Debra Van Asten 1,2, B.J. de Wit-van der Veen 2, A.D.R. Huitema 1,3,4, Hinke Huisman-Siebinga 1,2
1 Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute (Amsterdam, The Netherlands), 2 Department of Nuclear Medicine, The Netherlands Cancer Institute (Amsterdam, The Netherlands), 3 Department of Clinical Pharmacy, University Medical Center Utrecht (Utrecht, The Netherlands), 4 Princess Máxima Center for Pediatric Oncology (Utrecht, The Netherlands)
Objectives:
[¹⁷⁷Lu]Lu-PSMA-617 is an approved radioligand therapy that prolongs survival in metastatic castration-resistant prostate cancer (PCa). The PROQURE‑I trial investigated its use in combination with radiotherapy as a curative regimen for treatment-naïve patients with N1M0 PCa, to improve recurrence rates [1]. In this trial, [¹⁷⁷Lu]Lu-PSMA-617 was added to standard-of-care whole‑pelvis external beam radiotherapy (EBRT) and long‑term androgen deprivation therapy (ADT) to evaluate safety and tolerability.
In a population pharmacokinetic (pop-PK) sub-analysis, we aimed to quantify the distribution and between‑subject variability (BSV) of [¹⁷⁷Lu]Lu-PSMA-617 in the PROQURE‑I. Furthermore, we explored if covariates previously identified for [¹⁷⁷Lu]Lu-PSMA monotherapy, could also account for the substantial variability in tumor exposure observed in this trial [2,3]. Finally, a maximum tumor-binding capacity (Bmax), was explored to describe the observed nonlinearity in exposure profiles at higher doses.
Methods:
The PROQURE‑I was a multicenter phase I dose‑escalation study (NCT05162573) in N1M0 PCa patients. Cohort A received single doses of 3, 6, or 9 GBq (n=7) [¹⁷⁷Lu]Lu-PSMA-617 two weeks after start EBRT. Cohort B received two 7.4 GBq cycles (n=5) (two-week interval) during EBRT. Pelvic SPECT/CT scans acquired at 4, 24, and 168 hours post-administration were analyzed using MIM-software (v7.3.6) to obtain both the concentration (MBq/L) and the volume (L) of the prostate tumor. Plasma samples were collected at 5, 15, 30 minutes and 1, 2, 3, 6, 24, 48 and 168 hours post-administration to measure ¹⁷⁷Lu-concentrations (MBq/L).
A four-compartment pop-PK model was developed using NONMEM (v7.5) to describe tracer distribution across plasma, tumor, PSMA-expressing organs, and other tissues. Structural parameters included the plasma volume of distribution (V₁), systemic excretion rate (k₁₀) and rate constants k_in and k_out to other compartments. The constants k_in and k_out for other tissues were fixed to previously published values [3]. BSV was evaluated for V₁, k₁₀, and uptake-related rate constants. It was evaluated whether cycle‑dependent tumor uptake (i.e. lower uptake in the second cycle) and tumor‑volume related uptake (i.e. higher uptake with higher tumor volumes) effects could be identified. Furthermore, non-linear tumor uptake (Bmax), as observed in the exposure profiles at the 9 GBq dose level, was evaluated in the model. A posthoc stochastic simulation and estimation (SSE) procedure was performed to determine the number of subjects required to estimate these covariate effects with 80% power.
Results:
Data from 12 patients were included for analysis. The [¹⁷⁷Lu]Lu-PSMA-617 pop-PK model demonstrated good fit and precision for fixed-effects parameters (THETA RSEs < 24%) and acceptable precision for random-effect parameters (OMEGA RSEs < 66%) given the limited sample size. The clearance was estimated at 1.31 L/h (RSE k₁₀ = 4.5%, V₁ = 5.1%), which is lower than reported previously due to using plasma instead of whole-blood samples.
Tumor uptake (k₁₂) was slow (0.00059 h⁻¹) relative to uptake (0.0219 h⁻¹) in the PSMA‑expressing organs. The corresponding k_outs were similar for tumor (0.0122 h⁻¹) and PSMA-expressing organs (0.0170 h⁻¹). This is both in line with results for monotherapy in a metastatic setting [2]. However, absolute tumor uptake rates were lower, likely reflecting altered target‑mediated drug disposition in this earlier treatment line. The BSV for k₁₀, k₁₂ and uptake in other tissues was 23%, 89% and 46% (CV), respectively. Tumor uptake in cycle 2 decreased to 58% of cycle 1, a greater reduction than seen with monotherapy [2], potentially reflecting response to EBRT+ADT. Tumor uptake increased with 122% for patients with a twofold higher tumor volume compared to the median.
Inclusion of treatment-cycle and tumor-volume as covariates reduced the BSV on tumor uptake from 205% to 89% (CV), though substantial unexplained variability in tumor exposure remained. The potential Bmax could not be precisely estimated due to sample‑size limitations. Posthoc SSE indicated that a sample size of at least 65 patients would be required to reliably estimate a clinically relevant Bmax with 80% power (α = 0.05).
Conclusions:
The pop-PK model showed adequate fit and confirmed altered tumor uptake of [¹⁷⁷Lu]Lu-PSMA-617 in a multimodal treatment setting versus monotherapy, likely due to target‑mediated drug disposition. Variability was largely captured by expected covariates, including a strong decrease in tumor uptake in the second treatment cycle caused by the combined therapies. Indications of nonlinear tumor uptake highlight the need to consider saturation in tumor accumulation for future studies with larger sample sizes.
References:
[1] van der Sar ECA, Braat AJAT, van der Voort-van Zyp JRN, van der Veen BS, van Leeuwen PJ, de Vries-Huizing DMV, Hendrikx JMA, Lam MGEH, Vogel WV. Tolerability of concurrent external beam radiotherapy and [177Lu]Lu-PSMA-617 for node-positive prostate cancer in treatment naïve patients, phase I study (PROQURE-I trial). BMC Cancer. 2023 Mar 23;23(1):268.
[2] Siebinga H, de Wit-van der Veen BJ, de Vries-Huizing DMV, Vogel WV, Hendrikx JJMA, Huitema ADR. Quantification of biochemical PSA dynamics after radioligand therapy with [177Lu]Lu-PSMA-I&T using a population pharmacokinetic/pharmacodynamic model. EJNMMI Phys. 2024 Apr 24;11(1):39.
[3] Siebinga H, Privé BM, Peters SMB, Nagarajah J, Dorlo TPC, Huitema ADR, de Wit-van der Veen BJ, Hendrikx JJMA. Population pharmacokinetic dosimetry model using imaging data to assess variability in pharmacokinetics of 177 Lu-PSMA-617 in prostate cancer patients. CPT Pharmacometrics Syst Pharmacol. 2023 Aug;12(8):1060-1071
Reference: PAGE 34 (2026) Abstr 12014 [www.page-meeting.org/?abstract=12014]
Poster: Drug/Disease Modelling - Oncology