Early prediction of the response to 177Lu-PSMA therapy in metastatic prostate cancer

PSMA (prostate-specific membrane antigen) is a glycoprotein highly expressed on the surface of malignant prostate tumor cells. Thus, it represents a suitable target for both imaging and therapy of prostate cancer (PCa). In fact, PSMA ligands are widely used either as tracers for positron emission tomography/computed tomography (PET/CT) imaging or as therapeutic agents comprising PSMA-directed radionuclide therapy and immunotherapy [1]. Notably, 177Lu-PSMA-617 (vipivotide tetraxetan) received approval by the U.S. Food and Drug Administration (FDA) and the ­European Medicines Agency (EMA) in March 2022 and December 2022, ­respectively. It is authorized for treating PSMA-positive metastatic castration-­resistant prostate cancer (mCRPC) ­patients, who constitute approximately 30 % of PCa-patients, and have pre­viously been treated with androgen ­receptor pathway inhibitors and taxanes [2].

PSA levels and the probability of detecting metastases at primary PCa staging

While PSMA is a valid target for both imaging and therapy in PCa, with radiolabeled ligands commonly used in PET/CT scans, the measurement of prostate-specific antigen (PSA) levels in the bloodstream serves as a standard method to assess disease progression [3]. The objective of a retrospective study presented at EANM 2023 by Luining ­Wietske was to evaluate whether PSA levels correlate with findings on PSMA PET/CT for primary staging, regarding the proportion and site of prostate cancer metastases [4].

Patients newly diagnosed for PCa between January 2017 and April 2022, presenting with evaluable PSMA-PET/CT results for primary staging and PSA values, were retrospectively analyzed. Data were stratified based on PSA levels, and the primary objective was to evaluate the risk of metastatic disease on PSMA PET/CT. Additionally, the proportion of ­PSMA-positive lesions in different anatomical locations was investigated. Correlations between PSMA PET/CT and PSA levels were analyzed by logistic regression.

A total of 1,306 patients with a median PSA of 16.5 ng/mL (IQR, 8.4-40.4) were included. PSMA PET/CT scans revealed metastases in 548 patients (42 %): 15 % had metastases in regional lymph nodes (miN1), 16 % in extra-pelvic lymph nodes (miM1a), 22 % in bones (miM1b) and 2.5 % in soft tissues (miM1c, according to EANM standardized reporting guidelines v1.0 [5]). The percentage of patients with metastases correlated positively with PSA levels (Table 1). Overall, the initial PSA level was a significant predictor for detecting metastases in PSMA PET/CT scans that were found in 42 % of patients at primary staging.

The authors concluded that these results support the use of PSMA PET/CT scans in the initial staging of PCa.

Table 1 PSA levels at primary prostate cancer staging and the associated proportions of patients with metastases.

68Ga-PSMA PET/CT parameters used as diagnostic tool

The efficacy of 177Lu-PSMA radioligand therapy (177Lu-PSMA-RLT) is highly variable and early prediction of its outcome, especially in terms of survival, still needs to be established. However, the utility of 68Ga-PSMA PET/CT to assess the local and metastatic burden of advanced PCa, typically in biochemically recurrent or advanced disease, has already been extensively utilized [6]. A retrospective study presented by Burak Demir at this year’s EANM aimed at determining useful parameters, derived from 68Ga-PSMA PET/CT, in predicting the efficacy of 177Lu-PSMA-RLT in mCRPC patients [7].

A total of 55 patients with mCRPC who received two to six cycles of 177Lu-PSMA-RLT and had evaluable pre-treatment 68Ga-PSMA PET/CT results were retrospectively analyzed. They were separated into responders and non-responders based on PSA response, defined as a reduction of at least 50 % of the baseline value according to PCWG3 criteria (Prostate Cancer Clinical Trials Working Group 3) [8]. The standard uptake volume (SUV) max, SUVmean, ­SUVpeak, total tumor metabolic volume (TT-MV) and total tumor PSMA uptake (TT-PSMA) – as well as overall survival (OS) were determined.

Patients in the responder group had significantly higher SUV values and TT-PSMA than in the non-responder group (47.78 vs 26.80 for SUVmax, p = 0.002; 13.62 vs 8.47 for SUVmean, p = 0.038; 32.25 vs 16.96 for SUVpeak, p = 0.007; 839.68 vs 1627.00 for TT-PSMA). While the median TT-MV was slightly lower in the responder group compared to the non-responder group (162.12 vs 168.61 cm3), the median OS was significantly longer (17.1 vs 10.2 months; p = 0.003). Similarly, patients with a TT-MV lower than 162.12 cm3 before treatment showed a significant longer median OS than those with a TT-MV of at least 162.12 cm3 (18.9 vs 9.3 months; p < 0.001) (Figure 1).

The receiver operating characteristic (ROC) curve analysis was used on 68Ga-PSMA PET/CT parameters in predicting the PSA response to 177Lu-PSMA-RLT treatment. AUC values for ­SUVmax, ­SUVmean and SUVpeak at baseline were 0.772, 0.681 and 0.736, respectively, and the most specific cut-off to predict a positive PSA response was determined to be a SUVmax value of 50.70, with a sensitivity of 47.1 % and a specificity of 87.9 %, respectively.

Considering these results, the authors concluded that this approach might help to select mCRPC patients benefitting from a 177Lu-PSMA-RLT therapy.

Figure 1: Kaplan-Meier curve of the overall survival of mCRPC patients treated by 177Lu-PSMA-RLT with high versus low total metabolic tumor volume (MTV, cut-off 162.12 cm3) at baseline determined by 68Ga-PSMA PET/CT.

Figure 1: Kaplan-Meier curve of the overall survival of mCRPC patients treated by 177Lu-PSMA-RLT with high versus low total metabolic tumor volume (MTV, cut-off 162.12 cm3) at baseline determined by 68Ga-PSMA PET/CT.

18F-rhPSMA-7.3 PET/CT parameters following ­177Lu-PSMA RLT

PET/CT imaging of primary PCa and mCRPC is based on PSMA radiolabeled ligands such as the first PET imaging agent – gozetotide (68Ga-PSMA-11) – approved at the end of 2020. However, a new class of 18F-labeled-PSMA-ligands attracts growing attention with the recent approval of piflufolastat (18F DCFPyL) by the FDA in May 2021 and the EMA in July 2023 [9]. The 18F-radio­hybrid prostate-specific membrane antigen-7.3 (18F-rhPSMA-7.3) belongs to these innovative PET imaging compounds and is currently under investigation in two multicenter phase 3 trials. At EANM 2023, Kimberley Hansen described how baseline 18F-rhPSMA-7.3 parameters could be predictive of the clinical response to 177Lu-PSMA-RLT in mCRPC patients [10].

A retrospective analysis was performed on 188 mCRPC patients having received 177Lu-PSMA-RLT and showing reliable pre-treatment data (routine clinical and laboratory parameters as well as 18F-rhPSMA-7.3 PET/CT imaging). ­Tumoral lesions were analyzed using a PROMISE® software and a series of quantitative parameters were calculated, such as SUVmax, SUVmean, SUVpeak, total lesion number and total tumor volume (TTV).

The median OS was 11.8 months (95 % CI, 10.0-13.0). Negative prognostic factors for OS revealed by univariable COX regression included the total lesion number, the TTV, increasing levels of alkaline phosphatase, lactate dehydrogenase (LDH) and PSA, a decreasing level of hemoglobin, as well as prior chemotherapy and visceral metastases at baseline. The further multivariate analysis identified the total lesion number, increasing levels of LDH and prior visceral metastases as significant negative prognostic factors. A cut-off was established using the median TTV value of 394 ml, revealing that patients with a lower TTV experienced a significantly longer OS (15.9 vs 10.1 months; p < 0.001). The ­median number of prior-to-treatment metastases demonstrated similarly that patients with less than 127 lesions on 18F-rhPSMA-7.3 PET had a significantly increased OS (16.3 vs 9.7 months; p < 0.001).

This retrospective study in mCRPC patients indicates that 18F-rhPSMA-7.3 PET/CT increasingly replacing 68Ga-PSMA-11 has prognostic value for the 177Lu-­PSMA-RLT outcome. Moreover, TTV prior 177Lu-PSMA-RLT seems to be an independent prognostic factor of survival.

Early prediction of 177Lu-PSMA-I&T response with interim 18F-PSMA-1007-PET/CT

The efficacy of 177Lu-PSMA for imaging and therapy (177Lu-PSMA-I&T) is usually evaluated after four cycles of therapy based on serum PSA and PSMA-­PET/CT imaging. However, there are several confounding factors affecting PSA. Thus, the objective of a study presented by Shing-Kee William-­Cheung at EANM 2023 was to evaluate if 18F-PSMA-1007 would be a good surrogate biomarker of 177Lu-­PSMA-I&T treatment effectiveness in mCRPC patients [11].

Patients with mCRPC recruited between August 2020 and December 2022 were subjected to four 177Lu-PSMA-I&T cycles of approximately 7.4 GBq each at six-week intervals. Additionally, patients underwent PSA measurement and 18F-PSMA-1007 PET/CT at baseline (bPET), after two cycles of therapy (iPET, interim PET) and a final evaluation (fPET) three months after the last treatment cycle. A positive PSA response was defined as a reduction by ≥ 50 % of the baseline value as per PCWG3 criteria [8]; an imaging response was evaluated based on tumor volume as per RECIP 1.0 [12] and classified as complete (CR, all lesions normalized), partial (PR, reduction of ≥ 30 % of tumor volume and no new ­lesion) or non-response (NR).

A total of 24 patients, with a mean age of 73.5 years, were enrolled in the study. ­After the second cycle of 177Lu-PSMA, a positive PSA response was observed in 79 % of patients while a positive imaging response was detected in 46 % of the ­patients with one patient showing a CR and ten patients a PR. At the final evaluation, a positive PSA response was reported in 46 % of the patients and a positive imaging response in 42 % (all PR), respectively. Overall, 46 % of the patients were considered as responders based on the combined “PSA + imaging responses” (Figure 2).

While the interim imaging response was consistent with the classification of patients in responders or non-responders, the interim PSA response incorrectly classified 8/19 patients (42 %) as positive responders, despite the disco­very of new lesions on iPET/fPET.

This study showed that after the 2nd cycle of 177Lu-PSMA-I&T treatment in mCRPC patients, interim 18F-­PSMA-­1007 PET/CT serves as a valuable surrogate biomarker for monitoring treatment progress and predicting the ultimate therapeutic outcome.

Figure 2: PSA response (A) and imaging response (B) compared to post-treatment outcome

Figure 2: PSA response (A) and imaging response (B) compared to post-treatment outcome


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