Challenges with ¹⁷⁷Lu-PSMA-617 Radiopharmaceutical Therapy in Clinical Practice

IMAGING-BASED PATIENT ELIGIBILITY

There has been much debate about optimal patient selection for ¹⁷⁷Lu-PSMA-617 RPT, which entails both nonimaging and imaging criteria. Here, we focus on the continued debate on the imaging criteria—debate that has ranged from opinions in favor of no imaging requirement to dual PET/CT scans with both PSMA-targeted radiotracer and ¹⁸F-FDG. Both qualitative and reproducible quantitative image analyses have also been used (4). The VISION trial took a pragmatic approach, which reflected the knowledge at the time of its conception, by requiring 1 PSMA PET/CT scan with a 2-pronged approach for patient eligibility: first, at least 1 lesion of any size in any organ with radiotracer uptake visually (i.e., qualitatively) above liver background activity, and second, no lymph node 2.5 cm or larger in the short axis and a RECIST 1.1–measurable visceral or soft-tissue component of bone lesions with radiotracer uptake visually equal to or below liver background activity. This relatively simple nonsemiquantitative methodology excluded 12.6% of patients from the trial (4.9% exclusion based on no single lesion with radiotracer avidity above liver background, and 8.7% based on measurable disease with no or low PSMA expression). However, in applying the VISION-like criteria to other independent patient cohorts, it appears that there may be patients with relatively extensive disease who would probably have benefited from ¹⁷⁷Lu-PSMA-617 RPT but would be considered ineligible on the basis of single or few measurable but non–PSMA-expressing lesions (5). In general, however, VISION-ineligible patients had poorer outcomes than patients who were eligible. Moreover, retrospective application of the VISION-like criteria to another independent cohort has demonstrated that ¹⁸F-FDG PET/CT information may impact eligibility for ¹⁷⁷Lu-PSMA-617 RPT in only a relatively small number of patients (6). Therefore, it appears that the approach taken by the VISION investigators is reasonable (7). It is also worth noting that the currently approved PSMA radiotracers (⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL, and ¹⁸F-rh-PSMA-7.3) are generally considered equivalent in their detection efficacy, although the slightly higher hepatic uptake of ¹⁸F-rhPSMA-7.3 may impact selection of a small number of patients for ¹⁷⁷Lu-PSMA-617 RPT compared with patients screened with ⁶⁸Ga-PSMA-11 or ¹⁸F-DCFPyL (8). However, it is noted that the current approval of ¹⁷⁷Lu-PSMA-617 RPT is in a very late phase of the disease; hence, many patients receive this treatment as the last line of therapy. Generally, a pragmatic approach for more lenient selection criteria in the later phase of the disease and more stringent selection criteria in the earlier phases of the disease may be appropriate in the setting of other competitive effective treatment options.

THERAPY SCHEDULE AND DOSE MODIFICATION

After a patient is deemed eligible for ¹⁷⁷Lu-PSMA-617 RPT on the basis of imaging and nonimaging considerations, there may be clinical situations that call for interruption, delays, reduction, or possible intensification of therapy. Ideally, these situations are addressed by a dedicated multidisciplinary tumor board, which can recommend the optimal strategy for an individual patient. It is also important to determine when to cease treatment if its continuation is associated with more toxicity than clinical benefit. In the context of VISION, the recommended treatment schedule and dosage per the approved package insert is administration of 7.4 GBq (200 mCi) of ¹⁷⁷Lu-PSMA-617 every 6 wk for up to 6 doses. The administration scheme was derived from prior empiric clinical experience with ¹⁷⁷Lu-PSMA-617 and other established targeted RPTs. Dosing discontinuation, delays, or reduction may be necessary to manage adverse reactions to the treatment. Per the label, the dose may be reduced and the dosing interval may be extended depending on the clinical setting, including the initial response to treatment and alternative treatment options. Treatment modification may be considered after completion of the second treatment dose on the basis of an amalgamated assessment of changes in the serum prostate-specific antigen (PSA) and other relevant blood panel levels, imaging patterns, and the clinical profile. The treatment may be continued if the patient is clinically stable or receiving benefit despite minimal radiographic progression or a serum PSA rise. A treatment interruption, delay, or dose reduction may be considered to manage grade 3 or 4 hematologic toxicity, which in the interest of treatment preservation and, through a multidisciplinary disease management approach, may be supported with either transfusions (e.g., red blood cells) or marrow stimulation (e.g., romiplostim) to bridge the patient to the following treatment cycle. Treatment discontinuation should be considered if there is clinical decline or radiographic progression (e.g., new liver lesions). There are currently no guidelines for safe intensification of treatment dose or schedule in cases of early observation of treatment resistance, which in and of itself needs to be clearly defined. In patients with exceptional responses, consideration may be given to a therapy “holiday,” with active follow-up in determining if and when to restart the ¹⁷⁷Lu-PSMA-617 RPT or other treatment regimens. A prospective phase 2 randomized clinical trial (FLEX MRT; NCT06216249) is currently under way to determine the safety and efficacy of a flexible or extended schedule of ¹⁷⁷Lu-PSMA-617 therapy for up to 12 cycles with potential treatment holidays in comparison to patients treated with the standard fixed dosing schedule of a maximum 6 treatment cycles every 6 wk (9). Although the holiday concept has been shown to be feasible in a few reports, there are currently no specific guidelines for the definition or management of an exceptional response to ¹⁷⁷Lu-PSMA-617 RPT (10).

RETREATMENT

Sparse experience with an RPT rechallenge in patients who have responded to the initial full course of RPT has been reported. In a retrospective study of 30 patients who had received a median of 3 cycles of ¹⁷⁷Lu-PSMA-617 RPT, an additional median of 3 cycles (range, 1–6 cycles) of RPT was administered after a median of 6 mo (range, 2–26 mo) from the end of the initial course of RPT. The rechallenge RPT had an acceptable safety profile, and responders experienced relatively longer overall survival than nonresponses (11). In another small study of 8 patients who received a median of 2 cycles (range, 1–4 cycles) after a median of 5.4 mo (range, 4–15 mo) from the end of the initial cycles, a decline in baseline PSA level by 50% or more was achieved in 38% of patients, with no grade 4 toxicity (12). Similar results have been reported by Violet et al. in an expanded cohort of 50 patients and by Mader et al. in 26 patients with high-volume residual tumor (according to CHAARTED) after completion of standard RPT and no alternative treatment option (13,14). In summary, the preliminary small-scale clinical experience suggests that patients who have responded to the initial 6 cycles of ¹⁷⁷Lu-PSMA-617 RPT without major adverse events may continue to respond to additional cycles of RPT, although there are diminishing returns on response and there is cumulated toxicity (15). The prospective phase 2 RE-LuPSMA trial (NCT06288113) will assess the treatment efficacy of a ¹⁷⁷Lu-PSMA-617 RPT rechallenge, for a maximum of 6 additional cycles, in patients with metastatic castration-resistant prostate cancer who had a favorable response to a prior regimen of ¹⁷⁷Lu-PSMA-617 RPT. However, there are currently no specific guidelines to identify those patients who may most benefit from ¹⁷⁷Lu-PSMA-617 RPT retreatment, aside from the potential challenges with reimbursement, at least in the United States, in view of off-label use despite apparent clinical feasibility.

RENAL IMPAIRMENT

The traditional irradiation threshold of 23 Gy to limit nephrotoxicity is based on homogeneous external irradiation of the kidney, which differs substantially from low-dose-rate RPT-induced irradiation (16). Nevertheless, there is potential for cumulated radiation-induced nephrotoxicity from ¹⁷⁷Lu-PSMA-617 RPT, particularly in patients with baseline acutely impaired renal function, such as in obstructive uropathy. In the VISION trial, grade 3/4 acute renal injury was noted in 3.2% of patients who received ¹⁷⁷Lu-PSMA-617 versus 2.9% of patients in the control arm. In current clinical practice, it is recommended that there be no ¹⁷⁷Lu-PSMA-617 RPT dose reduction in patients with reduced renal function at baseline unless the estimated glomerular filtration rate is steadily below 30 mL/min (17). In the event of an acute decline in estimated glomerular filtration rate, the reasons for such a decline (e.g., obstructive uropathy or dehydration) should be investigated and mitigated. Despite these recommendations, it has been debated whether the nephrotoxic potential of ¹⁷⁷Lu-PSMA-617 RPT may be overestimated and not of clinical priority during the last line of therapy, especially in stable chronically reduced renal function (18,19). With the use of ¹⁷⁷Lu-PSMA-617 RPT earlier in the disease course on the horizon, potential concerns about treatment-induced nephrotoxicity and other long-term toxicity are heightened. Studies have suggested that although serious adverse renal events are not a frequent phenomenon after ¹⁷⁷Lu-PSMA-617 RPT, a pretherapy glomerular filtration rate of less than 77 mL/min/1.73 m² or extrapolation of individual data from dosimetry of the first cycle may be predictive of renal impairment during follow-up (20–22). ¹⁷⁷Lu-PSMA-617 RPT has also been reported to be feasible in patients with a single functioning kidney or on hemodialysis (23,24). It should be remembered, however, that in patients with diminished renal function undergoing RPT, the prolonged blood-pool activity may enhance tumor uptake but may also increase the marrow dose and potential toxicity.

DIFFUSE MARROW DISEASE

The VISION trial excluded bone scan superscans in keeping with marrow safety considerations in the context of enhancing the successful outcome of the trial. However, in a retrospective multicenter study of 43 patients undergoing ¹⁷⁷Lu-PSMA-617 RPT, a similar hematologic safety profile was noted in comparison to the previously reported data that excluded patients with diffuse marrow disease (25). These and other small-scale data appear not to support exclusion of patients with a superscan imaging pattern from ¹⁷⁷Lu-PSMA-617 trials or in clinical practice. Although a marked decrease in marrow function can be noted in patients with extensive osseous metastases, there is also the opportunity to regain marrow function if tumor burden can be decreased. As a last line of therapy, the risk and benefit of treatment in patients with extensive osseous disease must be considered. One remaining challenge in this clinical setting is to isolate progressive marrow disease from ¹⁷⁷Lu-PSMA-617 myelosuppression, which may require a multipronged diagnostic approach. Multidisciplinary tumor boards would be the proper setting to discuss decisions about transfusion and use of growth factors.

THERAPY RESPONSE ASSESSMENT

Specific guidelines on the assessment of response to ¹⁷⁷Lu-PSMA-617 RPT remain an evolving issue. The expression of PSMA may be influenced by certain medications (e.g., androgen deprivation therapy, either up- or down-regulated), RPT-induced cellular killing, or loss of PSMA expression and increased heterogeneity due to biologic evolutionary changes (e.g., neuroendocrine transdifferentiation). Therefore, PSMA expression does not have the same linear significance as in the Warburg effect for ¹⁸F-FDG. Thus, for example, loss of PSMA PET signal does not necessarily translate into a favorable response to RPT. Furthermore, changes in PSMA PET signal, serum PSA level, and clinical profile may be discordant. Despite these challenges, several attempts have been made to devise a framework for a robust PSMA PET-based measurement of response to RPT, although bone scintigraphy and CT remain relevant and used in response assessment. RECIP 1.0 used a software-based quantitative assessment of PSMA-positive total tumor volume changes between the pretreatment and the interim PET after 2 cycles of therapy. The total tumor volume change and new lesions were associated with a robust performance in separating progressive disease (PD) from non-PD (26) and in several cases were superior to PSA assessment. Similar findings have also been noted with qualitative (visual) and end-of-treatment PSMA PET/CT performed within 6 mo of the last PSMA RPT (27).

A recent report compared the traditional RECIST 1.1, the adapted criteria of Prostate Cancer Working Group 3, the adapted PERCIST, the PSMA PET Progression criteria, and the RECIP 1.0 in separating PD from non-PD in 124 metastatic castration-resistant prostate cancer patients undergoing ¹⁷⁷Lu-PSMA-617 RPT (28). RECIP 1.0 was associated with the highest interreader reliability and the lowest PD overall. More recently, the visual RECIP 1.0 comparing baseline (before therapy) findings with those after cycle 2 of ¹⁷⁷Lu-PSMA-617 were shown to be prognostic for PSA progression-free survival (29) The comparative efficacy of candidate response criteria in the setting of RPT will need additional prospective external validation including within phase 3 trials and optimization of the required procedural time.

Biomarker-guided treatment response assessment using ¹⁷⁷Lu-PSMA-617 SPECT/CT in combination with PSA and potential incorporation of dosimetry may also allow for personalization of therapy regimens (30–32). An implementation of same-day posttherapy quantitative SPECT/CT performed 1–2 h after ¹⁷⁷Lu-PSMA-617 infusion has also been shown to be a potentially promising method for assessing treatment response (33). A phase 2 randomized clinical trial (FLEX MRT; NCT06216249) currently under way will use SPECT/CT obtained 24 h after injection of a ¹⁷⁷Lu-PSMA-617 therapy cycle and PSA to determine tumor response and potential treatment holiday periods (9).

SEARCH FOR PREDICTIVE AND PROGNOSTIC BIOMARKERS

Biomarkers are essential in precision cancer therapy. Predictive biomarkers convey the likelihood of response to specific treatments. Prognostic biomarkers are agnostic to specific therapy and inform on the aggressiveness of cancer (34). Biomarkers may be based on a combination of big omics data (genomics, proteomics, transcriptomics, metabolomics, radiomics). Artificial intelligence algorithms can provide insights into identification of optimal combinations that incorporate tumor heterogeneity for accurate actionable characterization of disease behavior. In the context of the TheraP trial, a mean SUV of 10 or higher on PSMA PET was found to be a predictive biomarker for response (decline in baseline PSA level by 50% or more and radiographic progression-free survival) to ¹⁷⁷Lu-PSMA-617 versus cabazitaxel but not for overall survival (35). A metabolic tumor volume of 200 mL or higher on ¹⁸F-FDG PET was also found to be a useful prognostic biomarker in view of association with lower odds of PSA response regardless of the type of therapy (36). However, as an editorial by Sartor notes, none of these biomarkers informed about overall survival, although the trial was not devised with overall survival as the primary outcome endpoint (37). The editorial also advocated for multivariate analysis of the relevant biomarkers that are pragmatic in routine clinical practice to inform on overall survival, preferably before or early after ¹⁷⁷Lu-PSMA-617 RPT. A nomogram has been developed with parameters such as time since the initial diagnosis of prostate cancer, chemotherapy status, baseline hemoglobin concentration, and the PSMA PET/CT parameters (molecular imaging TNM classification and tumor burden) (38). In a similar manner, biomarkers that may provide early information on potential resistance to ¹⁷⁷Lu-PSMA-617 can be useful. Circulating tumor DNA assay of gene amplifications (e.g., FGFR1 and CCNE1) may provide useful information on predicting response or resistance to ¹⁷⁷Lu-PSMA-617 RPT (39). A higher fraction of non–PSMA-expressing circulating tumor cells appears to be associated with both poor response to ¹⁷⁷Lu-PSMA-617 RPT and poor outcome, even despite sufficient PSMA expression on PSMA PET, thus indicating the intrinsic heterogeneity of metastatic castration-resistant prostate cancer (40). Further understanding of the underlying biologic mechanisms of resistance to ¹⁷⁷Lu-PSMA-617 RPT will be helpful in the quest to align most optimally with the essence of precision oncology.

DISCLOSURE

No potential conflict of interest relevant to this article was reported.