Results of a Prospective Phase 2 Pilot Trial of 177Lu–PSMA-617 Therapy for Metastatic Castration-Resistant Prostate Cancer Including Imaging Predictors of Treatment Response and Patterns of Progression

Emmett, Louise; Crumbaker, Megan; Ho, Bao; Willowson, Kathy; Eu, Peter; Ratnayake, Lalith; Epstein, Richard J.; Blanksby, Ashley; Horvath, Lisa G.; Guminski, Alex; Mahon, Kate; Gedye, Craig; Yin, Charlotte; Stricker, Phillip D.; Joshua, Anthony M.

doi:10.1016/j.clgc.2018.09.014

Cited by 146 publications

(122 citation statements)

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“…A recent publication on LnCAP cell lines demonstrated increased uptake and internalization of 177 Lu-PSMA in PCa cells pretreated with enzalutamide (13). There is also an association between 68 Ga-PSMA PET quantitative intensity scores and treatment response to 177 Lu-PSMA (15). The increase in 68 Ga-PSMA intensity with AB reported in men with mCRPC in this study suggests that combination treatment ( 177 Lu-PSMA 1 androgen-signaling inhibitors) may be more effective than 177 Lu-PSMA alone in mCRPC.…”

Section: Discussionmentioning

confidence: 91%

Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial ⁶⁸Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade

et al. 2018

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Prostate-specific membrane antigen (PSMA) may be targeted for both diagnostic and therapeutic purposes in the management of prostate cancer (PCa). In preclinical models, androgen blockade (AB) increases expression of PSMA in both hormone-sensitive and castrate-resistant xenotypes. The aim of this study was to evaluate the effect of AB treatment on 68 Ga-PSMA-11 PET imaging in hormone-naive (luteinizing hormone-releasing hormone [LHRH] ± bicalutamide) and in castrate-resistant men (enzalutamide or abiraterone) with metastatic PCa. Methods: Serial 68 Ga-PSMA-11 PET was prospectively performed at baseline and on days 9, 18, and 28 in 8 men with measurable metastatic hormone-sensitive PCa commencing LHRH ± bicalutamide (cohort 1) and 7 men with castrate-resistant PCa commencing either enzalutamide or abiraterone (cohort 2). Gleason score, age, time since diagnosis, and prior treatments were documented. Testosterone and prostate-specific antigen (PSA) were measured at baseline and all imaging time points. PET/CT was quantitatively analyzed for SUV max , SUV mean , and total tumor volume. Results: In cohort 1, a median 30% (interquartile range [IQR], 5-61) reduction in SUV max was recorded by day 9 after AB. A reduction from baseline SUV max occurred in 86.5% (6/7) men by day 9 (P , 0.04), with an associated PSA response in 100% men (P , 0.03). Total tumor volume reduced in all men by 74.5% (IQR, 27-97) (P , 0.02). After day 9, PSMA response heterogeneity was noted, with persistently high or increasing SUV max in 37.5% (3/8) and marked reduction in 62.5% (5/8). In cohort 2, a median 45% (IQR, 12.7-66) increase in intensity of PSMA SUV was recorded by day 9 after AB. All men demonstrated an increase in SUV max and SUV mean on PSMA PET compared with baseline (P , 0.04). This increase at day 9 plateaued by day 28. PSA responses were more delayed in cohort 2 (−15% [IQR, 70−138]), with 2 of 7 men demonstrating PSA progression. Conclusion: There is rapid dichotomous response on 68 Ga-PSMA PET imaging to AB-dependent on the presence of a hormone-sensitive or castrate-resistant PCa phenotype. This has important implications for interpretation of PSMA PET, and in the timing and sequencing of PSMA-targeted therapy. http://jnm.snmjournals.org/content/60/7/950 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

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Section: Discussionmentioning

confidence: 91%

Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial ⁶⁸Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade

et al. 2018

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“…Nevertheless, this result is in line with results of a previous phase II trial study that included 30 mCRPC patients with progressed disease treated with PSMA-RLT at 6 weekly interval after failure of the standard treatments and indicated a PSA reduction of ≥ 50% in 57% among the studied participants [10]. Furthermore, in the study of Emmett et al that included 18 mCRPC patients receiving a mean dose of 7.0 GBq PSMA-RLT with 6 weeks interval between the cycles, a therapy response in terms of PSA reduction in 71% of the treated patients was reported [17]. In 36% of them, there was a reduction in PSA level of ≥ 50%.…”

Section: Discussionmentioning

confidence: 98%

Clinical outcome of standardized 177Lu-PSMA-617 therapy in metastatic prostate cancer patients receiving 7400 MBq every 4 weeks

Rasul

Hacker

Kretschmer-Chott

et al. 2019

Eur J Nucl Med Mol Imaging

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Purpose [ 177 Lu]Lu-PSMA-617 radio-ligand therapy (PSMA-RLT) is emerging in patients with an advanced metastatic castration-resistant prostate cancer (mCRPC). Here, we aimed to estimate the results of PSMA-RLT in terms of response, progression-free survival (PFS), and overall survival (OS) in patients receiving a highly standardized treatment regimen due to mCRPC. The toxicity of PSMA-RLT has also been evaluated. Patients and methods Fifty-four patients (mean age 72 ± 7 years, median PSA at time of initial therapy 66 [range 1.0-4890 μg/L]), receiving three PSMA-RLT cycles (mean 7315 ± 573 MBq) at four weekly intervals, were included in this retrospective analysis. Hematological and biochemical parameters were regularly determined in every patient. Kaplan-Meier estimates were used to assess PFS and OS and a Cox proportional hazard model was used to analyze significant associations. Treatment response was based on PSA measurements 4 weeks after the 3rd treatment. Results The majority of patients were previously treated with abiraterone/enzalutamide (69%) and docetaxel/cabazitaxel (67%). In total, 79% of the patients showed a decrease in PSA (median PSA decrease from 66 to 19.8, range 0.7-4563 μg/L, P < 0.001) 1 month after the 3rd therapy cycle. Among them, 58% and 35% demonstrated a PSA-decline of > 50% and > 80%, respectively. Median OS was 119 weeks; median PFS was 25 weeks. Patients presenting with a PSA decline had significantly longer PFS (27 vs. 15 weeks, P < 0.0001) and OS (median survival not reached vs. 52 weeks, P < 0.001) than patients with no PSA reduction. Moreover, patients with reduction in PSA levels ≥ 50% (median survival not reached vs. 52 weeks, P < 0.0001) and ≥ 80% (median survival not reached vs. 87 weeks, P = 0.008) lived significantly longer. While hemoglobin did not change during treatment, levels of platelets (236 ± 71 g/L vs. 193 ± 67 g/L) and leucocytes (6.5, range 2.9-13.7 g/L vs. 4.8, range 1.5-12.3 g/L) decreased significantly, both P < 0.001. Two grade 3 leukocytopenia and one grade 3 anemia were observed. Conclusion Intense PSMA-RLT regime with four weekly intervals between the cycles is well-tolerated and offers favorable response rates, PFS, and survival rates for patients with mCRPC.

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“…Demonstration of high uptake on 68 Ga‐PSMA‐PET is used for selection of patients for 177 Lu‐PSMA therapy. A number of retrospective studies with substantial variability in treatment regimens have demonstrated favourable PSA responses of >50% in 31–72% of heavily pre‐treated patients with mCRPC .…”

Section: Introductionmentioning

confidence: 99%

TheraP: a randomized phase 2 trial of ¹⁷⁷Lu‐PSMA‐617 theranostic treatment vs cabazitaxel in progressive metastatic castration‐resistant prostate cancer (Clinical Trial Protocol ANZUP 1603)

et al. 2019

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ObjectiveTo assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with 177 Lu-PSMA-617, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in men with metastatic castration-resistant prostate cancer (mCRPC) who have received prior docetaxel treatment. Results and Conclusions177 Lu-PSMA-617 offers a potential additional life-prolonging treatment option for men with mCRPC. The results of this trial will determine, for the first time in a randomized design, the activity and safety of 177 Lu-PSMA-617, as compared with cabazitaxel chemotherapy in men with progressive mCRPC.

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Results of a Prospective Phase 2 Pilot Trial of 177Lu–PSMA-617 Therapy for Metastatic Castration-Resistant Prostate Cancer Including Imaging Predictors of Treatment Response and Patterns of Progression

Cited by 146 publications

References 17 publications

Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial ⁶⁸Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade

Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial ⁶⁸Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade

Clinical outcome of standardized 177Lu-PSMA-617 therapy in metastatic prostate cancer patients receiving 7400 MBq every 4 weeks

TheraP: a randomized phase 2 trial of ¹⁷⁷Lu‐PSMA‐617 theranostic treatment vs cabazitaxel in progressive metastatic castration‐resistant prostate cancer (Clinical Trial Protocol ANZUP 1603)

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Results of a Prospective Phase 2 Pilot Trial of 177Lu–PSMA-617 Therapy for Metastatic Castration-Resistant Prostate Cancer Including Imaging Predictors of Treatment Response and Patterns of Progression

Cited by 146 publications

References 17 publications

Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial 68Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade

Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial 68Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade

Clinical outcome of standardized 177Lu-PSMA-617 therapy in metastatic prostate cancer patients receiving 7400 MBq every 4 weeks

TheraP: a randomized phase 2 trial of 177Lu‐PSMA‐617 theranostic treatment vs cabazitaxel in progressive metastatic castration‐resistant prostate cancer (Clinical Trial Protocol ANZUP 1603)

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Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial ⁶⁸Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade

Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial ⁶⁸Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade

TheraP: a randomized phase 2 trial of ¹⁷⁷Lu‐PSMA‐617 theranostic treatment vs cabazitaxel in progressive metastatic castration‐resistant prostate cancer (Clinical Trial Protocol ANZUP 1603)