Safety of PSMA-Targeted Molecular Radioligand Therapy with 177Lu-PSMA-617: Results from the Prospective Multicenter Phase 2 Trial RESIST-PC (NCT03042312).

The purpose of this analysis was to report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion:177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

Prospective phase 2 trial of PSMA-targeted molecular RadiothErapy with 177Lu-PSMA-617 for metastatic castration-reSISTant Prostate Cancer (RESIST-PC): efficacy results of the UCLA cohort.

The objective of this study was to determine prospectively the efficacy profile of 2 activity regimens of 177Lu-PSMA therapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC): 6.0 vs. 7.4 GBq. Methods: RESIST-PC (NCT03042312) was a prospective multicenter phase 2 trial. Patients with progressive mCRPC after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, and sufficient PSMA expression by PSMA PET were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq) and received up to 4 cycles every 8 wk. The primary endpoint was the efficacy of 177Lu-PSMA measured by the prostate-specific antigen (PSA) response rate (RR) after 2 cycles (≥50% decline from baseline). Secondary endpoints included the PSA RR (≥50% decline) at any time (best response), and overall survival (OS). Results: The study was closed at enrollment of 71/200 planned patients because of sponsorship transfer. We report here the efficacy of the University of California Los Angeles cohort results only (n = 43). The PSA RRs after 2 cycles and at any time were 11/40 (28%, 95% CI 15-44), 6/13 (46%, 95% CI 19-75), and 5/27 (19%, 95% CI 6-38), and 16/43 (37%, 95% CI 23-53), 7/14 (50%, 95% CI 23-77), and 9/29 (31%, 95% CI 15-51) in the whole cohort, the 6.0-GBq group, and the 7.4-GBq group, respectively (P = 0.12 and P = 0.31). The median OS was 14.0 mo (95% CI 10.1-17.9), 15.8 (95% CI 11.8-19.4), and 13.5 (95% CI 10.0-17.0) in the whole cohort, the 6.0-GBq group, and the 7.4 GBq group, respectively (P = 0.87). OS was longer in patients who experienced a PSA decline ≥ 50% at any time than in those who did not: median, 20.8 versus 10.8 mo (P = 0.005). Conclusion: In this prospective phase 2 trial of 177Lu-PSMA for mCRPC, the median OS was 14 mo. Despite the heterogeneous study population and the premature study termination, the efficacy profile of 177Lu-PSMA appeared to be favorable and comparable with both activity regimens (6.0 vs. 7.4 GBq). Results justify confirmation with real-world data matched-pair analysis and further clinical trials to refine and optimize the 177Lu-PSMA therapy administration scheme to improve tumor radiation dose delivery and efficacy.

Impact of 68Ga-PSMA-11 PET on the Management of Recurrent Prostate Cancer in a Prospective Single-Arm Clinical Trial.

Prostate-specific membrane antigen (PSMA) ligand PET induces management changes in patients with prostate cancer. We aim to better characterize the impact of 68Ga-PSMA-11 PET (68Ga-PSMA PET) on management of recurrent prostate cancer in a large prospective cohort. Methods: We report management changes after 68Ga-PSMA PET, a secondary endpoint of a prospective multicenter trial in men with biochemical recurrence of prostate cancer. Pre-PET (Q1), post-PET (Q2), and posttreatment (Q3) questionnaires were sent to referring physicians recording site of recurrence and intended (Q1 to Q2 change) and implemented (Q3) therapeutic and diagnostic management. Results: Q1 and Q2 response was collected for 382 of 635 patients (60%, intended cohort), and Q1, Q2, and Q3 response was collected for 206 patients (32%, implemented cohort). An intended management change occurred in 260 of 382 (68%) patients. The intended change was considered major in 176 of 382 (46%) patients. Major changes occurred most often for patients with prostate-specific antigen of 0.5 to less than 2.0 ng/mL (81/147, 55%). By analysis of stage groups, management change was consistent with PET disease location, that is, a majority of major changes toward active surveillance (47%) for unknown disease site (103/382, 27%), toward local or focal therapy (56%) for locoregional disease (126/382, 33%), and toward systemic therapy (69% M1a; 43% M1b/c) for metastatic disease (153/382, 40%). According to Q3 responses, the intended management was implemented in 160 of 206 (78%) patients. In total, 150 intended diagnostic tests, mostly CT (n = 43, 29%) and bone scans or 18F-NaF PET (n = 52, 35%), were prevented by 68Ga-PSMA PET; 73 tests, mostly biopsies (n = 44, 60%) as requested by the study protocol, were triggered. Conclusion: According to referring physicians, sites of recurrence were clarified by 68Ga-PSMA PET, and disease localization translated into management changes in more than half of patients with biochemical recurrence of prostate cancer.

18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial.

BACKGROUND: National Comprehensive Cancer Network guidelines consider 18F-fluciclovine PET-CT for prostate cancer biochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific membrane antigen (PSMA) PET-CT. To the best of our knowledge, no prospective head-to-head comparison between these tests has been done so far. The aim of this study was to compare prospectively paired 18F-fluciclovine and PSMA PET-CT scans for localising biochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (<2·0 ng/mL). METHODS: This was a prospective, single-centre, open-label, single-arm comparative study done at University of California Los Angeles (Los Angeles, CA, USA). Patients older than 18 years of age with prostate cancer biochemical recurrence after radical prostatectomy and PSA levels ranging from 0·2 to 2·0 ng/mL without any prior salvage therapy and with a Karnofsky performance status of at least 50 were eligible. Patients underwent 18F-fluciclovine (reference test) and PSMA (index test) PET-CT scans within 15 days. Detection rate of biochemical recurrence at the patient level and by anatomical region was the primary endpoint. A statistical power analysis demonstrated that a sample size of 50 patients was needed to show a 22% difference in detection rates in favour of PSMA (test for superiority). Each PET scan was interpreted by three independent masked readers and a consensus majority interpretation was generated (two vs one) to determine positive findings. This study is registered with ClinicalTrials.gov, number NCT02940262, and is complete. FINDINGS: Between Feb 26, 2018, and Sept 20, 2018, 143 patients were screened for eligibility, of whom 50 patients were enrolled into the study. Median follow-up was 8 months (IQR 7-9). The primary endpoint was met; detection rates were significantly lower with 18F-fluciclovine PET-CT (13 [26%; 95% CI 15-40] of 50) than with PSMA PET-CT (28 [56%; 41-70] of 50), with an odds ratio (OR) of 4·8 (95% CI 1·6-19·2; p=0·0026) at the patient level; in the subanalysis of the pelvic nodes region (four [8%; 2-19] with 18F-fluciclovine vs 15 [30%; 18-45] with PSMA PET-CT; OR 12·0 [1·8-513·0], p=0·0034); and in the subanalysis of any extrapelvic lesions (none [0%; 0-6] vs eight [16%; 7-29]; OR non-estimable [95% CI non-estimable], p=0·0078). INTERPRETATION: With higher detection rates, PSMA should be the PET tracer of choice when PET-CT imaging is considered for subsequent treatment management decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL). Further research is needed to investigate whether higher detection rates translate into improved oncological outcomes. FUNDING: None.

Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial.

IMPORTANCE: In retrospective studies, 68Ga-PSMA-11 positron emission tomographic (PET) imaging improves detection of biochemically recurrent prostate cancer compared with conventional imaging. OBJECTIVE: To assess 68Ga-PSMA-11 PET accuracy in a prospective multicenter trial. DESIGN, SETTING, AND PARTICIPANTS: In this single-arm prospective trial conducted at University of California, San Francisco and University of California, Los Angeles, 635 patients with biochemically recurrent prostate cancer after prostatectomy (n = 262, 41%), radiation therapy (n = 169, 27%), or both (n = 204, 32%) underwent 68Ga-PSMA-11 PET. Presence of prostate cancer was recorded by 3 blinded readers on a per-patient and per-region base. Lesions were validated by histopathologic analysis and a composite reference standard. MAIN OUTCOMES AND MEASURES: Endpoints were positive predictive value (PPV), detection rate, interreader reproducibility, and safety. RESULTS: A total of 635 men were enrolled with a median age of 69 years (range, 44-95 years). On a per-patient basis, PPV was 0.84 (95% CI, 0.75-0.90) by histopathologic validation (primary endpoint, n = 87) and 0.92 (95% CI, 0.88-0.95) by the composite reference standard (n = 217). 68Ga-PSMA-11 PET localized recurrent prostate cancer in 475 of 635 (75%) patients; detection rates significantly increased with prostate-specific antigen (PSA): 38% for <0.5 ng/mL (n = 136), 57% for 0.5 to <1.0 ng/mL (n = 79), 84% for 1.0 to <2.0 ng/mL (n = 89), 86% for 2.0 to <5.0 ng/mL (n = 158), and 97% for ≥5.0 ng/mL (n = 173, P < .001). Interreader reproducibility was substantial (Fleiss κ, 0.65-0.78). There were no serious adverse events associated with 68Ga-PSMA-11 administration. PET-directed focal therapy alone led to a PSA drop of 50% or more in 31 of 39 (80%) patients. CONCLUSIONS AND RELEVANCE: Using blinded reads and independent lesion validation, we establish high PPV for 68Ga-PSMA-11 PET, detection rate and interreader agreement for localization of recurrent prostate cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02940262 and NCT03353740.

Impact of 68Ga-PSMA-11 PET/CT on the Management of Prostate Cancer Patients with Biochemical Recurrence.

In this prospective survey of referring physicians, we investigated whether and how 68Ga-labeled prostate-specific membrane antigen 11 (68Ga-PSMA-11) PET/CT affects the implemented management of prostate cancer patients with biochemical recurrence (BCR). Methods: We conducted a prospective survey of physicians (NCT02940262) who referred 161 patients with prostate cancer BCR (median prostate-specific antigen value, 1.7 ng/mL; range, 0.05-202 ng/mL). Referring physicians completed one questionnaire before the scan to indicate the treatment plan without 68Ga-PSMA-11 PET/CT information (Q1; n = 101), one immediately after the scan to denote intended management changes (Q2; n = 101), and one 3-6 mo later to document the final implemented management (Q3; n = 56). The implemented management was also obtained via electronic chart review or patient contact (n = 45). Results: A complete documented management strategy (Q1 + Q2 + implemented management) was available for 101 of 161 patients (63%). Seventy-six of these (75%) had a positive 68Ga-PSMA-11 PET/CT result. The implemented management differed from the prescan intended management (Q1) in 54 of 101 patients (53%). The postscan intended management (Q2) differed from the prescan intended management (Q1) in 62 of 101 patients (61%); however, these intended changes were not implemented in 29 of 62 patients (47%). Pelvic nodal and extrapelvic metastatic disease on 68Ga-PSMA-11 PET/CT (PSMA T0N1M0 and PSMA T0N1M1 patterns) was significantly associated with implemented management changes (P = 0.001 and 0.05). Conclusion: Information from 68Ga-PSMA-11 PET/CT brings about management changes in more than 50% of prostate cancer patients with BCR (54/101; 53%). However, intended management changes early after 68Ga-PSMA-11 PET/CT frequently differ from implemented management changes.

Most of the Intended Management Changes After 68Ga-DOTATATE PET/CT Are Implemented.

In this prospective referring-physician-based survey, we investigated the definite clinical impact of 68Ga-DOTATATE PET/CT on managing patients with neuroendocrine tumors (NETs). Methods: We prospectively studied 130 patients with 68Ga-DOTATATE PET/CT referred for initial or subsequent management decisions (NCT02174679). Referring physicians completed one questionnaire before the scan (Q1) to indicate the treatment plan without PET/CT information, one immediately after review of the imaging report to denote intended management changes (Q2), and one 6 mo later (Q3) to verify whether intended changes were in fact implemented. To further validate the Q3 responses, a systematic electronic chart review was conducted. Results: All 3 questionnaires were completed by referring physicians for 96 of 130 patients (74%). 68Ga-DOTATATE PET/CT resulted in intended management changes (Q2) in 48 of 96 patients (50%). These changes were finally implemented (Q3) in 36 of 48 patients (75%). Q3 responses were confirmed in all patients with an available electronic chart (36/96; 38%). Conclusion: This prospective study confirmed a significant impact of 68Ga-DOTATATE PET/CT on the intended management of patients with NETs (50% of changes) and notably demonstrated a high implementation rate (75%) of these intended management changes.