How Early Can Imaging Assess Response in End-Stage Prostate Cancer?

BARCELONA, Spain ― Using 177Lu-PSMA (prostate-specific membrane antigen) SPECT to monitor tumor response at week 12 after the third dose of the 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 at the European Association of Nuclear Medicine (EANM) 2022 meeting.

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

Such early imaging biomarkers might help determine intensification or deintensification of therapy to the benefit of patients for whom time and quality of life have added importance.

For the week-12 study, Louise Emmett, MD, PhD, director of theranostics and nuclear medicine at St. Vincent’s Hospital Sydney, in Australia, used SPECT to evaluate 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 a larger number of patients and in combination with other biomarkers, such as prostate-specific antigen [PSA] and CT,” remarked Emmett in an interview with Medscape Medical News.

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

In email correspondence with Medscape Medical News, Andrei Gafita, MD, a nuclear medicine physician from UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California, noted the “very important topic of treatment response assessment.”

“Dr Emmet’s work showed that 177Lu-PSMA SPECT has great potential to become a biomarker that could enable early response evaluation to 177Lu-PSMA radioligand therapy,” he noted, adding, “It may greatly benefit particularly institutions where PSMA-PET/CT is not available or not reimbursed for the purpose of response evaluation.”

Ken Herrmann, MD, associate professor of nuclear medicine at the University of Duisburg-Essen, Germany, also commented on the biomarker study. “Establishing quantitative post-177Lu PSMA administration SPECT as a new surrogate marker for assessing response to treatment has potential upsides, including the potential replacement of interim and post-therapy PSMA PET ― which is cost-saving, radiation exposure–saving, and is more convenient, as well as improving therapy guidance, such as determining whether a therapy holiday, continuation or discontinuation is warranted.

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

Adding NOX66 ― a Radiation Sensitizer ― to 177Lu-PSMA-617

Regarding the prolonging of the treatment effect of 177Lu-PSMA-617, Emmett, who is a physician-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 — die too soon, and this happens again and again,” she said in 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 US Food and Drug Administration in March 2022 for PSMA-positive mCRPC in combination with a PSMA imaging agent for select patients. However, radiation resistance remained in a subset of men and was likely the key driver in treatment failure, she explained.

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

Biomarkers to Determine Treatment Success or Failure Earlier

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

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

“These were men who were pulled out of palliative care,” noted Emmett.

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

Emmett then conducted the biomarker subanalysis to determine whether quantitative parameters on serial 177Lu-SPECT/CT imaging 24 hours after a dose of 177LuPSMA-617 were predictive of treatment response and PFS.

All lesions that were quantitatively identified were manually reviewed, and the physiologic activity was determined. TTV, standardized uptake value (SUV) max, and SUVmean were derived.

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

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

Of these data, SPECT-TTV was reduced between baseline and week 12 in 68%, while it increased in 31%. An increase of 30% or more in SPECT-TTV by week 12 was seen in 19%, reported Emmett.

Again, over the 12 weeks, SUVmax decreased between baseline and week 12 in 91%, and SUVmean decreased in 84%.

Comparing the 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 significantly worse PSA-PFS — over fourfold worse (hazard ratio [HR], 4.1; 95% CI, 1.5 – 11.2).

The median PSA-PFS in those with an increase in SPECT-TTV was 4.5 months (95% CI, 2.8 – 5.6), compared to 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). Also, those patients (8/32) who showed progression in their PSA at week 12 had a significantly worse PSA-PFS (HR, 26.5; 95% CI, 5.4 – 131).

When the PSMA-PET measure was compared to the SPECT, there was a strong correlation between PSMA-PET TTV and the 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, findings were similar in a cohort of 130 patients, confirming that “decisions about treatment planning can be made at the 6-week mark and not wait until the 12-week mark,” she asserted.

She suggested further questions that needed research. “We know we can’t identify very small lesions with SPECT compared to PET, but is that important when we’re looking at interim response biomarkers?” she said.

In conclusion, she said that 177Lu-SPECT-CT seems 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 evaluation at 6 weeks, Gafita added that “further research will tell us more whether 177Lu-PSMA SPECT performed at 6 weeks can offer guidance for clinicians in the decision-making process for patient management.”

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

“There are limited data on whether this imaging technique allows assessment of treatment efficacy while therapy is still in progress and allows conclusions to be drawn about patient outcomes,” he said. “This study highlights the importance of SPECT imaging after 177Lu-PSMA radioligand therapy, since increasing total tumor volume during therapy was associated with shorter PFS. Thus, a change in therapeutic regimen due to nonresponse to 177Lu-PSMA therapy could occur earlier.”

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

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

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