When can imaging assess response in end-stage prostate cancer?

BARCELONA, Spain ― Usage ¹⁷⁷Lu-PSMA (prostate-specific membrane antigen) SPECT to monitor tumor response at week 12 after third dose of targeted radioligand ¹⁷⁷Lu-PSMA-617 (Pluctivo, Novartis) has potential as an early predictive biomarker for men with end-stage metastatic castration-resistant prostate cancer (mCRPC), according to data reported during the 2022 meeting of the European Association of Nuclear Medicine (EANM).

The same researcher suggests that ¹⁷⁷Lu-PSMA SPECT, if used even earlier, after only 6 weeks, could also be a reliable biomarker.

These early imaging biomarkers could help determine the intensification or de-intensification of treatment for the benefit of patients for whom time and quality of life are of increased importance.

For the 12-week study, Louise Emmett, MD, PhD, director of theranostics and nuclear medicine at St. Vincent’s Hospital in Sydney, Australia, used SPECT to assess response to ¹⁷⁷Lu-PSMA-617 in LuPIN, a phase 1/2 trial of a combination of ¹⁷⁷Lu-PSMA-617 with the added radiation sensitizer NOX66 (idronoxil) in men with mCRPC.

“¹⁷⁷Lu-SPECT-CT has potential as a biomarker in these patients with end-stage disease, but this needs to be validated in larger numbers of patients and in combination with other biomarkers, such as antigen prostate specific [PSA] and CT,” Emmett remarked in an interview with Medscape Medical News.

Essentially, Emmett and his colleagues found that an increase in total tumor volume (TTV) on ¹⁷⁷Lu-SPECT/CT at 12 weeks (or at the start of the third cycle) of treatment with ¹⁷⁷Lu-PSMA-617 predicted shorter progression-free survival (PFS), suggesting ¹⁷⁷Lu-SPECT/CT may have a future role as a biomarker of imaging response.

In email correspondence with Medscape Medical News, Andrei Gafita, MD, nuclear medicine physician, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, Calif., emphasized the “very important topic of evaluating treatment response.”

“Dr. Emmet’s work has shown that ¹⁷⁷Lu-PSMA SPECT has great potential to become a biomarker that could allow early assessment of response to ¹⁷⁷Lu-PSMA radioligand therapy,” he noted, adding, “This could greatly benefit institutions where PSMA-PET/CT is not available or not reimbursed for the purpose of evaluating answer.”

Ken Herrmann, MD, associate professor of nuclear medicine at the University of Duisburg-Essen, Germany, also commented on the biomarker study. “Establish a post-quantitative¹⁷⁷The administration of Lu PSMA SPECT as a new surrogate marker to assess treatment response has potential advantages, including the potential replacement of intermediate and post-treatment PSMA PET ― which saves costs, saves radiation exposure and is more convenient, as well as improving treatment guidance, such as determining whether discharge, continuation or discontinuation of treatment is warranted.

“I’m personally intrigued and excited by this approach,” he said.

Addition of NOX66 ― a radiation sensitizer ― to ¹⁷⁷Lu-PSMA-617

With regard to prolonging the effect of the treatment of ¹⁷⁷Lu-PSMA-617, Emmett, who is a medical researcher, explained that “¹⁷⁷Lu-PSMA-617 is really good, but it just doesn’t work for all patients and it doesn’t work long enough. These men – and some are quite young – are dying too soon, and it happens over and over again,” she said, explaining what made this trial so important to her.

¹⁷⁷Lu-PSMA-617 alone improved overall survival with efficacy equivalent to that of cabazitaxel chemotherapy. It was approved by the United States Food and Drug Administration in March 2022 for PSMA-positive mCRPC in combination with a PSMA imaging agent for certain patients. However, radiation resistance remained in a subset of men and was likely the main factor in treatment failure, she explained.

In an attempt to combat this radiation resistance, NOX66 was added to the treatment with ¹⁷⁷Lu-PSMA-617. Safety and efficacy were monitored by clinical, blood and imaging biomarkers.

Biomarkers to determine treatment success or failure earlier

In the study, 56 men underwent fluorodeoxyglucose (FDG) and PSMA PET entry and exit, and PSMA SPECT (single-photon emission CT) at each cycle (24 hours after each treatment dose). They received up to six doses of ¹⁷⁷Lu-PSMA-617 (7.5 GBq) on day 1 in combination with NOX66 suppository on days 1-10 of each 6-week cycle.

The average age of the men was 61 years old. The average PSA level at cycle 1 was 115 (46–476). All men had previously received docetaxel and 91% cabazitaxel, and 66% had at least 20 metastases.

“These are men who have been taken out of hospice care,” Emmett noted.

lupine found that when men were given the combination of ¹⁷⁷Lu-PSMA-617 plus NOX66, the median PSA response rate at 50% was 61%, with 86% showing a PSA response. Median PFS was 7.5 months (6–9) and median overall survival was 19.7 months (10–30).

Emmett then performed the biomarker sub-analysis to determine if the quantitative parameters on the series ¹⁷⁷Lu-SPECT/CT imaging 24 hours after a dose of ¹⁷⁷LuPSMA-617 was predictive of treatment response and PFS.

All quantitatively identified lesions were manually examined and physiological activity was determined. TTV, standardized absorption value (SUV) max and SUVmean were derived.

“We wanted to know if the [differences in the] frames between the first injection dose frame [¹⁷⁷Lu-SPECT/CT imaging] and the image from the third dose could help us predict the course of the patient,” Emmett said. Medscape Medical News.

In terms of SPECT imaging, data from 32 of 56 patients were analyzable at baseline and at week 12.

Of these data, SPECT-TTV was reduced from baseline to week 12 in 68%, while it increased in 31%. A 30% or greater increase in SPECT-TTV at week 12 was seen in 19%, Emmett reported.

Again, over the 12 weeks, SUVmax decreased from baseline to week 12 in 91%, and SUVaverage decreased in 84%.

Comparing changes in SPECT-TTV with PFS (to help determine the role of SPECT in predicting response), Emmett found that any increase in SPECT-TTV between baseline and week 12 was associated with a PSA- PFS significantly worse – more than four times worse (risk ratio [HR], 4.1; 95% CI, 1.5 – 11.2).

The median PSA-PFS in those with increased SPECT-TTV was 4.5 months (95% CI, 2.8 – 5.6), versus 7.1 months (95% CI, 6.3 – 10.7) for those in whom there was no increase in SPECT-TTV.

Alternatively, an increase in SPECT-TTV of at least 30% was associated with shorter PSA-PFS (HR, 3.3; 95% CI, 1.3, 8.6). Additionally, patients (8/32) who showed progression in their PSA at week 12 had significantly worse PSA-PFS (HR, 26.5; 95% CI, 5.4, 131).

When PSMA-PET measurement was compared to SPECT, there was a strong correlation between PSMA-PET TTV and baseline ¹⁷⁷Lu-SPECT TTV (R = 0.87; 95% CI, 0.74, 0.93).

RESPECT Study ― Prediction After Two Treatments ― Week 6

In a recently published study by Emmett and colleagues, the results were similar in a cohort of 130 patients, confirming that “decisions about treatment planning can be made at week 6 and not wait until week 12”, a- she asserted..

She suggested other questions that needed research. “We know we can’t identify very small lesions with SPECT compared to PET, but does that matter when we’re looking at intermediate response biomarkers?” she says.

In conclusion, she said that ¹⁷⁷Lu-SPECT-CT appears to have strong potential as a predictive biomarker in radionucleotide therapy for men with mCRPC, but the results need to be validated in larger cohorts.

On the 6-week evaluation, Gafita added that “further research will tell us more if ¹⁷⁷Lu-PSMA SPECT performed at 6 weeks can offer guidance to clinicians in the decision-making process for patient management. »

Christoph Rischpler, MD, a nuclear medicine specialist at the University of Duisburg-Essen, Germany, also reflected on the study, who said SPECT imaging after ¹⁷⁷Lu-PSMA radioligand therapy is a standard procedure that is easy to perform but further research on the use of the technique as a biomarker was needed.

“There are limited data on whether this imaging technique can assess treatment effectiveness while treatment is still ongoing and allow conclusions to be drawn about patient outcomes,” he said. -he declares. “This study highlights the importance of SPECT imaging after ¹⁷⁷Lu-PSMA radioligand therapy, as increased total tumor volume during therapy was associated with shorter PFS. Thus, a change in treatment regimen due to non-response to ¹⁷⁷Lu-PSMA therapy could take place sooner.”

Emmett, Herrmann and Gafita have disclosed no relevant financial relationship. Rischpler has received speaker fees from Adacap, Alnylam, BTG, Curium, GE Healthcare, Pfizer, Siemens Healthineers; served in an advisory role for Adacap Adacap (now called Novartis Radiopharmaceuticals sells Pluvicto in the US) and Pfizer, and received a research grant from Pfizer.

European Association of Nuclear Medicine (EANM) 2022: Abstract OP-158. Presented October 16, 2022.

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