4). Progression on interim PSMA-PET by RECIP 1.0 was also found to be prognostic for OS in mCRPC patients treated with PSMA-RLT. However, the prognostic value of progression on ePET by RECIP 1.0 has not, to our knowledge, been previously investigated.
In this retrospective study, we aimed to evaluate the prognostic value of progression on ePET by RECIP 1.0 in mCRPC patients treated with PSMA-RLT.
MATERIALS AND METHODS
Patients and Study Design
In this single-center retrospective study, mCRPC patients who underwent PSMA-PET or PSMA-RLT between October 2016 and April 2022 at UCLA were retrospectively screened for inclusion. Eligible patients underwent PSMA-RLT, had available baseline PET (bPET) and ePET performed within 6 mo of the last PSMA-RLT cycle, and had available survival data. The cutoff date for follow-up was November 5, 2022. Patients who did not have a confirmed date of death and had a follow-up time of less than 3 mo were excluded. This retrospective analysis was approved by the Ethics Committee (UCLA institutional review board approval 20-000954), which waived the study-specific consent requirement. The primary outcome of the study was to evaluate the prognostic value of ePET for OS. The secondary outcome was to evaluate the correlation of prostate-specific antigen (PSA) changes with ePET.
PSMA-PET Image Acquisition
Twenty pairs of PET scans (40 PET scans total) were used for this analysis. 68Ga-PSMA-11 (Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBEDCC)]) was used as the PSMA ligand. PSMA-PET/CT images were acquired after intravenous injection of a median of 191 MBq of 68Ga-PSMA-11 (interquartile range [IQR], 183–204 MBq) and a median uptake time of 63 min (IQR, 59–68 min). Thirty-six of 40 (90%) PET scans were done at UCLA, whereas 4 of 40 (10%) were done at outside institutions. Twenty-one of 40 (53%) PET scans were acquired on a Siemens Biograph 64 Truepoint scanner (image reconstruction parameters: no time of flight, ordered-subsets expectation maximization 2-dimensional [2 iterations, 8 subsets], 5-mm gaussian postreconstruction filter), 18 of 40 (45%) on a Siemens Biograph 64 mCT scanner (image reconstruction parameters: no time of flight, ordered-subsets expectation maximization 3-dimensional [2 iterations, 24 subsets], 5-mm gaussian postreconstruction filter), and 1 of 40 (2%) on a GE Healthcare Discovery VCT scanner (image reconstruction parameters: 3-dimensional, no time of flight).
Image Analysis
Changes in Tumor Burden
The PSMA-positive tumor lesions on bPET and ePET were segmented by 1 nuclear medicine physician, who was masked to outcome data, using qPSMA software as described previously (8). PSMA-VOL was extracted, and percentage changes on ePET relative to bPET were calculated. Patients were classified as having PD (progressive PSMA-VOL, ≥20% increase) versus non-PD.
New Lesions
Pairs of bPET and ePET were interpreted by 1 nuclear medicine physician. The appearance of at least 1 new lesion on ePET was recorded.
Statistical Analysis
OS was calculated in a landmark analysis from time of bPET (to permit comparisons with the VISION trial) and from time of ePET (for Kaplan–Meier analyses) to death or date of last follow-up alive. PSA progression status at the time of ePET was recorded and categorized according to Prostate Cancer Clinical Trials Working Group 3 criteria (2).
Patient characteristics and study variables were summarized overall and by group (progressive RECIP vs. nonprogressive RECIP) using frequencies (percentages) or medians (quarters 1–3) unless otherwise noted. To assess the association between OS and clinical parameters such as changes in PSMA-VOL, appearance of new lesions, RECIP 1.0, and PSA progression status at the time of ePET, we used the Kaplan–Meier method. The 95% CIs for the median OS (if it existed) were computed and the corresponding P values from the log-rank test were used to formally assess the associations of interest. The correlations between percentage changes in serum PSA and percentage changes in PSMA-VOL from bPET to ePET were assessed using Spearman rank correlation coefficients. The associations between PSMA-PET–derived parameters and PSA progression status at the time of ePET were evaluated using the Fisher exact test. Analyses were performed using Jamovi, and P values of less than 0.05 were considered statistically significant.
RESULTS
Patients
Retrospective data from 425 men with prostate cancer who underwent 2 PSMA-PET scans between October 2016 and April 2022 were screened. Of these, 20 mCRPC patients treated with PSMA-RLT with available bPET and ePET met the eligibility criteria and were included (Fig. 1). Patients were treated with PSMA-RLT at UCLA and other international sites. Seven of 20 (35%) patients were treated with PSMA-RLT under compassionate-access programs, 10 of 20 (50%) in a phase II clinical trial (NCT03042312), and 3 of 20 (15%) under an expanded-access protocol (NCT04825652) (9). Baseline characteristics are summarized in Table 2.
Study flowchart.
Baseline Characteristics
PSMA-RLT
The median number of treatment cycles was 3.5 (IQR, 2–4). The median activity per cycle was 7.3 GBq (IQR, 6.6–7.4 GBq). Injected activity data were not available in 5 patients for 8 cycles. The median time between bPET and cycle 1 of PSMA-RLT was 1.0 mo (IQR, 0.7–1.8 mo), whereas the median time between the last cycle of PSMA-RLT and ePET was 1.9 mo (IQR, 1.2–3.5 mo).
Clinical Outcomes
Twelve of 20 patients (60%) had died at last follow-up. The median follow-up time from ePET for survivors was 31.2 mo (IQR, 6.8–40.7 mo). The median OS was 19.5 mo from bPET (IQR, 16.3–36.6 mo) and 11.4 mo from ePET (IQR, 6.8–30.7 mo).
Image Analysis
Case summary images for each patient are provided in the supplemental figures (supplemental materials are available at http://jnm.snmjournals.org). Four of 20 patients (20%) did not have sufficient PSA data to document changes during PSMA-RLT. Sample cases of PSMA-PET and PSA responders and nonresponders are also shown in Figure 2.
Sample cases. (A) 48-y-old man with mCRPC treated with 4 cycles of PSMA-RLT between bPET and ePET. Patient had no new lesions on ePET, was classified as non-PD on basis of PSMA-VOL and RECIP 1.0, and experienced PSA decrease of 100% from bPET to ePET. Patient had follow-up of 41.5 mo from ePET. (B) 77-y-old man with mCRPC treated with 2 cycles of PSMA-RLT between bPET and ePET. Patient had new lesions on ePET, was classified as PD on basis of PSMA-VOL and RECIP 1.0, and experienced PSA increase of 582.5% from bPET to ePET. Patient had OS of 5.0 mo from ePET. (C) 59-y-old man with mCRPC treated with 3 cycles of PSMA-RLT between bPET and ePET. Patient had new lesions on ePET but was classified as non-PD on basis of PSMA-VOL and RECIP 1.0 and experienced PSA decrease of 79% from bPET to ePET. Patient had OS of 9.7 mo from ePET. (D) 65-y-old man with mCRPC treated with 5 cycles of PSMA-RLT between bPET and ePET. Patient had no new lesions on ePET and was classified as non-PD on basis of PSMA-VOL and RECIP 1.0 but experienced PSA increase of 103.9% from bPET to ePET. Patient had OS of 11.8 mo from ePET.
New Lesions
Eleven of 20 patients (55%) had new lesions on ePET and had a shorter OS than patients without new lesions (median OS, 10.7 mo (95% CI, 9.2–12.2) vs. not reached; P = 0.002; Fig. 3).
Kaplan–Meier curves. (A) Appearance of new lesions on ePET. (B) Progressive PSMA-VOL vs. nonprogressive PSMA-VOL on ePET. (C) Progressive RECIP vs. nonprogressive RECIP on ePET. (D) PSA progression status at time of ePET. PD = progressive disease.
PSMA-VOL Changes
The median change in PSMA-VOL on ePET relative to bPET was +21.5% (IQR, −76.9% to +266.5%). Ten of 20 patients (50%) had progressive PSMA-VOL at the time of ePET and had a shorter OS than patients with nonprogressive PSMA-VOL (median OS, 10.7 mo [95% CI, 9.7–11.7 mo] vs. not reached; P = 0.007; Fig. 3).
RECIP
Ten of 20 patients (50%) had progressive RECIP at the time of ePET and had a shorter OS than patients with nonprogressive RECIP (median OS, 10.7 mo [95% CI, 9.7–11.7] vs. not reached; P = 0.007; Fig. 3).
PSA and ePET
Eighteen of 20 patients (90%) had available serum PSA values to assess PSA progression status at the time of ePET. Ten of 18 patients (55.6%) experienced PSA progression at the time of ePET. Two of 18 patients (11.1%) experienced PSA progression at the time of ePET but were classified as non-PD by RECIP 1.0. PSA progression at the time of ePET was associated with shorter OS (median, 10.9 mo [95% CI, 9.4–12.4] vs. not reached; P = 0.028; Fig. 3). Associations between progression by PSMA-VOL, new lesions, and RECIP 1.0 with PSA progression status at ePET are summarized in Table 3. Changes in PSA and PSMA-VOL between bPET and ePET were strongly correlated (Spearman ρ = 0.776; P < 0.001).
ePET and PSA Progression
DISCUSSION
In this single-center retrospective cohort study of 20 mCRPC patients treated with PSMA-RLT, progression on ePET by RECIP 1.0 was prognostic for OS. Changes in PSMA-VOL correlated with changes in PSA and were associated with PSA progression status.
These findings are consistent with Michalski et al., who found that progression on ePET using modified PSMA-PET progression criteria was prognostic for OS in mCRPC patients treated with PSMA-RLT (5). Our results are also consistent with Pathmanandavel et al., who demonstrated that changes in total tumor volume on ePET were prognostic for OS, independent of 18F-FDG parameters, in mCRPC patients who underwent PSMA-RLT (7). Although RECIP 1.0 was initially introduced using interim PSMA-PET, our analysis now suggests that response assessment on ePET using RECIP 1.0 can be prognostic for OS (4).
Because the extraction of quantitative, whole-body PSMA-PET parameters is not widely available in clinical practice, lesion-based response criteria still provide easily accessible prognostic information. Similar to prior reports, we found that the appearance of new lesions on ePET is prognostic for OS (4,5). However, it should also be noted that the appearance of new lesions on ePET as a single lesion assessment may not fully capture disease heterogeneity. In our analysis, among 11 of 20 patients who had new lesions on ePET, 1 (9%) patient (case 9, supplemental materials) was classified as non-PD by PSMA-VOL and RECIP 1.0 and had an OS of 9.7 mo after ePET. In the original RECIP 1.0 study, which analyzed 124 patients, 13% of patients had new lesions despite a decrease in tumor volume and were classified as having stable disease, with a different survival outcome from true progressors (4). This discrepancy illustrates the importance of incorporating quantitative, whole-body PSMA-PET parameters in response assessment. Furthermore, in a comparative analysis of criteria for therapy response assessment in mCRPC, RECIP 1.0 identified fewer patients with PD, and patients classified as PD had a higher risk of death than non-PD patients by RECIP 1.0 compared with PSMA PET Progression criteria (10). These findings suggest that the incorporation of changes in PSMA-VOL in response evaluation may be more informative than per-lesion analyses (10).
Automatic segmentation software is currently in development to provide fast and reproducible tools to extract whole-body quantitative PSMA-PET metrics and enable their widespread use in clinical practice (8,11). As an alternative to the extraction of whole-body quantitative PSMA-PET parameters, a recent study also demonstrated that RECIP 1.0 determined by visual reads had excellent interreader reliability and agreement with quantitative RECIP 1.0 as determined by semiautomatic segmentation software, and progression by visual RECIP 1.0 was prognostic for OS in mCRPC patients undergoing PSMA-RLT (12). Visual RECIP can serve as an effective surrogate for quantitative changes derived from a tumor segmentation software.
The prognostic value of ePET has been extensively explored with 18F-FDG in lymphoma both using visual scores (Deauville/IHC) and using quantitative parameters (changes in SUVmax and metabolic tumor volume) (13–16). 18F-FDG PET is a response assessment and surveillance tool routinely incorporated in the management of lymphoma patients. Response monitoring and prognostic assessments based on multiple PSMA-PET parameters including ePET may be considered in the management of mCRPC patients to guide treatment decisions in a more personalized manner. However, the value of ePET for clinical management may be more limited in mCRPC patients undergoing treatment with PSMA-RLT than is end-of-treatment 18F-FDG PET in lymphoma patients, since mCRPC patients rarely have a complete response to PSMA-RLT. Still, changes in PSMA-PET parameters from baseline to end of treatment may be able to predict OS and progression-free survival in mCRPC patients. If ePET is shown to be an independent predictor of OS and progression-free survival in large, prospective trials, it can serve as an expedited novel endpoint for clinical trials assessing novel drugs.
For other molecular targeted theranostics, there are only limited series reporting on the prognostic value of end-of-treatment PET/CT with 68Ga-DOTATATE in patients with neuroendocrine tumors undergoing treatment with somatostatin receptor-targeted RLT (17). In a retrospective analysis of 12 patients, decreases in the H-lesion SUVmax on end-of-treatment DOTATATE PET indicated a lower risk for PD within 20 mo of therapy (18). In another retrospective analysis of 30 patients, increases in whole-body somatostatin receptor tumor volume on end-of-treatment DOTATATE PET were associated with lower OS (19). Future studies that investigate the prognostic value of whole-body targeted PET imaging metrics in patients undergoing targeted therapy are warranted.
The main limitation of this study is the selection bias inherent in its retrospective design. First, we only included patients who survived long enough to undergo ePET. Therefore, the OS from bPET in our cohort was 19.5 mo, compared with 15.3 mo from randomization in the treatment arm of the VISION trial. This difference in OS can also be explained by the difference in patient populations: multiple patients in our cohort did not previously undergo taxane-based chemotherapy, which was a prerequisite for enrollment in the VISION trial. Second, patients were more likely to be referred to undergo a restaging PSMA-PET scan after their last PSMA-RLT cycle because of suspicion of disease progression based on PSA. Therefore, there was a general concordance between PSA progression status and characteristics on PSMA-PET. There were only 2 patients (cases 5 and 15, supplemental materials) who experienced PSA progression at ePET but were classified as non-PD on the basis of RECIP 1.0. Given the small size of our cohort, we were not able to directly compare the prognostic value of PSA with PSMA-PET in this analysis. In the original RECIP 1.0 study, among the patients without a PSA response at 12 wk (76/124, 61%), patients classified as RECIP-PR (10/76, 13%) had an OS superior to that of patients without RECIP-PR (66/76, 87%): 22.7 versus 9.0 mo (4). These results demonstrate the potential added value of PSMA-PET to PSA for therapy response assessment.
Other limitations of this retrospective study include the small sample size, the use of a single PET reader, the heterogeneous number of PSMA-RLT cycles administered for each patient before ePET, and the heterogeneity of prior and concomitant mCRPC therapies. Five patients initiated other treatments in addition to PSMA-RLT between bPET and ePET (supplemental materials). Thus, the impact of PSMA-RLT on PSMA-PET findings could not be teased out in these patients.
Larger prospective trials are necessary to define the prognostic value of progression on ePET by RECIP 1.0 for progression-free survival and OS. These trials could provide data to support the use of PSMA-PET as a novel surrogate endpoint in clinical trials.
CONCLUSION
In this retrospective cohort of 20 mCRPC patients treated with PSMA-RLT, progression on ePET by the appearance of new lesions, changes in PSMA-VOL, and RECIP 1.0 was prognostic for OS. These findings warrant validation in a larger, multicentric patient cohort.
DISCLOSURE
Jeremie Calais reports prior consulting services for Advanced Accelerator Applications, Astellas, Blue Earth Diagnostics, Curium Pharma, DS Pharma, EXINI, GE Healthcare, Isoray, IBA RadioPharma, Janssen Pharmaceuticals, Lightpoint Medical, Lantheus, Monrol, Novartis, Progenics, POINT Biopharma, Radiomedix, Sanofi, and Telix Pharmaceuticals outside the submitted work. Johannes Czernin is the founder of Sofie Biosciences and Trethera Therapeutics and serves as a scientific advisor for Point Biopharma, RayzeBio, Jubilant Radiopharma, and Amgen. Matthew Rettig reports consulting services for Progenics, Amgen, INmune Bio, Bayer, Astra-Zeneca, and Myovant; receives research funding from Novartis, Merck, and Progenics; and is on the speakers’ bureau for Bayer and Janssen. No other potential conflict of interest relevant to this article was reported.
KEY POINTS
QUESTION: What is the prognostic value of ePET in mCRPC patients treated with PSMA-RLT?
PERTINENT FINDINGS: In this retrospective study of 20 mCRPC patients treated with PSMA-RLT, progression on ePET by the appearance of new lesions, changes in PSMA-VOL, and RECIP 1.0 was prognostic for OS.
IMPLICATIONS FOR PATIENT CARE: Progression on ePET by RECIP 1.0 is prognostic for OS and may be considered in the management of mCRPC patients to guide treatment decisions in a more personalized manner.
Footnotes
↵* Contributed equally to this work.
Guest Editor: Carolyn J. Anderson, University of Missouri
Published online Sep. 7, 2023.
- © 2023 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication November 7, 2022.
- Revision received June 21, 2023.
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