A post-hoc exploratory analysis of the phase 3 VISION trial identified quantitative PET-Imaging parameters of 68Ga-PSMA-11 PET / CT associated with improved efficacy outcomes with 177Lu-PSMA-617 (LuPSMA, Pluvicto) in patients with metastatic castration-resistant prostate cancer (mCRPC).1
Specifically, study author Andrew J. Armstrong, MD, explained that, “Among men in the VISION trial with PSMA-positive mCRPC on 68Ga-PSMA-11 PET / CT treated with 177Lu-PSMA-617, a higher whole-body SUVmean was strongly associated with improved long-term clinical outcomes. Patients in the highest SUVmean The quartile had a median radiographic progression-free Survival (rPFS) of 14.1 months and a median overall Survival (OS) of 21.4 months versus 5.8 and 14.5 months, respectively, for those in the lowest quartile, along with improved objective and PSA Responses. “
Overall, the open-label phase 3 VISION trial (NCT03511664) included 831 patients (1179 initially screened) with progressive PSMA-positive mCRPC who received at least 1 novel androgen axis drug (eg, enzalutamide [Xtandi] or abiraterone acetate [Zytiga]) and were previously treated with 1 to 2 taxane regimens.PET Imaging with 68Ga-PSMA-11 was used to determine PSMA positivity.
Patients were randomized in a 2: 1 ratio to LuPSMA (7.4 GBq every 6 weeks x 6 cycles; n = 551) plus standard of care (SOC) or SOC alone (n = 280). Individual Investigators determined the SOC; however, radium-223 (Xofigo) and cytotoxic chemotherapy were not allowed. The coprimary end points of the trial were OS and rPFS.
At a median follow-up of 20.9 months for the primary analysis, the median OS was 15.3 months in the LuPSMA arm versus 11.3 months in the SOC alone arm, translating to a 38% reduction in the risk of death (HR, 0.62; 95 % CI, 0.52-0.74; P <.001) .The rPFS was 8.7 versus 3.4 months, respectively, translating to a 60% reduction in the risk of progression or death (HR, 0.40; 99.2% CI, 0.29-0.57; P <.001).2
Based on these results, the FDA approved the targeted radioligand therapy in March 2022 for the treatment of patients with PSMA-positive mCRPC in the post-androgen receptor pathway inhibition, post-taxane-based chemotherapy setting.3
Providing some context for this posthoc analysis, Armstrong, a Professor of Medicine, Surgery, and Pharmacology and Cancer Biology at Duke University, said, “PSMA Imaging can be used to measure the uptake and intensity of the target of 177Lu-PSMA-617 treatment, ”adding that the study Investigators sought to evaluate several quantitative PET-Imaging parameters as a prognostic tool for key efficacy end points of the phase 3 VISION trial in order to optimize treatment with 177Lu-PSMA-617.
Armstrong defined key terms and PET-Imaging parameters used in the study as follows:
- SUV: “The ratio of activity per unit volume of a region of interest to the activity per unit whole-body volume.”
- SUVmean: “The mean number of counts from all voxels within the whole body, including all lesions pool together. The voxel is a component of an array of imaging elements of volume that represent a 3D space. ”
- SUVmax: “The uptake of the voxel with the highest number of counts among all voxels within the whole body, including all lesions pooled together.”
- Tumor volume: “The volume of PSMA-positive lesions within the whole body is calculated from the total volume of voxels with positive uptake.”
- Tumor load: “The product of PSMA-positive tumor volume and SUVmean in the whole body.”
- Presence of PSMA-positive lesion by region (pattern of spread): “Positive 68Ga-PSMA-11 uptake within a segmented anatomical region / PSMA-positive pattern of spread within the segmented anatomical regions.”
Of the 551 patients treated with LuPSMA in the overall study population, the posthoc analysis included 548 patients for evaluations of objective response rate (ORR), and 382 patients for evaluations of rPFS and PSA response.
“SUVmean was statistically significant as a Predictor for all of the efficacy endpoints (rPFS, OS, ORR, and PSA response). SUVmaxhowever, was not significant as a Predictor for most of the end points, and neither were tumor load and tumor volume, ”said Armstrong.
SUVmean quartile distribution data showed that the higher the SUVmeanthe better the rPFS benefit:
- ≥10.2 (highest): median rPFS, 14.1 months
- ≥7.8, <10.2: median rPFS, 9.8 months
- ≥6.0, <7.8: median rPFS, 7.8 month
- <6 (lowest): median rPFS, 5.8 months
The increased rPFS benefit with higher SUVsmean was statistically significant in both univariate analyzes (HR, 0.88; 95% CI, 0.84-0.91; P <.001) and multivariate analysis (HR, 0.86; 95% CI, 0.82-0.90; P <.001).
The SUVmean quartile distribution for OS showed a similar benefit with higher SUVsmean:
- ≥9.9 (highest): median OS, 21.4 months
- ≥7.5, <9.9: median OS, 14.6 months
- ≥5.7, <7.5: median OS, 12.6 months
- <5.7 (lowest): median OS, 14.5 months
The increased OS benefit with higher SUVmean was statistically significant in both univariate analysis (HR, 0.92; 95% CI, 0.89-0.95; P <.001) and multivariate analysis (HR, 0.88; 95% CI, 0.84-0.91; P <.001).
The pattern of spread parameter was also shown to have prognostic value. In the VISION study, patients primarily had a bone dominant pattern of spread, explained Armstrong. Overall, 92.7% of patients had 68Ga-PSMA-11 uptake in the bone and 13.1% had 68Ga-PSMA-11 uptake in the liver.
Armstrong said that the “presence of liver metastases hit all of the efficacy endpoints as being independently prognostic for OS, PFS, ORR, and PSA response. ” Bone metastases were prognostic of OS, PFS, and ORR, but not PSA response. Lymph node metastases were only prognostic of the ORR.
Patients with no liver metastases had a significantly higher rPFS versus patients with PSMA-positive liver lesions at a median of 9 vs 4 months, respectively (HR, 0.48; 95% CI, 0.34-0.67; P <.001). Similarly, patients with no bone metastases had a significantly higher rPFS vs patients with PSMA-positive bone lesions at a median of 11.5 vs 8.7 months, respectively (HR, 0.45; 95% CI, 0.26-0.78; P <.004).
“The absence of PSMA-positive lesions in bone or liver was associated with a decrease in the risk of an rPFS event compared with the presence of ≥1 PSMA-positive lesion in these organs,” summarized Armstrong.
In his concluding remarks, Armstrong said, “These data support use of 68Ga-PSMA-11 PET / CT scans to identify men with mCRPC who could benefit now from PSMA-targeted radioligand therapy, ”adding,“ PSMA-PET Imaging reports on individual lesions of patients with mCRPC could include SUVmean prior to starting 177Lu-PSMA-617 therapy to provide important prognostic information on potential treatment Responses and long-term outcomes. ”
1. Kuo P, Hesterman J, Rahbar K, et al. [68Ga]Ga-PSMA-11 PET baseline Imaging as a prognostic tool for clinical outcomes to [177Lu]Lu-PSMA-617 in patients with mCRPC: A VISION substudy. J Clin Oncol 40, 2022 (suppl 16; abstr. 5002). doi: 10.1200 / JCO.2022.40.16_suppl.5002
2. Morris MJ, De Bono JS, Chi KN, et al. Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol 39, 2021 (suppl 15; abstr LBA4)
3. Novartis Pluvicto ™ approved by the FDA as the first targeted radioligand therapy for the treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. March 23, 2022. https://www.novartis.com/news/media-releases/novartis-pluvictotm-approved-fda-first-targeted-radioligand-therapy-treatment-progressive-psma-positive-metastatic-castration-resistant -prostate-cancer