The treatment landscape for mCRPC has undergone radical change in recent years, with the current standard approach comprising a combination of anti-androgen therapy, chemotherapy, secondary hormonal therapies, and immunotherapy [15]. 177Lu-labelled radiopharmaceuticals such as the recently FDA-approved [177Lu]Lu-PSMA-617 provide a further option if the cancer is PSMA-positive. [177Lu]Lu-PSMA-617 has been shown to improve overall survival in patients with progressive mCRPC previously treated with androgen receptor inhibitors and taxane chemotherapy [2], and an alternative 177Lu-labelled PSMA ligand, [177Lu]Lu-PSMA-I&T, shows comparable favourable efficacy and safety profile in the same setting [16].

However, despite the growing armamentarium of therapeutic options for the management of mCRPC, a need exists for further or improved options for those patients who still show disease progression once all standard approaches have been exhausted.

The next-generation radioligand therapy, [177Lu]Lu-rhPSMA-10.1, has been developed with optimized properties for therapeutic use. Wurzer et al. have shown that even small modifications to the structure of rhPSMA radiopharmaceuticals can bring remarkable changes to their biodistribution [3], and their work has led to the selection of [177Lu]Lu-rhPSMA-10.1, which makes use of a DOTA metal chelator and has the diaminopropionic acid branching unit in the d-Dap stereoconfiguration, as the lead rhPSMA molecule for therapeutic use [17].

[177Lu]Lu-rhPSMA-10.1 has undergone extensive preclinical evaluations which show it to have a favourable therapeutic profile, with a high tumour-to-kidney dose ratio [17, 18]. Preclinical studies highlight a number of factors that likely contribute to this favourable biodistribution, including binding affinity, internalization, lipophilicity, net charge, and the extent to which human serum albumin binding occurs. However, intriguingly, there are several examples in the literature of “improved” radioligand therapy candidates in animal models, which fail to translate this potential to the human patient setting. This suggests that the in vitro properties of the radioligand therapy are perhaps less significant than the human specific pharmacokinetics which, of course, cannot be replicated in mice. Reassuringly, the first clinical data with [177Lu]Lu-rhPSMA-10.1 from an intra-patient comparison with [177Lu]Lu-PSMA-I&T in patients with mCRPC show [177Lu]Lu-rhPSMA-10.1 to have a more favourable tumour-to-kidney therapeutic index than [177Lu]Lu-PSMA-I&T and is supportive of the preclinical observations [6]. The way this improved profile is achieved seems to relate to achieving a very long tumour effective half-life, without a proportional increase in retention in the normal organs. However, the exact mechanism underlying the long tumour retention remains unclear and is not purely a function of increased plasma half-life.

Among the same first cohort of patients to receive radioligand therapy with this novel radiopharmaceutical, promising efficacy data were achieved, with, a 35–100% PSA response was observed after 4–6 treatment cycles [10]. In order to explore if [177Lu]Lu-rhPSMA-10.1 may be of benefit to patients who were showing disease progression despite exhausting all standard treatment options, including with [177Lu]Lu-PSMA-I&T, here we report data on [177Lu]Lu-rhPSMA-10.1 rescue therapy from a compassionate use program in Germany.

Importantly, this population of patients developed resistance to [177Lu]Lu-PSMA-I&T during dosing and were switched to [177Lu]Lu-rhPSMA-10.1 based on this observation. We contrast this with some experiences in the literature whereby patients with good responses to therapy return for further re-challenge therapy several months later and likely represent a different patient population.

While some of the patients in this experience initially showed a partial response (5/10) or stable disease (1/10), before subsequently becoming unresponsive to [177Lu]Lu-PSMA-I&T, 4/10 never showed any response to [177Lu]Lu-PSMA-I&T. Such a complete lack of response to [177Lu]Lu-PSMA-I&T highlights the importance of identifying predictive factors indicative of successful outcomes prior to initiation of 177Lu-PSMA-based radioligand therapy, such as through use of nomograms, radiomics and artificial intelligence based on pre-therapeutic imaging [20,21,22]. Notably, one patient with primary resistance to [177Lu]Lu-PSMA-I&T, as illustrated by a continuous PSA progression from 890 to 1700 ng/mL while undergoing [177Lu]Lu-PSMA-I&T radioligand therapy, showed an immediate response to [177Lu]Lu-rhPSMA-10.1 rescue therapy. His PSA decreased after the first cycle to 1300 ng/mL. Unfortunately, this patient suffered from a fatal ischemic stroke shortly before the second treatment cycle, so no further follow-up, including imaging to confirm radiographic response, was possible. As data with [177Lu]Lu-PSMA-617 in mCRPC patients show, the ability to deliver a higher radiation dose to the tumour results in greater efficacy [7, 22], and as our previous data show, [177Lu]Lu-rhPSMA-10.1 delivers a significantly higher radiation dose to the tumour compared with [177Lu]Lu-PSMA-I&T [6], potentially overcoming primary or acquired radiation resistance and thus enabling a response to [177Lu]Lu-rhPSMA-10.1 after progression on [177Lu]Lu-PSMA-I&T. Together, this perhaps suggests that not all PSMA-based radioligand therapy agents are equal and that failure to respond to one agent should not preclude rechallenge or rescue therapy with another. However, data from a multicenter retrospective analysis of patients who received [177Lu]Lu-PSMA-617 or [177Lu]Lu-PSMA-I&T, either as extended continuous treatment (n = 43), or as a rechallenge (n = 68), show that a treatment break preserved the efficacy of 177Lu-labelled radioligand therapy [23], Moreover, rates of those showing a 50% PSA decline were significantly higher in the rechallenge group than in the continuous group (57/63 [90%] versus 26/42 [62%]; P = 0.006). Although we note the median therapy–free interval was longer (7.2 months) than in the present study and likely represents a different patient population with more favourable disease, it remains possible that the short break in [177Lu]-PSMA-I&T therapy (6–12 weeks) may also have prompted a renewed response among our cohort. This should be evaluated further in future studies.

177Lu-labelled radiopharmaceuticals are generally well tolerated [6, 9, 10], however, the kidneys remain one of the most important normal organs to consider when planning radioligand therapy due to the risk of delayed radiation nephropathy [24]. Although appropriate renal radiation dose limits are yet to be established for patients undergoing radioligand therapy with newly established beta emitting radiopharmaceuticals, minimizing the radiation exposure to the kidney while maximizing the effective tumour dose should be a key consideration when selecting an agent for radioligand therapy [6]. In this cohort the conventionally defined kidney dose limits (23 Gy) were likely exceeded in several patients. While we did observe three cases (30%) of grade 2 nephrotoxicity without any more severe decline of kidney function in our cohort, we found severe bone marrow toxicity in one case of grade 4 thrombocytopenia (10%), one case of grade 3 leukopenia (10%) and two cases of grade 3 anaemia (20%). This is more than found before in primary RLT using [177Lu]-PSMA-I&T for which in a study including 100 patients grade 3/4 toxicities were 4% for thrombocytopenia, 6% for neutropenia and 9% for anaemia [1]. Similar magnitudes have been reported for [177Lu]-PSMA-617 [2]. However, despite the low number of patients, the patients in our cohort were heavily pre-treated. The patient suffering from grade 4 thrombocytopenia was already presenting with grade 2 thrombocytopenia prior to [177Lu]Lu-rhPSMA-10.1 therapy. In general, this is a common finding in such cohorts, as patients have already undergone treatment with a large number of potentially bone marrow toxic treatments prior to [177Lu]Lu-rhPSMA-10.1, including taxane-based chemotherapy and [177Lu]Lu-PSMA-I&T. Therefore, it should be expected that a higher level of toxicity might be observed [10].

There are some limitations to the present work. Data are reported from only a small case series of patients who were the first to receive rescue therapy with [177Lu]Lu-rhPSMA-10.1 as part of a compassionate use program at our clinic. While the findings suggest that rechallenge with another radioligand may be beneficial despite previous progression on another agent, this should be confirmed in future prospective clinical trials.