Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a radiolabelled small-molecule inhibitor that binds with high affinity to PSMA and delivers β particle radiation. \[177Lu\]Lu-PSMA-617 (Pluvicto) was approved by the U.S. Food and Drug administration (FDA) in patients with late-stage, PSMA positive metastatic castration-resistant prostate cancer (mCRPC) based on the results from the phase 3 VISION trial \[1\].
Early identification of tumor progression may reduce unnecessary therapy cycles and their associated risk of adverse events as well as reducing costs and improving patient care by initiating an earlier change in treatment towards a possibly more efficacious therapy.
Response Evaluation Criteria In PSMA-imaging (RECIP) version 1.0 is an evidence-based framework to evaluate therapeutic efficacy in metastatic prostate cancer using PSMA-imaging\[2,3\]. Interim PSMA-PET/CT by RECIP 1.0 criteria performed at 10 weeks after two cycles of PSMA theranostics (\[177Lu\]Lu-PSMA- 617 or \[177Lu\]Lu-PSMA-I\&T) is prognostic for overall survival\[2\]. RECIP 1.0 criteria were validated based on overall survival outcome for measuring response in metastatic prostate cancer during androgen receptor-signaling inhibitors\[4\], as well as in early-stage prostate cancer in patients with biochemical recurrence after initial therapy\[5\].
Lutetium-177 is a beta therapy that also emits 11% gamma rays, which can be utilised to derive whole-body tomographic images similar to PSMA-PET/CT. Serial Lutetium-177 PSMA-targeted single photon emission tomography/computed tomography \[177Lu\]Lu-PSMA-SPECT/CT henceforth referred to as LuPSMASPECT/ CT has potential as an imaging response biomarker for 177Lu-PSMA therapy. This principle enables image quantitation and evaluation after every treatment dose. SPECT/CT post \[177Lu\]Lu-PSMA administration represents a potentially cost-effective alternative to interim PSMA-PET/CT.
Preliminary results have shown a good correlation between changes in LuPSMASPECT/ CT during PSMA theranostics and clinical outcome. LuPSMA-SPECT/CT can provide effective response information as early as 6 weeks after initiation of \[177Lu\]Lu-PSMA-I\&T, i.e. any increase in total tumor volume on SPECT/CT imaging was associated with shorter PSA-PFS (median: 3.7 vs 6.7 months; HR, 2.5; 95% CI 1.5-4.2; p\<0.001)\[6\]. Changes in total tumor volume on 12-week LuPSMASPECT/ CT were also found to be correlated with progression-free survival after \[177Lu\]Lu-PSMA-I\&T\[7\].
The growing evidence suggesting that LuPSMA-SPECT/CT is a new, early surrogate marker for assessing response to treatment has several potential upsides, including the potential replacement of interim PSMA-PET/CT, therefore costsaving, radiation exposure-saving, and SPECT/CT imaging being more convenient and widely available.
Given that data regarding SPECT/CT-based treatment response monitoring during PSMA theranostics are limited, this study aims to prospectively investigate the role of LuPSMA-SPECT/CT imaging for response evaluation during treatment with \[177Lu\]Lu-PSMA in mCRPC patients.
Adult aged 18 or older with proven adenocarcinoma of the prostate
Diagnosis of progressive metastatic castration-resistant prostate cancer.
Progression or intolerance on a novel anti-androgen therapy (i.e. abiraterone, enzalutamide, apalutamide or darolutamide)
Prior therapy with at least one taxane-based chemotherapy during the course of prostate cancer or the patient is symptomatic and assessed as unfit for chemotherapy.
Patient opposed to the use of his data for clinical research.
Patients from the investigator's department only
Cohort
Prospective
Not listed
Confirm prospectively the prognostic value of post-therapy SPECT/CT imaging for response evaluation during [177Lu]Lu- PSMA
Associations between response on 177Lu-PSMA-SPECT with OS, defined as the associations between best overall response achieved on LuPSMA-SPECT/CT at any time during treatment with overall survival. The associations will be considered positive if difference in OS between PD vs nPD is statistically significant (p\<0.05) as per Kaplan-Meier analysis (log-rank test).
Validate prognostic value of interim PSMA-PET/CT performed at 10 weeks after initiation of [177Lu]Lu-PSMA
Associations between response on 10-week PSMA-PET/CT with OS. The associations will be considered positive if difference in OS between PD vs nPD or PD vs SD vs PR according to RECIP 1.0 is statistically significant (p\<0.05) as per Kaplan-Meier analysis (log-rank test).
To compare cost-effectiveness of SPECT/CT versus PET/CT treatment response strategy
Determine clinical significance of performing interim PSMA-PET/CT versus SPECT/CT for treatment response evaluation during \[177Lu\]Lu- PSMA. Percentage of participants with ≥1 new lesion detected on interim PSMA-PET that is not detected on LuPSMA-SPECT imaging performed at 6 weeks and/or 12 weeks. The interim PSMA-PET will be considered of clinical value if patients with ≥1 new lesion detected only on interim PSMAPET have statistically significant (p\<0.05) shorter PFS and/or OS compared to patients without new lesions detected on PSMA-PET and/or LuPSMASPECT, as per Kaplan-Meier analysis (log-rank test).
Investigate added value of interim [18F]FDG PET to PSMA-PET/CT for response evaluation during [177Lu]Lu-PSMA
Determine the added value of interim \[18F\]FDG-PET to PSMA-PET/CT for response evaluation during \[177Lu\]Lu-PSMA. Presence of new lesion, volume and tumor uptake changing on \[18F\]FDG-PET performed at 10 weeks. The interim FDG-PET will be considered of clinical value if patients with progression on FDG-PET have statistically significant (p\<0.05) shorter PFS and OS compared to patients without new lesions detected on PSMA-PET and/or LuPSMA-SPECT and/or CT images, as per Kaplan-Meier analysis (log-rank test).
Determine clinical impact of performing interim PSMA-PET/CT versus LuPSMA-SPECT/CT for response evaluation during [177Lu]Lu-PSMA
Correlations of LuPSMA-SPECT/CT progression-free survival (LuSPECTPFS) with OS. LuSPECT-PFS is defined as the time from treatment initiation to the date of progression on 177Lu-PSMA-SPECT/CT according to RECIP 1.0 criteria or death due to any cause, whichever occurs first \[3\]. The correlations will be significant if the Spearman coefficient r is higher than 0.6 and p\<0.01 \[8\].
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University Hospital, Grenoble
Lead sponsor
Johns Hopkins University
Collaborator
LMU Klinikum
Collaborator
Gustave Roussy, Cancer Campus, Grand Paris
Collaborator
