Explorative analysis of a score predicting the therapy response of patients with metastatic, castration resistant prostate cancer undergoing radioligand therapy with ¹⁷⁷Lu-labeled prostate-specific membrane antigen

Prostate cancer has the highest incidence and the third highest cancer related mortality for men in Europe [1]. In the last decade, several treatment options for patients with metastatic, castration-resistant prostate cancer (mCRPC) have become established, including abiraterone, enzalutamide, docetaxel and cabazitaxel [2]. More recently, radioligand therapy (RLT) with ¹⁷⁷Lu prostate-specific membrane antigen (PSMA) was developed and has shown promising results with regard to prostate-specific antigen (PSA) response rates and radiographic responses [3]. Retrospective as well as early prospective data confirmed the favourable safety profile of RLT [4, 5].

Although up to 60% of the patients showed some degree of response to RLT, some do not benefit from this treatment [4, 5]. The presence of visceral metastases, alkaline phosphatase (ALP) ≥ 220 U/L [5], high platelet count, a regular need for analgesics [6] or elevated lactate dehydrogenase [7] has been identified as a negative predictor for the outcome, whereas ALP < 220 U/L, a cumulative injected activity ≥ 18.8 GBq [8], albumin ≥ 38.6 g/L, aspartate transaminase (AST) ≤ 24 U/L, haemoglobin ≥ 10.4 g/dL, absence of liver metastases [9], and higher standardized uptake value (SUV) mean or max in positron emission tomography (PET) with PSMA ligands have been reported to be associated with favourable outcomes [10]. However, the predictive value of these factors varies significantly between studies.

The aim of this study was first, to identify predictive factors for the outcome of RLT with ¹⁷⁷Lu PSMA considering laboratory parameters, medical history and imaging obtained before the first RLT and second, to derive a predictive score which can simplify the selection of patients who are or are not likely to benefit from RLT.

This single-institution retrospective study was approved by the institutional ethics review board (EA2/177/17). All patients signed a written informed consent form for the study.

To the best of our knowledge, although there have been several previous reports on prognostic or predictive factors for RLT with ¹⁷⁷Lu PSMA in patients with mCRPC [5‐10], this is the first simple clinical score to predict the outcome after the first two cycles of ¹⁷⁷Lu PSMA. The score combines laboratory (PSA, ALP) and imaging (SUVmax) parameters and can identify both patients likely to benefit from RLT and potential non-responders to RLT.

MCRPC patients with higher PSA levels have a higher likelihood to develop PD under treatment than patients with lower PSA levels. Especially, a high baseline serum PSA level of > 200 ng/ml seems to be a significant predictor of an unfavorable outcome. This is consistent with the results of former studies showing that high serum PSA levels correlate strongly with the risk of prostate cancer progression, not only in the initial stage of disease, but also in advanced disease [17].

In the present study, a high ALP of > 135 U/l was also defined as a significant predictive factor for unfavorable outcome after RLT. This is in line with previous studies showing a poor outcome after RLT with ¹⁷⁷Lu PSMA in patients with elevated ALP [5, 8, 18]. A similar outcome has been also reported for patients treated with chemotherapy [19]. ALP is a marker for bone turnover [19], which has led to the hypothesis that a high ALP correlates with progressive bone metastases. However, the presence of bone metastases was not a potential predictive parameter in the current analysis because almost every patient (44/46 patients) showed bone metastases, regardless of outcome. The reason why visual extent of disease did not correlate with outcome, is probably that the extent of disease could also be affected by lymph node metastases (present in 39/46 patients), which do not result in an increased ALP.

Low baseline SUVmax (< 45) in ⁶⁸Ga PSMA PET also suggested an unfavorable outcome after RLT in the current study, which persisted in multivariable binary logistic regression after adjustment for PSA and ALP. The SUVmax/mean denotes the maximum/mean uptake in a specified region of interest (e.g., a lesion) and is the most commonly used semi-quantitative parameter in PET. This may be explained by the requirement for a targeted therapy of a minimum level of PSMA expression on the cell surface to achieve adequate lutetium internalization into the cell. The SUVmax of a radiotracer has a significant role in the diagnosis and treatment selection for different types of tumors, e.g. lymphoma [20], head and neck squamous cell carcinoma [21], pancreatic tumor [22], neuroendocrine tumors [23] or even prostate cancer [24]. A recent pilot study on 14 prostate cancer patients showed that patients with a PSA response ≥ 50% after treatment with ¹⁷⁷Lu PSMA had a significantly higher baseline SUVmax in a pre-therapeutic scan with ⁶⁸Ga PSMA-PET (44 vs. 17) [10]. This study also reported significantly higher SUVmean in patients with PSA response ≥ 50% (10 vs. 6) [10]. Likewise, SUVmean in ⁶⁸Ga PSMA-PET was a significant predictive factor of response in the present analysis. However, it was not included in the combined predictive score because of its high inter-rater variability and limited reproducibility [25, 26]. The current study used the SUVmax of a single “hottest” lesion as a predictor of PSA response. SUVmax can be obtained intuitively, conveniently and with presumably high interobserver agreement up to 100% [25], because minimal observer interaction is required to obtain the highest SUVmax among potentially dozens of (confluent) lesions without necessitating a specific volume of interest. However, this method does not account for potential inter-lesional heterogeneity of PSMA expression or ⁶⁸Ga PSMA uptake [27], respectively. One may note that in the most relevant patient group with low SUVmax (i.e., higher risk for PD), a low SUVmax in the “hottest” lesion is per se representative of all lesions because any other lesion in the same patient has—by definition—an even lower uptake. Furthermore, inter-lesional SUV heterogeneity in these patients is limited because “adequate uptake of PSMA ligands on the basis of a pre-therapy imaging study” in every lesion is demanded for eligibility of these patients for RLT according to current guidelines [28].

The practice of limiting assessment to a single lesion is in line with the PET Response Criteria in Solid Tumors [29] criteria, where only the “hottest single tumor lesion” is defined as the “target lesion”.

Not all potential imaging parameters were examined in our study, e.g. textural heterogeneity was recently postulated as a predictive factor in ¹⁷⁷Lu PSMA treatment [30]. Our goal was however, to derive a predictive score that is simple and intuitive for clinical use. Hence, only parameters which are determined routinely and quickly before treatment were analyzed and included.

Clear limitations of this study are the retrospective design and small sample size, which may explain why predictive factors reported by other studies [5‐10], e.g. blood count parameters or visceral metastases, were not significant in our analyses. Moreover, multivariable binary logistic regression did not prove the independent predictive value of PSA and ALP in addition to SUVmax—despite previous studies demonstrating their importance in the context of ¹⁷⁷Lu PSMA treatment [5, 8, 9]. The observed odds ratios of approximately 3 to 4 and p values of < 0.2 in multivariable analysis for PSA and ALP may indicate that there is true independent value in both factors, but the power of the current multivariable analysis was insufficient to prove it, due to the small sample size. Consequently, our results are only hypothesis-generating and need to be confirmed in further, larger studies.

In this study, a score for easy clinical use to predict the treatment response to 2 cycles of RLT with ¹⁷⁷Lu PSMA based on pretreatment PSA, ALP, and SUVmax of the “hottest lesion” in ⁶⁸Ga PSMA-PET is presented, so that response rates of RLT can be increased and the rate of unnecessary adverse events can be reduced. This is a hypothesis-generating study, and further trials in independent, larger cohorts will be needed to test and validate this predictive score.