The ⁶⁸Ga/¹⁷⁷Lu-theragnostic concept in PSMA-targeting of metastatic castration–resistant prostate cancer: impact of post-therapeutic whole-body scintigraphy in the follow-up

In recent years, the ⁶⁸Ga-PSMA-labelled PSMA conjugate (Glu-NH-CO-NH-Lys-(Ahx)-[⁶⁸Ga(HBED-CC)]) (PSMA-11) has successfully been used for lesion detection in case of biochemical recurrence as well as for improving primary staging in prostate cancer (PC) patients [1]. In accordance with the theragnostic concept, ⁶⁸Ga-PSMA-11 PET/CT can be used to assess response to therapy with ¹⁷⁷Lu-/²²⁵Ac-PSMA-617 in patients with metastatic castration–resistant PC (mCRPC). The currently most commonly used Reponse Evaluation Criteria In Solid Turmors (RECIST) [2] are based on cross-sectional abdominopelvic imaging together with bone scintigraphy and PSA serum levels. ⁶⁸Ga-PSMA-11 PET/CT revealed a higher probability for a positive PET-finding in patients with low PSA values (≤ 0.5 ng/ml) than any other imaging modality including ¹⁸F-choline PET/CT [3], which can substantially influence the clinical management. In fact, ⁶⁸Ga-PSMA-11 provides more accurate assessment than conventional imaging [4] and can also be superior to ¹⁸F-sodium fluoride PET/CT for the evaluation of bone metastases in response to ²²³Ra-chloride therapy [5].

In line with the theragnostic concept [6], ⁶⁸Ga-labelled PSMA ligands are increasingly used to detect lesions in patients with mCRPC, prior to PSMA-directed radioligand therapy (PRLT), and as diagnostic response tool in the follow-up of PRLT-treated patients [1].

In this study, we used the modified PET Response Criteria In Solid Tumors (PERCIST, Visual and Semiquantitative “PET Score”) [7] and compared the results to the post-therapeutic 24 h whole-body (WB) scans (visual and semiquantitative “WB Score”) as well as to the PSA response (“PSA Score”) in 32 consecutive mCRPC patients undergoing serial ¹⁷⁷Lu-PSMA-617 treatment. Progression free survival (PFS) and overall survival (OS) was correlated to each one of the scores, and different aspects of response assessment are discussed.

We report on a single-center study in a total of 32 consecutive mCRPC patients treated with ¹⁷⁷Lu-PSMA-617. All patients were heavily pre-treated and were followed until death. mCRPC patients received up to 6 therapy cycles, 6 GBq each, 6 to 10 weeks apart. In all patients, visual interpretation and semiquantitative calculation of PET/CT (SUV_max, i.e., “PET Score”) and 24 h WB scans (TU/BG ratios, i.e., “¹⁷⁷Lu Score”) were performed and compared with PSA response over the course of disease. The median PFS was 7 months, the median OS was 12 months, and responders to 2 × 6 GBq therapy lived significantly (p < 0.05) longer than non-responders, i.e., 6 months (Fig. 5).

The response evaluation in terms of CR, PR, SD, or PD is usually assessed by biochemical response and metabolic/radiologic response based on modified PERCIST criteria [7]. However, the reported follow-up duration of the ¹⁷⁷Lu-PSMA-617-treated patients in the literature varies between the different centers and together with different treatment regimes (i.e., treatment dose, number of treatment cycles, time span between the cycles, response evaluation), an appropriate comparison of treatment results is rather difficult. Therefore, published data are usually single-center studies, and moreover, only retrospective ones in most cases [1]. Some patients may also show a MX response which we have defined as disappearance of tumor lesions at one location and development of new lesions in at least one different location. In our study, in about 15% of patients a MX response was observed in both “Visual and Semiquantitative WB Score (i.e., “¹⁷⁷Lu Score”)” as well as “PET Score” (i.e., SUV_max). This observation of MX response underlines the well-known development of heterogeneity of PC lesions over time. Textural heterogeneity parameters may also play an important role explaining these findings [14]. In fact, all our patients with MX response also showed increasing PSA values over time und thus disease progression.

In the majority (approximately 2/3) of patients, the response in terms of decreasing “¹⁷⁷Lu Score“ was well correlating with the “Visual 24 h WB Score” as well as “Visual and Semiquantitative (SUV_max) “PET Score,” and the “PSA Score.” Following the first therapy cycle with 6 GBq of ¹⁷⁷Lu-PSMA-617, 19/32 (60%) patients showed decreased visible tracer uptake in all lesions in the WB scintigraphy, in 24/32 (75%) patients in the “¹⁷⁷Lu Score“, in 11/13 (85%) patients in all visible lesions in the ⁶⁸Ga-PSMA-11 PET/CT, and in 23/32 (72%) patients in the “PSA Score” (i.e., biochemical response).

Whereas most responding patients had significant improvement already after the first treatment cycle with 6 GBq (only), in roughly 15% of patients, a delayed response after the second or more treatment cycles with additional 6 GBq each (accumulated dose 12 to 24 GBq) was observed by the “PSA Score” in 5/28 (16%) patients and in the “¹⁷⁷Lu Score” in 4/29 (14%) patients and in 11/13 (85%) patients by the “PET Score.” Such a delayed response in patients who did not respond to the first cycle was also communicated earlier by Rahbar et al. [15] in 12/41 (29%) patients. This observation is of great clinical importance indicating the necessity to continue ¹⁷⁷Lu-PSMA-617 therapy even if patients have failed to respond to the first cycle, and allows also the conclusion that higher therapy doses should be used, at least along with the first cycle. Yordanova et al. [16] recently reported a clinical benefit in 30 ¹⁷⁷Lu-PSMA-617 re-treated patients with a median OS of 25 months versus 9 months in patients who received only one ¹⁷⁷Lu-PSMA-617 treatment period, each period consisting of several treatment cycles. Similar beneficial results were reported for ¹⁷⁷Lu-PSMA-I&T re-treatment by Grubmüller et al. [17] and Gafita et al. [18]. Basically, these retrospective analyses raise the question whether higher activities than 6 GBq of ¹⁷⁷Lu-PSMA-617 would fit more appropriate as Grade 4 toxicity is rare, even in rechallenged patients, with reasonable efficacy.

Despite of the increasing world-wide use of PSMA Ligand Radionuclide Therapy (PLRT), published survival data on ¹⁷⁷Lu-PSMA-617-treated mCRPC patients are still rare. Basically, our data on PFS and OS in consecutive patients are less pronounced compared with those of some other centers reporting retrospective analyses which might be partly due to heavier pre-treatment of our patients. In their initial report in 56 patients, Baum et al. [19] reported a PFS of 13.7 months and a OS of 15.5 months using ¹⁷⁷Lu-PSMA-I&T. In a more recent study by Yadav et al. [20] in 31 patients, the median PFS was 12 months and the median OS was 16 months. While these numbers on OS compare well with docetaxel-based results [21], our recent meta-analysis [22] in mCRPC patients was more favorable for PSMA-targeted radioligand therapy (PRLT) with approximately 43% PSA response versus 22% in third-line chemotherapy-treated patients. In addition, therapy with ¹⁷⁷Lu-PSMA-617 does not only work better than third-line chemotherapy but also works after third-line chemotherapy with prolonged survival [23].

The results of this study in 32 consecutive patients show that patients receiving at least 2 therapy cycles of ¹⁷⁷Lu-PSMA-617 (i.e., 12 GBq) and responding to therapy—and these are roughly 2/3 of patients—live 6 months longer than “non-responders.” Though this result has to be taken with caution due to the rather small number of patients reported herein, it clearly underlines the current hype for this type of therapy for mCRPC patients. A significant difference in median OS between responders and non-responders for a change in PSA was also reported by Ahmadzadehfar et al. [24] in 52 patients showing a survival benefit of 9 months.

In the presently only available prospective Phase II single-center study in 30 mCRPC patients by Hofman et al. [25], the estimated PFS was 7 months and the median OS was 13.5 months which compares favorably with our single-center cohort of 32 patients who were consecutively assigned for treatment and who were followed until death. Despite of the similar study design between both our centers, at this advanced stage of PC disease of heavy pre-treatments, the results of the presently recruiting prospective VISION phase 3 trial [26] will be very important as this trial is designed randomized against best supportive care. As it will take years for long-term survival results of the VISION trial, the WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) initiative of gathering all available retrospective data on ¹⁷⁷Lu-PSMA-617 into a database [27] will hopefully bring more light earlier into important issues of PRLT. Issues consist in several open questions such as response prediction, and thus patient selection [28, 29].

The assessment of treatment response is challenging while being critical in the oncological practice. RECIST performs well in assessment of tumor shrinkage as a criteria for response. PERCIST based on ⁶⁸Ga-PSMA-11 PET/CT may perform better than RECIST in a patient with PSA progression. ⁶⁸Ga-PSMA-11 PET/CT plays an important role in patient selection and probably in predicting treatment response to ¹⁷⁷Lu-PSMA-617. In their recent report on the value of ⁶⁸Ga-PSMA-11 PET/CT, Emmett el al. [30] found that an increased SUV_max value of the tumor lesions goes along with the prediction of treatment response in terms of PSA reduction. While by large variation our SUV_max values decreased under therapy in PSA-responding patients, we could not find a significant correlation for neither PFS nor OS. On the other hand, a reduced tracer uptake may not necessarily translate into a longer survival time. In fact, the results of our evaluation indicate a good agreement of the visual interpretation of ⁶⁸Ga-PSMA-11 PET/CT and 24 h WB scans and implicate the value of post-therapy imaging. Moreover, serial PSA measurements together with 24 h WB scintigraphy seem to be sufficiently accurate for the follow-up of ¹⁷⁷Lu-PSMA-617-treated patients. Of course, more lesions can be seen on ⁶⁸Ga-PSMA-11 PET/CT compared to 24 h WB scintigraphy. However, very often it is rather difficult to count numerous lesions on PET/CT as well as on 24 h WB scans in the individual patient. It is also time-consuming, expensive, and sometimes difficult to perform repeated ⁶⁸Ga-PSMA-11 PET/CT in heavily bone-metastasized patients, who often cannot endure the imaging acquisition time due to bone pain. In contrast, the performance of 24 h WB scintigraphy after therapy is simple and cost-effective and seems accurate enough to allow a conclusion on response to therapy—especially together with PSA measurements. RECIST [2] is based on cross-sectional abdominopelvic imaging together with bone scintigraphy and PSA serum levels. While ⁶⁸Ga-PSMA-11 PET/CT has a higher sensitivity especially in patients with lower PSA values than any other imaging modality [3], it may give also controversial in patients with dedifferentiated tumors. In fact, Heinzel, et al. [31] recently reported a moderate sensitivity of 85% and a specificity of about 60% only for ⁶⁸Ga-PSMA-11 PET/CT for monitoring ¹⁷⁷Lu-PSMA-617 therapy.

Calculation of the absorbed tumor dose may be an important predictor for clinical response. In our mCRPC patients, the absorbed dose of ¹⁷⁷Lu-PSMA-617 of tumor lesions was significantly higher than that of normal organs, especially kidneys and bone marrow. Despite the fact that a mCRPC patient may show variable uptake of ¹⁷⁷Lu-PSMA-617 in the multiple tumor lesions, dosimetry occurs clinically relevant for healthy organs. A recent retrospective analysis in a total of 167 patients indicated that taxane chemotherapy pre-treated patients will also benefit from ¹⁷⁷Lu-PRLT treatment with rare Grade 3 or 4 toxicity [32]. In fact, in all retrospective reports on ¹⁷⁷Lu-PSMA-617 [20, 24, 33‐38] or ¹⁷⁷Lu-PSMA-I&T [17‐19, 39], hematotoxicity and nephrotoxicity were rare, and the treatment safe even in patients with a single kidney [40]. In fact, with the kidneys presenting the critical organ, a cumulative activity of 30 GBq of ¹⁷⁷Lu-PSMA-617 appears to be safe and justifiable. A recent study by Okamoto et al. [41] using ¹⁷⁷Lu-PSMA-I&T demonstrated gradually decreasing tumor dose estimates from one cycle to the other and correlation between pre-therapeutic SUV values and absorbed tumor dose estimates. In our study, only a weak correlation was found for SUV_max values of LN metastases with absorbed dose estimates but not for skeletal and visceral metastases. Whereas dose estimates were similarly high with values of around 3 Gy/GBq, an explanation of this divergent finding between the Munich group and out center could lie in the use of different PSMA ligands. Also Zang et al. [42] reported only a moderate correlation of SUV_max values in a limited number of patients, both for ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-EB-PSMA-617. Violet et al. [43] estimated a significant correlation between SUV_mean of the tumor lesions and the mean absorbed dose and reduced salivary and kidney doses in patients with higher tumor burden. Probably patients with pre-dominant LN-mCRPC may benefit from ¹⁷⁷Lu-PSMA-617 therapy the most [44] as especially skeletal metastases may show MX responses more often. In this study, all patients with a MX response also showed PSA progression over time. While one would expect a correlation of SUV_max, TU/BG ratios, and/or tumor dose estimates at baseline, there are factors which may explain the divergent finding of this study cohort in a limited number of 32 patients. First, the radiotracers used for imaging (PSMA-11) and therapy (PSMA-617) are not exactly the same, despite of being similar. Second, especially smaller lesions are problematic for absorbed dose calculation due to the partial volume effect. This is why in Fig. 3, we have tried to exclude tumor lesions with a volume < 7 ml; however, we could not find a correlation for our cohort. Furthermore, the variety of different pre-treatments, ongoing bone-targeted therapy, or heterogeneity of tumor lesions may also count for divergent findings which might be better ruled out in a future study involving a higher number of patients.

In 8/32 (25%) patients of this study, the only mentionable side effect was transient or permanent xerostomia (Table 4), despite of a somewhat higher incidence rate than reported in the German retrospective multicenter study [45]. In roughly 2/3 of patients, not only in the WB studies but also in the PET/CT studies, a decreased uptake was found along with treatment. The dosimetric calculations for salivary glands (Table 5) show a trend for correlation of SUV_max and estimated absorbed dose values for salivary glands, parotid as well as submandibular glands, both in line with volume reduction of the glands after up to 4 therapy cycles. This observation indirectly outlines the concept of irradiation effects on tumor volume resulting in tumor shrinkage after radioisotope irradiation. In fact, several interventions have been discussed for salivary gland protection including the use of cool bags [46], botox, and steroid injection [47]. A similar high rate of appearance of xerostomia was mentionably reported in the prospective study with ¹⁷⁷Lu-PSMA-617 and was attributed to specific questioning of this potential toxicity within the trial setting [25]. Grade 2 xerostomia was also reported for 17% of the patients in the evaluation of Kalmthout et al. [48] whereas in the German multicenter study it occurred in 8% only [45]. With newer developments of PRLT, especially ²²⁵Ac-PSMA-617, the radiation-induced effects on salivary gland function must be taken seriously and seem to be much higher [49, 50]. Furthermore, a recent report by Violet et al. [43] showed reduced salivary doses in patients with higher tumor burden, increased body mass, and body surface area, referred to as “tumor-sink” effect and providing a rational personalized treatment dosing. Personalization of treatment seems to be relevant also for hematotoxicity in patients with diffuse red marrow infiltration and extensive chemotherapeutic pre-treatments [38, 51].

Finally, the application of PRLT as opposed to the guideline-recognized ²²³Ra-therapy in mCRPC patients [52] should gain better overall results, probably with a treatment response longer than 3.6 months, highlighting the advantage of a tumor-targeted ligand rather than exclusively bone-seeking agent.

Whereas our results from a single center in prospective consecutive manner direct for future study planning, the results have to be confirmed in future-controlled studies. Our center evaluation underlines that PSMA-directed therapy has the potential to change the clinical management of mCRPC patients. Several prospective PSMA-targeting studies are in progress of which the VISION study [25] will provide data on OS as the primary endpoint versus best standard of care. An important question if patients with a longer PFS also have a longer OS cannot be answered from the current study due to the limited patient number studied. Furthermore, in this study, neither initial PSA values nor initial TU/BG ratios and SUV_max values correlated with PFS and OS. This again can be due to the rather low number of patients included and significantly outlines the importance of prospective study results.