Radioligand therapy of metastatic castration-resistant prostate cancer: current approaches

Metastatic castration-resistant prostate cancer (mCRPC) patients can undergo treatment with taxane-based therapies (docetaxel and cabazitaxel) and with second line hormonal therapies (including enzalutamide and abiraterone). Both these therapies moderately improve patient survival time, but they are only temporarily effective and patients can develop resistance [18, 19]. Hence, more specific targeted therapies have to be developed for eliminating the prostate cancer visceral and bony lesions. Studies have shown that PSMA is overexpressed in around 90–100% of local prostate cancer lesions, along with many bony lesions and lymph node metastases. Furthermore, many studies have shown that the PSMA expression levels increase in the case of metastatic, high-grade and castration-resistant prostate cancer [20‐22] (Fig. 1). The current essential inclusion criteria, as stated in the 2016 consensus recommendations of the German Society of Nuclear Medicine [23], cover:

The standard administered activity of ¹⁷⁷Lu-PSMA has varied across the literature as institutions undertake safety and toxicity trials [16]. Single injected doses have ranged from 3 to 9.3 GBq, with up to nine injections given to patients, generally at a minimum of six-week intervals [14, 24‐31].

Up to 80% of patients with mCRPC will have a treatment response to ¹⁷⁷Lu-PSMA shown by any PSA decline [14, 24‐30, 32‐34] (Table 1).

Studies using ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA-I&T have observed a reduction in PSA levels by 50% or more in 32–60% of patients. Moreover, 47% of patients have experienced a stable disease [14, 24‐30, 32‐34]. In 2016, a group from Heidelberg, Germany, started the first human treatments with ²⁵⁵Ac-PSMA-617 in two patients with red marrow infiltration and resistance to other therapies, and these patients showed complete responses to the therapy [35, 36]. A study by Zechmann et al., using a ¹³¹I-labelled PSMA ligand, showed a 50% or greater decline in PSA in more than 60% of patients [37]. This finding was in line with a recent study by Afshar-Oromieh et al. who studied 36 patients who had received PSMA-RLT with ¹³¹I-IMP-1095, and found the best therapeutic effect was achieved by the first therapy, which showed that PSA declined by more than 50% in 70.6% of the patients. The second and third therapies from their study showed reduced effectiveness [38].

Ferdinandus et al. evaluated the prognostic value of various pre-therapeutic parameters on therapy response, based on changes in PSA after the first cycle of RLT. Their multivariate analysis of these parameters, which considered any decrease in PSA after 2 months, showed that patients with a high platelet count or a regular need for analgesics had a significantly worse response to the first RLT cycle. When a PSA decline of ≥ 50% was considered, patients with a regular need for analgesics showed a worse response in the multivariate analysis; however, other pre-therapeutic parameters had no impact on the response to RLT. In this study, the standard uptake value maximum of ⁶⁸Ga-PSMA-11 was not a significant predictor of the response to RLT. One explanation for this could be that more aggressive tumours may express higher PSMA levels. However, despite the better uptake of ¹⁷⁷Lu-PSMA-617 due to the rapid growth of metastases, the response rate did not correlate with the uptake, which could be due to different washout times of ¹⁷⁷Lu-PSMA-617 in the respective metastases [29].

Rahbar et al. reported a potential survival benefit of ¹⁷⁷Lu-PSMA, where they matched the patient population (n = 28) to a historical cohort of 20 patients receiving the best supportive care (BSC) to examine potential survival benefits. Apart from the more heavily pre-treated patients and the more visceral metastases in the ¹⁷⁷Lu-PSMA group, the groups were comparable. This finding highlights that the estimated median survival period was 29.4 weeks, being significantly longer than the survival time in the historical control group at 19.7 weeks [39].

In a study by Ahmadzadehfar et al. with 52 patients who underwent a total of 190 cycles of RLT, 80.8% of patients showed a decline in PSA levels 2 months after the first cycle, with 44.2% showing a PSA decline of ≥ 50%. The median OS was 60 weeks in all patients. The median OS was significantly longer for patients who showed a PSA decline after the first cycle compared to patients without a PSA decline (68 versus 33 weeks respectively) [27]. In another study from the same group, 100 patients who received a total of 347 cycles of ¹⁷⁷Lu-PSMA (median three cycles) were analysed. All patients had a history of therapy with abiraterone or enzalutamide, or both. In total, 70% of the patients had at least one line of chemotherapy and 36% had a history of radionuclide therapy with ²²³Ra. Sixty-nine patients showed a decline in PSA 2 months after the first cycle, and 38 of these patients showed a PSA decline of ≥ 50%. The median OS was 60 weeks. In the multivariate analysis, the median OS was significantly longer in those patients without hepatic involvement, with high levels of albumin and haemoglobin (Hb), and with low levels of AST. Moreover, in the univariate analysis, a PSA decline after the first RLT, as well as any decline > 50%, were significant predictors of a longer OS. A decline in PSA levels of more than 14% was the most important response parameter with regard to OS [40]. In a bicentric study, 104 patients were treated with 351 cycles of ¹⁷⁷Lu-PSMA-617. All of them had a history of therapy with at least one line of chemotherapy as well as either abiraterone or enzalutamide. Thus, in this study, the patients received all recommended guideline therapies. A PSA decline occurred in 70 (67%) patients, with a PSA decline ≥ 50% in 34 (33%) patients after the first cycle. The median OS was 56.0 weeks (95% CI: 50.5–61.5). Any initial PSA decline, an initial alkaline phosphatase (ALP) < 220 U/L and a cumulative injected activity of ≥18.8 GBq were associated with a longer survival. A step-by-step analysis revealed a PSA decline of ≥ 20.9% as the most noticeable cut-off prognosticating longer survival, which remained an independent prognosticator of improved OS in the multivariate analysis [41]. These studies have shown that responders to PSMA therapies live longer than non-responders, and a PSA response should not necessarily be defined as a PSA decline of > 50%. Interestingly, prior therapies, such as chemotherapy, had no impact on OS.

The distribution of small molecules of PSMA ligands in tissue is quick and, over time, the uptake in prostate cancer tissue increases, whereas the uptake in healthy tissue declines [42]. In normal healthy tissue, salivary glands have the highest PSMA binding, followed by normal kidney tissue.

Kabasakal et al. [15] reported their dosimetry results with ¹⁷⁷Lu-PSMA-617 and showed the highest radiation estimated doses in parotid glands and kidneys. Calculated radiation-absorbed doses per megabecquerel were 1.17 ± 0.31 mGy for parotid glands and 0.88 ± 0.40 mGy for kidneys. The radiation dose given to bone marrow was significantly lower than those of kidney and parotid glands (p < 0.05). The calculated radiation dose to bone marrow was 0.03 ± 0.01 mGy/MBq.

These results were reproduced by Delker et al. [43] who reported their dosimetry results with ¹⁷⁷Lu-PSMA-617 and calculated a mean absorbed dose to bone marrow, kidneys, liver, spleen, and salivary glands of 0.012 Gy/GBq, 0.6 Gy/GBq, 0.1 Gy/GBq, 0.1 Gy/GBq and 1.4 Gy/GBq respectively.

There are several profound fears with regards to the damage caused to salivary glands. Based on external beam radiotherapy (EBRT) data, irreversible damage to salivary glands occurs after the administration of 30–40 Gy. With a mean absorbed dose of 1.4 Gy/GBq of ¹⁷⁷Lu-PSMA-617, and the absence of permanent xerostomia or hypogeusia in the initial treatment studies, the salivary glands do not appear to be a dose-limiting organ [43].

The second fear concerns the absorbed dose to kidney tissues [15, 43], where, based on the EBRT data, a dose of 23 Gy may result in permanent damage. The mean absorbed kidney dose of ¹⁷⁷Lu-PSMA is 0.53–0.8 Gy/GBq, quite like the absorbed kidney dose mentioned in the published data on ¹⁷⁷Lu-DOTATATE (0.64 ± 0.16 Gy/GBq) [44].

In a study with 135 patients undergoing diagnostics using ⁶⁸Ga-PSMA PET-CT, Gaertner et al. [45] compared three groups of patients with low, moderate, and high tumour loads according to their tumour volume. Their results indicate that patients with high tumour loads may receive less toxicity in their non-target organs.

As a result of previous findings, the safety and efficacy of targeted radionuclide therapies can be improved using patient-specific dosimetry, which may help to guide successful tumour dosing and act as an early indicator of organ toxicity.