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Baseline Imaging Derived Predictive Factors of Response Following [¹⁷⁷Lu]Lu-PSMA-617 Therapy in Salvage Metastatic Castration-Resistant Prostate Cancer: A Lesion- and Patient-Based Analysis.

ABSTRACT: Earlier studies have mostly identified pre-therapeutic clinical and laboratory parameters for the prediction of treatment response to [¹⁷⁷Lu]Lu-PSMA-617 in metastatic castration resistant prostate cancer patients (mCRPC). The current study investigated whether imaging-derived factors on baseline [⁶⁸Ga]Ga-PSMA-11 PET/CT can potentially predict the response after two cycles of [¹⁷⁷Lu]Lu-PSMA-617 treatment, in a lesion- and patient-based analysis in men with mCRPC. Included patients had histologically proven mCRPC and a [⁶⁸Ga]Ga-PSMA-11 PET/CT before and after two cycles of [¹⁷⁷Lu]Lu-PSMA-617 treatment. The imaging-based response was evaluated on lesion-level (standardized uptake value (SUV) reduction) and patient-level (total lesion PSMA (TL-PSMA) reduction). In the lesion-level analysis, a clear relationship was found between SUV_peak/max and the imaging-based response to [⁶⁸Ga]Ga-PSMA-11 PET/CT (most avid lesion SUV_peak/max ≥ 30% reduction) (p < 0.001), with no significant difference in cut-off values between different sites of metastases (i.e., lymph node, bone or visceral metastasis). In patient-level analysis, baseline PSA and SUV_peak values of most avid metastasis were significantly associated with imaging-based response (TL-PSMA ≥ 30% reduction) (p = 0.019 and p = 0.015). In pre-treatment with [⁶⁸Ga]Ga-PSMA-11 PET/CT, a clear accumulation-response relationship in lesion-level was found for SUV_peak/max in men with mCRPC receiving two cycles of [¹⁷⁷Lu]Lu-PSMA-617 treatment. The SUV_peak of the most avid lesion was the only image-derived factor predictive of the imaging-based response at the patient-level.

SUBMITTER: van der Sar ECA

PROVIDER: S-EPMC9313142 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Baseline Imaging Derived Predictive Factors of Response Following [<sup>177</sup>Lu]Lu-PSMA-617 Therapy in Salvage Metastatic Castration-Resistant Prostate Cancer: A Lesion- and Patient-Based Analysis.

van der Sar Esmée C A ECA Kühr Adinda J S AJS Ebbers Sander C SC Henderson Andrew M AM de Keizer Bart B Lam Marnix G E H MGEH Braat Arthur J A T AJAT

Biomedicines 20220701 7

Earlier studies have mostly identified pre-therapeutic clinical and laboratory parameters for the prediction of treatment response to [177Lu]Lu-PSMA-617 in metastatic castration resistant prostate cancer patients (mCRPC). The current study investigated whether imaging-derived factors on baseline [68Ga]Ga-PSMA-11 PET/CT can potentially predict the response after two cycles of [177Lu]Lu-PSMA-617 treatment, in a lesion- and patient-based analysis in men with mCRPC. Included patients had histologica ...[more]

PMID: 35884878

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Project description:177Lu-PSMA-617 is an effective and novel treatment in metastatic castration-resistant prostate cancer (mCRPC). Our ability to assess response rates and therefore efficacy may be improved using predictive tools. This study investigated the predictive value of serial 177Lu-PSMA-617 SPECT/CT (177Lu SPECT) imaging in monitoring treatment response. Methods: Fifty-six men with progressive mCRPC previously treated with chemotherapy and novel androgen signaling inhibitor were enrolled into the LuPIN trial and received up to 6 doses of 177Lu-PSMA-617 and a radiation sensitizer (3-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol [NOX66]). 68Ga-PSMA-11 and 18F-FDG PET/CT were performed at study entry and exit, and 177Lu SPECT from vertex to mid thighs was performed 24 h after each treatment. SPECT quantitative analysis was undertaken at cycles 1 (baseline) and 3 (week 12) of treatment. Results: Thirty-two of the 56 men had analyzable serial 177Lu SPECT imaging at both cycle 1 and cycle 3. In this subgroup, median prostate-specific antigen (PSA) progression-free survival (PFS) was 6.3 mo (95% CI, 5-10 mo) and median overall survival was 12.3 mo (95% CI, 12-24 mo). The PSA 50% response rate was 63% (20/32). 177Lu SPECT total tumor volume (SPECT TTV) was reduced in 68% (22/32; median, -0.20 m3 [95% CI, -1.4 to -0.001]) and increased in 31% (10/32; median, 0.36 [95% CI, 0.1-1.4]). Any increase in SPECT TTV was associated with shorter PSA PFS (hazard ratio, 4.1 [95% CI, 1.5-11.2]; P = 0.006). An increase of 30% or more in SPECT TTV was also associated with a shorter PSA PFS (hazard ratio, 3.3 [95% CI, 1.3-8.6]; P =0.02). Tumoral SUVmax was reduced in 91% (29/32) and SUVmean in 84% (27/32); neither was associated with PSA PFS or overall survival outcomes. PSA progression by week 12 was also associated with a shorter PSA PFS (hazard ratio, 26.5 [95% CI, 5.4-131]). In the patients with SPECT TTV progression at week 12, 50% (5/10) had no concurrent PSA progression (median PSA PFS, 4.5 mo [95% CI, 2.8-5.6 mo]), and 5 of 10 men had both PSA and SPECT TTV progression at week 12 (median PSA PFS, 2.8 mo [95% CI, 1.8-3.7 mo]). Conclusion: Increasing SPECT TTV on quantitative 177Lu SPECT predicts a short PFS and may play a future role as an imaging response biomarker.

Project description:Baseline uptake on prostate-specific membrane antigen (PSMA)-targeted imaging is a prerequisite for radioligand therapy (RLT) with [177Lu]Lu-PSMA-617. This study aims to quantify lesion-based response to RLT in relation to pretreatment standard molecular imaging metrics derived from [68Ga]Ga-PSMA-11 PET/CT. Sixty-one patients with mCRPC underwent [68Ga]Ga-PSMA-11 PET/CT imaging before and after a median of 4 (IQR 2-6) RLT cycles. Maximum and mean standardized uptake values (SUVmax, SUVmean), as well as tumor-to-liver ratio (TLR), were assessed. A median of 12 (IQR 7-17) lesions was analyzed per patient, resulting in a total of 718 lesions. Lesions with ≥30% SUVmax decline or falling below the blood pool uptake were considered responsive; ≥30% SUVmax increase marked lesion progression. Additionally, 4-point visual scoring was performed according to E-PSMA consensus. In total, 550/718 (76.6%) lesions responded to RLT, including 389/507 (76.7%) bone metastases and 143/181 (79.0%) lymph node metastases. Baseline SUVmax, SUVmean, and TLR values were associated with lesion response by a moderate but significant correlation (rs = 0.33, p < 0.001, rs = 0.32, p < 0.001, and rs = 0.31, p < 0.001, respectively). For the classification of lesion progression based on baseline PSMA uptake, receiver operating characteristics (ROC) found SUVmax, SUVmean, and TLR to have comparable discriminatory value (AUC 0.85, 0.87, and 0.83). Of 42 tumor sites with baseline uptake below the liver (V-score < 2), 19/42 (45.2%) were responsive, 9/42 (21.4%) were stable, and 14/42 (33.3%) showed progression, leaving liver uptake a threshold with low prognostic value for the identification of RLT-refractory lesions (PPV 33%). This was observed accordingly for various liver uptake-based thresholds, including TLR < 1.5, <2.0 with a PPV at 24%, 20%, respectively. Standard uptake parameters quantified by routine baseline [68Ga]Ga-PSMA-11 PET/CT are moderately associated with post-treatment lesion response to [177Lu]Lu-PSMA-617. Commonly applied liver-based uptake thresholds have limited value in predicting refractory lesions at individual tumor sites.

Project description:BackgroundMyelosuppression is a potential dose-limiting factor in radioligand therapy (RLT). This study aims to investigate occurrence, severity and reversibility of hematotoxic adverse events in patients undergoing RLT with 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). The contribution of pretreatment risk factors and cumulative treatment activity is taken into account specifically.MethodsRLT was performed in 140 patients receiving a total of 497 cycles. A mean activity of 6.9 [Formula: see text] 1.3 GBq 177Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6 [Formula: see text] 15.9 GBq. Hematological parameters were measured at baseline, prior to each treatment course, 2 to 4 weeks thereafter and throughout follow-up. Toxicity was graded based on Common Terminology Criteria for Adverse Events v5.0.ResultsSignificant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT. Myelosuppression was significantly more frequent in patients with pre-existing grade 2 cytopenia (OR: 3.50, 95%CI 1.08-11.32, p = 0.04) or high bone tumor burden (disseminated or diffuse based on PROMISE miTNM, OR: 5.08, 95%CI 1.08-23.86, p = 0.04). Previous taxane-based chemotherapy was associated with an increased incidence of significant hematotoxicity (OR: 4.62, 95%CI 1.23-17.28, p = 0.02), while treatment with 223Ra-dichloride, cumulative RLT treatment activity and activity per cycle were not significantly correlated (p = 0.93, 0.33, 0.29).ConclusionHematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates.

Project description:PurposeThis translational study is designed to assess the safety, dosimetry and therapeutic response to a single, low-dose of 177Lu-EB-PSMA-617 in comparison to 177Lu-PSMA-617 in patients with mCRPC.MethodsFollowing institutional review board approval and informed consent, nine patients with mCRPC were recruited. Four patients accepted intravenous injection of 0.80-1.1 GBq (21.5-30 mCi) of 177Lu-EB-PSMA-617, then underwent serial whole-body planar and SPECT/CT imaging at 2, 24, 72, 120 and 168 h. The other five patients accepted intravenous injection of 1.30-1.42 GBq (35-38.4 mCi) 177Lu-PSMA-617, then underwent the same imaging procedures at 0.5, 2, 24, 48, and 72 h. All patients were evaluated by 68Ga-PSMA-617 PET/CT before and one month after the treatment. Dosimetry evaluation was compared in both patient groups.ResultsWhen the bone metastasis tumors with comparable baseline SUVmax in the range of 10.0-15.0 were selected from the two groups for comparison, the accumulated radioactivity of 177Lu-EB-PSMA-617 was about 3.02-fold higher than that of 177Lu-PSMA-617. Imaging dose of 177Lu-EB-PSMA-617 treatment showed significant decrease of 68Ga-PSMA-617 uptake within a month, which was not observed in patients imaged with 177Lu-PSMA-617 (SUV change: -32.43 ± 0.14% vs. 0.21 ± 0.37%; P = 0.002). 177Lu-EB-PSMA-617 also had higher absorbed doses in the red bone marrow and kidneys than 177Lu-PSMA-617 (0.0547 ± 0.0062 vs. 0.0084 ± 0.0057 mSv/MBq for red bone marrow, P < 0.01; 2.39 ± 0.69 vs. 0.39 ± 0.06 mSv/MBq for kidneys, P < 0.01).ConclusionThis first-in-human study demonstrated that 177Lu-EB-PSMA-617 had higher accumulation in mCRPC and that low imaging dose appears to be effective in treating tumors with high 68Ga-PSMA-617 uptakes. Elevated uptakes of 177Lu-EB-PSMA-617 in kidneys and red bone marrow were well tolerated at the administered low dose. Further investigations with increased dose and frequency of administration are warranted.

Project description:Background and objective[177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus the standard of care (SoC) significantly improved overall survival and radiographic progression-free survival versus SoC alone in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer in the VISION trial. We evaluated the safety of additional cycles of 177Lu-PSMA-617 and the impact of longer observation time for patients receiving 177Lu-PSMA-617 plus SoC.MethodsVISION was an international, open-label study. Patients were randomised 2:1 to receive 177Lu-PSMA-617 plus SoC or SoC alone. The incidence of treatment-emergent adverse events (TEAEs) was assessed in prespecified subgroups of patients who received ≤4 cycles versus 5-6 cycles of treatment and during each cycle of treatment. The TEAE incidence was also adjusted for treatment exposure to calculate the incidence per 100 patient-treatment years of observation. This analysis was performed for the first occurrence of TEAEs.Key findings and limitationsThe any-grade TEAE incidence was similar in cycles 1-4 and cycles 5-6. TEAE frequency was similar across all cycles of 177Lu-PSMA-617 treatment. No additional safety concerns were reported for patients who received >4 cycles. The exposure-adjusted safety analysis revealed that the overall TEAE incidence was similar between arms, but distinct trends for different TEAE types were noted and the incidence of events associated with 177Lu-PSMA-617 remained higher in the 177Lu-PSMA-617 arm.Conclusions and clinical implicationsLonger exposure to 177Lu-PSMA-617 plus SoC was not associated with a higher toxicity risk, and the extended time for safety observation could account for the higher TEAE incidence in comparison to SoC alone. The findings support a favourable benefit-risk profile for 6 cycles of 177Lu-PSMA-617 in this setting and the use of up to 6 cycles of 177Lu-PSMA-617 in patients who are clinically benefiting from and tolerating this therapy.Patient summaryFor patients with metastatic prostate cancer no longer responding to hormone therapy, an increase in the number of cycles of treatment with a radioactive compound called 177Lu-PSMA-617 from four to six had no additional adverse side effects.

Project description:Radiopharmaceutical therapies (RPTs) with 177Lu-prostate-specific membrane antigen (PSMA) ligands have demonstrated promising results for the treatment of metastatic castration-resistant prostate cancer. The lack of absorbed-dose-effect relationships currently prevents patient-specific activity personalization. To ease the implementation of dosimetry in the routine clinical workflow for RPT, simplified methods such as single-time-point (STP) instead of multiple-time-point (MTP) imaging protocols are required. This work aimed at assessing differences in the time-integrated activity (TIA) of STP versus MTP image-based dosimetry for 177Lu-PSMA-617 therapy. Methods: Twenty metastatic castration-resistant prostate cancer patients with MTP quantitative 177Lu-SPECT imaging data (∼24, 48, and 72 h post injection (p.i.)) available on first and second 177Lu-PSMA-617 therapy cycles were included in this study. Time-activity curves were fitted for kidneys and lesions to derive effective half-lives and yield a reference TIA. STP approaches involved the formula by Hänscheid (STPH) and a prior-information method (STPprior) that uses the effective half-lives from the first therapy cycle. All time points were considered for the STP approaches. Percentage differences (PDs) in TIA between STP and MTP were compared for the second therapy cycle. Results: Using STPH at 48 h p.i. for kidneys showed a -1.3% ± 5.6% PD from MTP, whereas STPprior showed a PD of 4.6% ± 6.2%. The smallest average PDs for the 56 investigated individual lesions were found using STPprior at 48 h p.i., at only 0.4% ± 14.9%, whereas STPH at 72 h p.i. had a smallest PD of -1.9% ± 14.8%. Conclusion: STP dosimetry for 177Lu-PSMA-617 therapy using a single SPECT/CT scan at 48 or 72 h p.i. is feasible, with a PD of less than ±20% compared with MTP. The validity of both STPH and STPprior has been demonstrated. We believe this finding can increase the adoption of dosimetry and facilitate implementation in routine clinical RPT workflows. Doing so will ultimately enable the finding of dose-effect relationships based on fixed therapy activities that may, in future, allow for absorbed-dose-based RPT activity personalization.

Project description:Rationale: Lu-177-PSMA-617 radioligand therapy (RLT) is currently under approval for treatment of metastatic castration resistant prostate cancer (mCRPC) patients with late stage disease. However, previous studies demonstrated both heterogeneity of prostate specific membrane antigen (PSMA) expression, as well as response to PSMA treatment among mCRPC patients. Thus, there is an unmet need for identifying predictive parametres prior or under PSMA-RLT treatment. We therefore aimed to correlate several clinical and molecular parameters with response to PSMA treatment in a cohort of mCRPC patients undergoing PSMA RLT followed by a detailed analysis of promising candidates. Methods: Nineteen patients, median age 68.8 years (range: 56.9 - 83.3) with mCRPC were included in this study. We performed baseline analysis of clinical parameters based on PSMA PET/CT, (metabolic tumor volume (MTV), total tumor volume (TTV)), serum PSA, ALP, LDH and gene expression analysis of circulating tumor cells (expression of AR full length (AR-FL), AR splice variant 7 (AR-V7), PSA and PSMA) as well as common markers for neuroendocrine differentiation (NED). Results: Patients presented with bone, lymph node, and visceral metastases (89%, 68%, and 21%, respectively). All patients were pretreated with docetaxel, either abiraterone or enzalutamide, or both. Biochemical response in terms of PSA decline ≥50 or ≥30% was observed in 42% and 63%, respectively. There were significant correlations between PSA and PSMA mRNA expression, as well as tumor volumes (both MTV and TTV), AR-FL and AR-V7 mRNA expression. However, there was no correlation with response to PSMA treatment. Furthermore, none of these parameters was significantly correlated with baseline serum PSA values. Common NED markers were shown to be specifically high expressed and revealed impact on OS independent from AR-V7 gene expression. Conclusion: We demonstrate that AR-FL and its splice variant AR-V7 might serve as prognostic biomarkers displaying high tumor burden in mCRPC patient prior to PSMA-RLT. Contrary, PSMA, which has been discussed as a biomarker for PSMA targeted treatment, does not display strong prognostic ability - at least on the mRNA level. Surprisingly, none of these parameters correlates to response to PSMA treatment. In contrast, commom NED markers such as SYP and ENO2 as well as FOXA1 expression level seem to predict OS, but not PFS, more reliably. We admit that a limitation of our study is the focus on mRNA expression of potential biomarkers only. Further investigations analyzing the potential role of protein expression of these markers are therefore warranted.

Project description:IntroductionThe impact of prior therapies, especially chemotherapy, on overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) receiving [177Lu]Lu-PSMA-617 therapy has been the subject of controversy. Therefore, WARMTH decided to plan a multicenter retrospective analysis (the "617 trial") to evaluate response rate and OS as well as the impact of prior therapies on OS in more than 300 patients treated with 177Lu-PSMA-617.Materials and methodsThe data of 631 metastatic CRPC (mCRPC) patients from 11 different clinics were evaluated. According to the inclusion and exclusion criteria, all patients had to have received at least abiraterone or enzalutamide prior to [177Lu]Lu-PSMA-617 therapy. The patients were divided into three groups: patients who had received prior chemotherapy, patients who avoided chemotherapy, and patients for whom a chemotherapy was contraindicated.ResultsThe analysis included the data of 416 patients, with a median age of 71.9 years. At the time of analysis, 87 patients (20,9%) were still alive. A total of 53.6% of patients had received both abiraterone and enzalutamide; 75.5% and 26.4% had a history of chemotherapy with docetaxel and cabazitaxel, respectively. A total of 20.4% had had Ra-223. The median OS was 11.1 months. Prior chemotherapy, the existence of bone and liver metastases, as well as Eastern Cooperative Oncology Group (ECOG) status, were significant prognosticators of worse overall survival in both univariate and multivariate analyses. Patients without any prior chemotherapy showed a significantly longer OS (14.6 months). The median OS in patients who received one or two lines of chemotherapy with docetaxel or docetaxel followed by cabazitaxel, respectively, was 10.9 months and 8.9 months. There was no difference in OS between patients who had not received chemotherapy and patients for whom chemotherapy was contraindicated. The other prior therapies did not have any significant impact on OS.ConclusionIn the present multicenter analysis, chemotherapy-naïve mCRPC patients receiving [177Lu]Lu-PSMA-617 therapy had a significantly longer OS than patients with a history of chemotherapy. This remained independent in the multivariate analysis besides presence of bone and liver metastases as negative prognosticators for survival, whereas an ECOG of 0-1 is associated with a longer OS.

Dataset Information

Baseline Imaging Derived Predictive Factors of Response Following [¹⁷⁷Lu]Lu-PSMA-617 Therapy in Salvage Metastatic Castration-Resistant Prostate Cancer: A Lesion- and Patient-Based Analysis.

Publications

Baseline Imaging Derived Predictive Factors of Response Following [<sup>177</sup>Lu]Lu-PSMA-617 Therapy in Salvage Metastatic Castration-Resistant Prostate Cancer: A Lesion- and Patient-Based Analysis.

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Dataset Information

Baseline Imaging Derived Predictive Factors of Response Following [177Lu]Lu-PSMA-617 Therapy in Salvage Metastatic Castration-Resistant Prostate Cancer: A Lesion- and Patient-Based Analysis.

Publications

Baseline Imaging Derived Predictive Factors of Response Following [<sup>177</sup>Lu]Lu-PSMA-617 Therapy in Salvage Metastatic Castration-Resistant Prostate Cancer: A Lesion- and Patient-Based Analysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Baseline Imaging Derived Predictive Factors of Response Following [¹⁷⁷Lu]Lu-PSMA-617 Therapy in Salvage Metastatic Castration-Resistant Prostate Cancer: A Lesion- and Patient-Based Analysis.