Patient outcomes following a response biomarker-guided approach to treatment using 177Lu-PSMA-I&T in men with metastatic castrate-resistant prostate cancer (Re-SPECT)

Louise Emmett; Nikeith John; Sarennya Pathmanandavel; William Counter; Maria Ayers; Shikha Sharma; Shikha Agrawal; Aron Poole; Elizabeth Hovey; Ganes Pranavan; Craig Gedye; Girish Mallesara; Alex Guminski; Adrian Lee; Martin R Stockler; Adam Hickey; Peter Eu; Anthony M Joshua; Megan Crumbaker; Andrew Nguyen

doi:10.1177/17588359231156392

Patient outcomes following a response biomarker-guided approach to treatment using 177Lu-PSMA-I&T in men with metastatic castrate-resistant prostate cancer (Re-SPECT)

Ther Adv Med Oncol. 2023 Mar 1:15:17588359231156392. doi: 10.1177/17588359231156392. eCollection 2023.

Authors

Louise Emmett^{1

2

3

4}, Nikeith John², Sarennya Pathmanandavel^{2

3

4}, William Counter², Maria Ayers², Shikha Sharma², Shikha Agrawal², Aron Poole², Elizabeth Hovey^{5

6}, Ganes Pranavan⁷, Craig Gedye⁸, Girish Mallesara⁸, Alex Guminski⁹, Adrian Lee⁹, Martin R Stockler¹⁰, Adam Hickey², Peter Eu², Anthony M Joshua¹¹, Megan Crumbaker^{3

4

11}, Andrew Nguyen^{2

4}

Affiliations

¹ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, 390 Victoria Street, Sydney, NSW 2010, Australia.
² Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia.
³ Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁴ St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.
⁵ Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
⁶ Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Sydney, NSW, Australia.
⁷ Department of Medical Oncology, The Canberra Hospital, Garran, ACT, Australia.
⁸ Calvary Mater Hospital, Newcastle, NSW, Australia.
⁹ Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia.
¹⁰ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
¹¹ The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia.

Abstract

Background: ¹⁷⁷LuPSMA is an effective treatment in metastatic castrate-resistant prostate cancer with trials adopting a standardised dose interval. Adjusting treatment intervals utilising early response biomarkers may improve patient outcomes.

Objective: This study evaluated progression-free survival (PFS) and overall survival (OS) based on treatment interval adjustment utilising ¹⁷⁷LuPSMA 24-h SPECT/CT (¹⁷⁷Lu-SPECT) and early prostate-specific antigen (PSA) response.

Design: Retrospective analysis of a clinical ¹⁷⁷Lu-PSMA-I&T treatment programme.

Methods: In all, 125 men were treated with 6-weekly ¹⁷⁷LuPSMA-I&T [median 3 cycles, interquartile range (IQR): 2-4], median dose 8.0 GBq [95% confidence interval (CI): 7.5-8.0]. Imaging screening involved ⁶⁸GaPSMA-11 PET/diagnostic CT. ¹⁷⁷Lu-SPECT/diagnostic CT was acquired following each therapy, and clinical assessments 3-weekly. Following dose 2 (week 6), a composite PSA and ¹⁷⁷Lu-SPECT/CT imaging response [partial response (PR), stable disease (SD), and progressive disease (PD)] determined ongoing management. Response group (RG) 1 (marked reduction in PSA/imaging PR) break in treatment until subsequent PSA rise, then re-treatment. RG 2 (stable or reduced PSA and/or imaging SD) 6-weekly treatments until six doses, or no longer clinically benefitting. RG 3 (rise in PSA and/or imaging PD) recommended for an alternative treatment.

Results: Overall PSA50% response rate (PSARR) was 60% (75/125), median PSA-PFS 6.1 months (95%CI: 5.5-6.7), and median OS 16.8 months (95%CI: 13.5-20.1). 35% (41/116) were classified as RG 1, 34% (39/116) RG 2, and 31% (36/116) RG 3. PSARRs by RG were 95% (38/41), 74% (29/39), and 8% (3/36); median PSA-PFS rates were 12.1 months (95%CI: 9.3-17.4), 6.1 months (95%CI: 5.8-9.0), and 2.6 months (95%CI: 1.6-3.1); and OS rates were 19.2 months (95%CI: 16.8-20.7), 13.2 months (95%CI: 12.0-18.8), and 11.2 months (95%CI: 8.7-15.6) for RG 1, 2, and 3, respectively. The median months of 'treatment holiday' for RG 1 was 6.1 months (IQR: 3.4-8.7). Nine men had received prior ¹⁷⁷LuPSMA-617 and were retreated with ¹⁷⁷LuPSMA-I&T, with a PSARR of 56% on re-treatment.

Conclusion: Personalising dosing regimens using early response biomarkers with ¹⁷⁷LuPSMA has the potential to achieve similar treatment responses to continuous dosing while allowing treatment breaks or intensification. Further evaluation of early response biomarker-guided treatment regimens in prospective trials is warranted.

Plain language summary: Lutetium-PSMA therapy is a new therapy for metastatic prostate cancer that is well tolerated and effective. However, not all men respond equally, with some responding very well and others progressing early. Personalising treatments require tools that can accurately measure treatment responses, preferably early in the treatment course, so adjustments to treatment can be made. Lutetium-PSMA can measure tumour sites after each therapy by taking whole body 3D images at 24 h using a small radiation wave from the treatment itself. This is called a SPECT scan. Previous work has shown that both prostate-specific antigen (PSA) response and changes in tumour volume on a SPECT scan can predict how patients will respond to treatment as early as dose 2. This study demonstrates that stratifying how men are treated based on the results of the 6-week SPECT scan and PSA response potentially allows a third of men to have break in treatment and that these men have both longer time to disease progression and OS. Men with an increase in tumour volume and increase in PSA early in treatment (6 weeks) had shorter time to disease progression and OS. Men with early biomarker disease progression were offered alternative treatments early in an attempt to allow the opportunity to allow a more effective potential therapy, if one was available. The study is an analysis of a clinical programme, and was not a prospective trial. As such, there are potential biases that could influence results. Hence, while the study is encouraging for the use of early response biomarkers to guide better treatment decisions, this must be validated in a well-designed clinical trial.

Keywords: SPECT; lutetium-PSMA; metastatic prostate cancer; response biomarker.