Prostate cancer is the most frequently diagnosed cancer in men and the second leading cause of cancer-specific deaths [1
]. Although it is initially sensitive to androgen deprivation therapy, it subsequently develops into a castration-resistant state. Castration-resistant prostate cancer (CRPC), especially when metastatic, is considered incurable and accounts for most prostate cancer-related deaths. Nevertheless, several approved and investigational systemic drugs such as enzalutamide, abiraterone, and 223
Ra have shown a survival benefit in clinical trials [2
], and it has become even more important to monitor response to these therapies for deciding on further management.
Currently, response assessment for systemic treatments in patients with metastatic CRPC is primarily done using conventional imaging and biochemical testing—that is, Response Evaluation Criteria in Solid Tumors (RECIST) on CT, bone scan, and serum prostate-specific antigen (PSA) [5
]. However, serum PSA levels have demonstrated limitations with regards to their ability to accurately assess therapeutic response and do not necessarily correlate with survival. In addition, there is difficulty in interpreting the significance of changes in bone metastases using CT and bone scan, the latter reflecting osteoblastic response in bone rather than the metastatic tumor itself. Therefore, newer methods to determine therapeutic response have been investigated including molecular imaging [7
] and circulating tumor cells [9
Prostate specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has the capability to detect metastatic disease more accurately than conventional imaging in both the recurrent and primary setting [10
], substantially impacting the management of patients with prostate cancer [12
]. A baseline PSMA PET is also highly recommended in patients with CRPC for accurate assessing of disease extent (i.e., non-metastatic, oligometastatic vs. polymetastatic) [13
] and appropriate selection of therapeutic strategy including metastasis-derived therapy or systemic treatment [14
]. Based on this, the notion of PSMA PET being used for response assessment has gained interest in recent years as shown in multiple recent papers that have used PSMA PET/CT or PET/magnetic resonance imaging (MRI) for this purpose [15
], in proposals for standardized PSMA PET progression criteria [7
], and in the consensus statement by the European Association of Urology (EAU) and European Association of Nuclear Medicine (EANM) in 2020 [8
]. Currently available literature on PSMA PET response mainly evaluates its concordance with PSA response, whereas only a few studies investigated its direct association with survival [15
]. To address this, we performed a systematic review and meta-analysis to assess the concordance between response evaluation using PSMA PET and PSA after systemic treatment and the association between PSMA PET and other robust endpoints of overall and radiologic progression-free survival in patients with metastatic CRPC.
In this meta-analysis, we investigated the agreement between PSMA PET and PSA for response assessment in ten studies that evaluated patients with metastatic CRPC treated systemically. Almost a fourth of patients (27%) showed discordance between the two tests. The inherent limitations of PSA and conventional imaging including CT and bone scan for determining treatment response are well known and together with the capability of PSMA PET to better identify presence, sites, and burden of metastatic tumor in CRPC, this discrepancy opens up opportunities for potentially better response assessment that may result in better therapeutic planning (continuing, changing, or adding type of therapies) with the hopes of achieving better survival. With the currently available data, it is not possible to establish whether PSMA PET is superior to PSA as a response marker, and we cannot completely grasp the clinical significance of the discordance between the two. For example, it remains unanswered what course of action should be taken when there is PSA response but lack of response on PSMA PET, or vice versa. However, few of the included studies additionally showed that response on PSMA PET was associated with overall survival while PSA was not, indicating the potential superiority of PSMA PET-based response assessment [15
]. In the context of clinical trials, PSMA PET should be encouraged for the purpose of response assessment in metastatic CRPC (especially as discordance cannot be predicted a priori at the moment) enabling future studies to answer and validate the clinical meaning of this discordance and their correlation with patient outcomes.
A multitude of different parameters and response assessment criteria were used across the ten included studies, probably because no clear response parameter for PSMA PET have been defined. In the limited sample we investigated, there were no significant differences between the various parameters and criteria with regards to their concordance with PSA response, and both PSMA uptake and volumetric measures may be useful for determining response in patients with metastatic CRPC. Nevertheless, it is conceivable that volumetric PET measurements in this patient population could provide additional value due to several reasons: (1) volumetric parameters like PSMA-TV or TL-PSMA capture the overall tumor burden [31
]; (2) the degree of PSMA uptake and extent of metastases have both been shown to be correlated with survival in metastatic CRPC [32
]; (3) volumetric measurements can be reproducibly performed using commercially available software [20
]; and (4) tumor volumetry on PET have achieved encouraging results in different cancers [33
]. Nevertheless, the biologic meaning of each PSMA response parameter is not fully understood. For example, a preclinical study found that PSMA expression of tumor cells did not change after taxane-based chemotherapy, and that tracer uptake was proportional to the number of viable cells [35
]. Nevertheless, further studies (both in vitro, in vivo, and clinical) are needed to establish the differences in the meaning of each parameter and how they can be differentially incorporated in response assessment for different types of treatments.
The discordance in response assessment based on PSMA PET and PSA were similarly distributed in both directions. Specifically, the proportion of patients showing response on PSMA PET but non-response with PSA was 12% (95% CI 8–17%) while the opposite (non-response on PSMA PET and response with PSA) was 13% (95% CI 8–20%). Although not directly deducible from the included studies, we proposed the following possible explanations for these discordances: (1) There could be inherent phenotypic differences between different clones emerging during progression in terms of their expression of PSMA- and PSA-related genes [36
]. (2) Mixed responses may occur between different metastatic sites, for example, a decrease in size of most tumors but increase in size (or even new appearance) in the minority of tumors [37
]. This could result in an overall decrease in the PSA, but even one new metastatic foci would be considered progressive disease on PSMA PET based on assessment criteria by all but one of the included studies [16
]. (3) Neuroendocrine or other forms of dedifferentiation of prostate cancer can manifest with low or variable levels of expression of PSA and PSMA [38
]. (4) Additionally, pseudoprogression and flare phenomena could affect the relationship between PSMA and PSA response assessments [37
Several limitations of our study deserve consideration. First, the sample size was relatively small for a meta-analysis, and all included studies were retrospective in design. This is probably because response assessment using PSMA PET is still in its early steps and has not been well established compared with other harder endpoints such as overall and radiologic progression-free survival. Nevertheless, this constitutes the largest body of evidence with the highest level of evidence until now. Second, although we were able to assess the overall concordance (or discordance) between PSMA PET and PSA for response assessment, we were unable to answer the clinical implications for this discordance, such as, when discordance is expected, what steps to take when we encounter such discordance, and correlation with patient outcomes. This was beyond the scope of our meta-analysis and will need to be investigated in future studies. Third, although we did not find significant difference in the concordance between PSMA PET and PSA between subgroups stratified to type of treatment, we cannot come to a hard conclusion for some treatments that only were used in a small number of studies (e.g., 223Ra radionuclide therapy in only one study).