ASCO 2022: Circulating Tumour Cells and PSMA PET Correlates in the Phase I PRINCE Trial of 177Lu-PSMA-617 Plus Pembrolizumab for Metastatic Castration Resistant Prostate Cancer

( At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster session focused on Prostate, Testicular, and Penile cancers on Monday afternoon included a presentation from Dr. Anis Hamid discussing the value of circulating tumor cells (CTCs) and PSMA PET correlates among patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing combination therapy with 177Lu-PSMA-617 plus pembrolizumab.

There has been significant interest recently in the field of theranostics for prostate cancer. The phase II TheraP and phase III VISION trials demonstrated the benefit of 177Lu-PSMA-617 in patients with heavily pre-treated mCRPC. However, there are numerous studies evaluating this treatment approach either earlier in the disease space or in combination. One such trial is the Phase I PRINCE trial (NCT03658447) which is evaluating the efficacy of 177Lu-PSMA-617 plus pembrolizumab for mCRPC. Pembrolizumab is approved in a tumor agnostic manner for the treatment of patients with MSI-high, including mCRPC. However, it is not widely utilized due to the rarity of this finding. In the PRINCE trial, the authors further sought to examine, in this abstract, the utility of serial monitoring of CTCs and PET as biomarkers of prognosis and the clinical benefit of 177Lu-PSMA-617-based therapy.

To do so, the authors performed serial CTC collections and repeated PSMA PET imaging (at baseline, every 12 weeks for 48 weeks and every 24 weeks thereafter) among 36 of 27 enrolled patients with high PSMA expression on PSMA PET.

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Using the Epic Sciences platform, the investigators enumerated CK+, CD45- CTCs from 3ml of blood and stained them for PSMA. Associations between PSMA+ CTC counts, PET molecular tumor volume (MTV), and total lesional activity (TLA; MTVxSUVmean) were assessed by Spearman correlation. Cox models assessed the association of CTC and PSMA PET parameters with radiographic progression-free survival (rPFS) and PSA progression-free survival (PSA-PFS). A subset of pre-treatment CTCs underwent single cell low-pass whole genome sequencing to characterize copy number aberrations.

Among the 26 patients with sequential test results, 32 (89%) had detectable CTCs (median 7, range 0-514) with 23 (64%) being PSMA+ (median 1, range 0-224) at baseline.

As of week 12, 23 of 33 evaluable patients (70%) had CTCs detected with 10 (30%) being PSMA+. Baseline PSMA+ CTC count and MTV were moderately correlated (rs= 0.57, p < 0.001).

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Among the 22 evaluable patients who had PSMA+ CTC at baseline, 18 (82%) showed decrease by week 12 with clearance in 13 patients. This paralleled reductions in MTV (-18% med relative change, IQR: -57 to -1) and TLA (-48% med relative change, IQR: -77 to -28).

However, total CTC and PSMA+ CTC counts at baseline, and PET parameters were not associated with PSA-PFS or rPFS. However, clearance of PSMA+ CTC by week 12 (13/22 pts) was associated with improved rPFS (median NR vs 3.0 months, HR 0.23, 95%CI 0.07-0.74, p = 0.007) and PSA PFS (median 11.2 vs 3.5 months, HR 0.28, 95%CI 0.11-0.73, p = 0.006).

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Patients with persisting PSMA-neg CTCs at week 12 had a non-significant but numerically worse rPFS (median 4.1 vs 12.3 months, p = 0.11) and PSA PFS (median 5.1 vs 12.3 months, p = 0.07). Among those patients who did not progress by week 12, a decrease in PSA (HR 0.83 per 10% decrease, 95%CI 0.74-0.93, p < 0.001), MTV (HR 0.85 per 10% decrease, 95%CI 0.75-0.96, p = 0.008), MTV > 30% decrease (HR 0.30, 95% CI 0.08-1.08, p = 0.05) and TLA (HR 0.88 per 10% decrease, 95%CI 0.78-1.00, p = 0.04) were associated with improved rPFS beyond week 12.

In exploratory analysis among 18 patients, pre-treatment CTCs exhibited genomic heterogeneity and frequent loss of PTEN, TP53 and RB1. Further, patients with compound TP53 and RB1 loss at baseline had PSMA+ CTCs in high proportion (median 91.3% of total CTCs).

Thus, the authors conclude that patients with PSMA PET-positive mCRPC (who were eligible for PRINCE) have a high rate of PSMA+ CTCs which decline with 177Lu-PSMA-617 plus pembrolizumab in parallel with PSMA MTV/TLA. Despite imaging suitability for therapy, CTCs had heterogenous PSMA expression and genomic alterations associated with aggressive disease. Early changes in PSMA+ CTCs and MTV/TLA were associated with outcomes and may aid in determining the clinical activity of LuPSMA-based therapy.

Presented by: Anis Hamid, MBBS, GU Oncology Research Fellow at Dana-Farber Cancer Institute

Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.



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