Precision medicine for patients with mCRPC What are the best predictive factors for successful treatment with Lu-PSMA?
receptor signalling inhibitors was not associated with an outcome in their models, which may be related to low statistical power [1]. A TheraP tertiary end-point was to investigate an association between total tumour quantitative parameters on PSMA PET, FDG PET and baseline characteristics with clinical outcomes [5]. In the analysis, conventional biomarkers (ECOG, alkaline phosphatase, haemoglobin, bone and liver metastases) were not found to be significant for determining PSA response rate, the primary endpoint of the TheraP trial [5]. However, two PET parameters were found to be statistically significant for therapy response in mCRPC patients: PSMA PET mean standardised uptake value (SUVmean) and FDG PET metabolic tumour volume (MTV) [5]. A mean standardised uptake value (SUVmean) of 10 at PSMA PET was predictive of a higher likelihood of favourable response to LU PSMA than cabazitaxel. No other PSMA PET parameters were found to be significant in predicting treatment response [5]. This result is concordant with the one from Gafita et al. [1]; even though PSMA expression correlates with the aggressiveness of prostate cancer, the higher the PSMA expression the greater the delivery of Lu PSMA to the tumour target [1]. The explanation of this result may reside in the intrinsic difference between SUVmax and SUVmean: while the first measures the highest concentration of the radiotracer in metastasis, SUVmean measures the average concentration of the radiotracer within the entire tumour volume. The higher this value, the greater the delivered radiation to tumour sites from Lu PSMA [5]. Even if today there is not a univocal PSMA PET parameter to select patients, a refinement of patient selection for Lu PSMA is needed to optimise outcome [6]. FDG PET shows tumour deposits with high glucose metabolism, which can be seen as dedifferentiation for prostate cancer and, therefore, a high proliferation rate. A metabolic tumour volume (MTV) greater than 207 mL was associated with lower responses regardless of the randomly assigned treatment. This means that these patients, regardless of the therapy received, may benefit from an intensification of treatments [5]. In the TheraP trial the “a priori” selection excluded patients with discordant results from FDG PET and PSMA PET.This was a consistent decision made upon previous results that FDG+/PSMA− lesions are a negative predictor of overall survival in patients with mCRPC undergoing RLT [7]. One of the things that was not taken into account in any the aforementioned studies is the evaluation of the homologous recombination repair gene mutation status of the patients. This is possibly due to the fact that the trials and studies evaluating Lu PSMA started before the results of the PARP inhibitor therapy came out [8]. In the future, adding
this parameter can lead to a better understanding of the response to Lu PSMA therapy As of now, few clinical trials have started patient enrolment going into this direction [9. Conclusion In summary, we want to highlight the best predictive factors currently known for successful treatment with Lu PSMA of mCRPC patients. It is now widely accepted that the selection of the patient has to be done carefully and attentively. To offer such a high-cost and specialised treatment, we must assess if the patient will benefit from it, and it may be possible that offering a better therapy for the current stage will lead to an optimisation of resources. References: 1. 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, multicentre, retrospective study. Lancet Oncol. 2021;22:1115-1125. 2. Hofman MS, Emmett L, Sandhu S, et al. [177Lu] Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397:797-804. 3. Sartor O, de Bono J, Chi KN, et al. Lutetium-177- PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385:1091-1103. 4. Fallah J, Agrawal S, Gittleman H, et al. FDA Approval Summary: lutetium Lu 177 vipivotide tetraxetan for patients with metastatic castration-resistant prostate cancer. Clin Cancer Res. December 2022:CCR-22-2875. 5. Buteau JP, Martin AJ, Emmett L, et al. PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [177Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial. Lancet Oncol. 2022;23:1389- 1397. 6. Hotta M, Gafita A, Czernin J, Calais J. Outcome of Patients with PSMA PET/CT Screen Failure by VISION Criteria and Treated with 177Lu-PSMA Therapy: A Multicenter Retrospective Analysis. J Nucl Med. 2022;63:1484-1488. 7. Michalski K, Ruf J, Goetz C, et al. Prognostic implications of dual tracer PET/CT: PSMA ligand and [18F]FDG PET/CT in patients undergoing [177Lu]PSMA radioligand therapy. Eur J Nucl Med Mol Imaging. 2021;48:2024-2030. 8. Keisner SV. Rucaparib and olaparib for the treatment of prostate cancer: A clinician’s guide to choice of therapy. J Oncol Pharm Pract. 2022;28:1624-1633. 9. Gafita A, Marcus C, Kostos L, Schuster DM, Calais J, Hofman MS. Predictors and Real-World Use of Prostate-Specific Radioligand Therapy: PSMA and Beyond. Am Soc Clin Oncol Educ Book. 2022;42:1-17.
toxicity of this therapy) the questions of how to correctly select patients, if there are predictive factors for successful treatment and which population can actually benefit from this treatment [5] should be answered in the future. Discussion Gafita et al [1] validated a nomogram predictive of outcomes after Lu-PSMA in patients with mCRPC. This nomogram is a multi-centre retrospective evaluation developed and validated using international data, where the primary endpoints were OS and PSA PFS. The secondary endpoint was PSA decline of 50% or more (PSA50). The model includes patients representative of the VISION trial patient cohort [1]. In this analysis they evaluated 18 pretherapeutic parameters as putative predictors for outcome after Lu PSMA. Out of all 18, the selected predictors for OS, PFS and PSA50 are showed in table 1 [1].
Dr. Francesca Serani DIMES, Alma Mater Studiorum University of Bologna Nuclear Medicine department, IRCCS Azienda Ospedaliero- Universitaria di Bologna (IT) Dr. Stefano Fanti DIMES, Alma Mater Studiorum University of Bologna Nuclear Medicine department, IRCCS Azienda Ospedaliero- Universitaria di Bologna (IT)
Outcome
Predictors
Overall Survival (OS)
Time since diagnosis Chemotherapy status Baseline haemoglobin Number of metastases Tumour SUVmean at PSMA PET Time since diagnosis Chemotherapy status Tumour SUVmean at PSMA PET Pelvic nodal involvment Bone involvement Liver involvement
177Lutetium Prostate-Specific Membrane Antigen (Lu-PSMA) is a radiolabelled small molecule inhibitor that binds with high affinity to PSMA delivering β particle radiation. It has been shown to have a high level of antitumour activity and a favourable safety profile for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) [1]. Although evaluating the same radiopharmaceutical in essentially the same population, these two successful trials differed in their predefined end-points and inclusion criteria.The TheraP trial was a randomised phase II trial comparing Lu PSMA with cabazitaxel. The primary endpoint was PSA response rate, defined by reduction of at least 50% from baseline, and the secondary endpoint was progression free survival (PFS) and radiographic progression, assessed with CT or bone scan [2]. Lu PSMA showed to be superior for PSA response and PFS compared to cabazitaxel. The VISION trial was a randomized phase III trial comparing Lu PSMA with standard care therapy to standard care therapy alone. The primary outcome was the evaluation of overall survival (OS) and image based PFS while the secondary endpoints were objective response, disease control and time to symptomatic skeletal events [3]. In this trial Lu PSMA improved OS and image based PFS. In addition, in the TheraP trial prostate cancer with known significant sarcomatoid, spindle cell or neuroendocrine small cell components were excluded from the trial, while there is no mention of it in the VISION trial. They both included a progressive mCRPC patient population, previously treated with one taxane, with adequate renal, bone and liver function with ECOG 0 to 2. All patients had to be selected for trial enrolment by a 68Ga-PSMA PET/CT (PSMA PET). That is where we started noticing the major differences in the selected populations: when we start talking “Nuclearese”, or for the newbies, the Nuclear Medicine language. The TheraP trial included patients who at PSMA PET showed a significant PSMA avidity, defined as a minimum uptake of maximum standardized uptake value (SUVmax) of 20 at a site of disease, and SUVmax greater than 10 at sites of measurable disease (≥10mm). Patients were excluded if they showed sites of disease positive in the 18Fluorine- fluorodeoxyglucose PET/CT (FDG PET), with minimal PSMA expression defined as FDG intensity greater than 68Ga-PSMA activity or 68Ga-PSMA SUVmax less than 10 [2]. The VISION trial included patients who were PSMA-positive at the PSMA PET, defined as lesion uptake greater than that of liver parenchyma. Patients with PSMA-negative metastatic lesion (lymph node with a short axis of at least 2.5 cm, solid-organ lesions with a short axis of at least 1.0 cm and bone lesion with a soft-tissue component of at least 1.0 cm in the short axis), defined as PSMA uptake equal to or lower than that of liver parenchyma, were excluded [3]. In this trial no FDG PET was performed.
PSA Progression Free Survival
Bone involvement Liver involvement
PSA decline ≥ 50% (PSA50)
Chemotherapy status Tumour SUVmean at PSMA PET Pelvic nodal involvment Liver involvement
Table 1: Predictors of Lu PSMA therapy response divided per end-point. Modified from (1)
The nomograms for OS, PSA PFS and PSA50 combine traditional clinical prognostic variables and incorporate novel prognostic variables that are relevant for the patient population taken in consideration [1]. A higher tumour SUVmean at PSMA PET is associated with a higher probability of response to LuPSMA treatment for OS, PSA PFS and PSA50. Previous treatment with chemotherapy has shown to have a negative impact on all the outcomes considered: OS, PSA PFS and PSA50, together with liver involvement [1]. This may be explained by the fact that this kind of patient has a more advanced disease that is more difficult to control. The presence of pelvic lymph node metastases correlated with a longer time to PSA progression and a decline ≥ 50% of PSA [1]. A longer time since first diagnosis is associated with better OS and PSA PFS, together with the absence of bone involvement. Several factors might be responsible for the resistance mechanism of bone metastases from prostate cancer, for instance tumour microenvironment and lower target expression [1]. It has been observed that higher levels of haemoglobin and less than 20 metastases are associated with better prognosis [1]. Eventually, the patient population was stratified into two risk groups (high risk vs low risk) using the calculated optimal cut-off for their risk scores (197 points for OS nomogram and 178 points for PSA PFS nomogram). The median OS for low-risk patients versus high-risk patients was 19,9 months versus 8,2 months in the complete set, and the median PSA PFS during Lu PSMA for low-risk patients versus high-risk patients was 8,8 months versus 3,3 months in the complete set [1]. In Gafita et al., the nomogram FDG PET was not evaluated because it was available only for a limited number of patients. Previous use of androgen
thor. Sunday 12 March 17:50 - 18:00 Thematic Session: Is precision medicine
possible in patients with mCRPC? Yellow Area, eURO Auditorium 1
2 0 2 3 BALTIC23 8th Baltic Meeting in conjunction with the EAU 26-27 May 2023, Riga, Latvia
www.baltic23.org
Given the high and numerous direct and indirect costs of Lu PSMA (and the low but not negligible
European Urology Today
12
February/March 2023
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