ASCO 2023: PSMA Expression and Response to 177Lu-PSMA-617 in Men with vs. Without DNA Damage Repair Mutations

(UroToday.com) The 2023 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between June 2^nd and June 6^th was host to a prostate, testicular, and penile cancers poster session. Dr. Ruben Raychaudhuri presented the results of a retrospective analysis evaluating PSMA expression and subsequent response to ¹⁷⁷Lu-PSMA-617 in prostate cancer patients with and without DNA damage repair (DDR) mutations.

¹⁷⁷Lu-PSMA-617, a radioligand targeting the cell surface protein prostate-specific membrane antigen (PSMA), is FDA approved for men with PSMA-positive mCRPC with prior progression following androgen receptor signalling inhibitor (ARSI) and docetaxel use, based on the results of two trials: TheraP and VISION.^1,2 DNA damage repair gene (DDR) mutations are common in mCRPC patients, and given that ionizing radiation induces DNA damage, the it has been hypothesized that the presence of such alterations could be associated with improved clinical responses to ¹⁷⁷Lu-PSMA-617. Further data also suggests that the presence of DDR mutations may be associated with PSMA expression levels, providing further impetus to evaluate whether DDR alterations are associated with the clinical activity of ¹⁷⁷Lu-PSMA-617.

This was a retrospective analysis of all patients from the Fred Hutchinson Cancer Center (Seattle, WA) who received at least one cycle of ¹⁷⁷Lu-PSMA-617 per the FDA label and who had panel-based sequencing performed (e.g., UW-Oncoplex, Foundation One). The DDR deficient cohort was defined as patients with either somatic or germline alterations in a DDR gene. Conversely, those with somatic testing negative for a DDR gene mutation were assigned to the DDR intact cohort. Clinical responses in the DDR mutated cohort were stratified by the specific gene mutation. Differences in baseline PSMA SUVmean and PSA₅₀ responses (i.e., ≥50% decline in PSA) were compared between the two cohorts.

The investigators identified 91 patients who had received ≥1 cycle of ¹⁷⁷Lu-PSMA-617, of whom 54 had genetic testing performed. Of these 54 patients, 64% had received ≥2 lines of prior ARSI therapy, 56% received ≥2 lines of prior chemotherapy, and 28% had received a prior PARP inhibitor. A DDR gene mutation was identified in 21 patients (DDR mutated cohort), whereas the remaining 33 patients had somatic testing without an identifiable DDR mutation.

There were no significant differences in PSMA SUVmean between the two groups: 8.04 (95% CI: 6.95 - 9.12) in the DDR intact versus 7.32 (95% CI: 6.23 – 8.41) in the DDR deficient cohort (p = 0.37). LUPSMA table

A PSA₅₀ response was observed in 11/21 (52%) patients in the DDR deficient group compared to 7/33 (21%) patients in the DDR intact group (p=0.018).

graph comparisons

LUPSMA table 2 and figure 3

No significant differences in PSA progression-free survival rates were observed between the DDR deficient versus intact groups.

PSA progression LUPSMA

Notably, rapid autopsy was performed in one subject with a BRCA2 mutation (baseline PSMA SUVmean was 5.6) and immunohistochemistry analysis revealed profound loss of PSMA expression following progression on ¹⁷⁷Lu-PSMA-617.

The investigators concluded that mutations in DDR genes were associated with an improved PSA₅₀ response rate following ¹⁷⁷Lu-PSMA-617 compared to patients without a DDR mutation. There was no difference in baseline PSMA expression based on DDR mutational status, suggesting that the higher PSA₅₀ response rates in the DDR cohort may have been mediated primarily by an increased sensitivity to ionizing radiation. Evaluation of the associations between DDR mutational status and survival endpoints is pending and will require a larger sample size and longer follow up. Rapid autopsy post-¹⁷⁷Lu-PSMA-617 revealed loss of PSMA expression, suggesting that antigen loss may be a relevant resistance mechanism.

Presented by: Ruben Raychaudhuri, Clinical Fellow, Hematology Oncology, Department of Medicine, Fred Hutch Cancer Center, University of Washington, Seattle, WA

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.

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