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)

Abstract

Background: Prostate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29-47%. [¹⁷⁷Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of [¹⁷⁷Lu]Lu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields.

Methods: The PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic [¹⁷⁷Lu]Lu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding [¹⁷⁷Lu]Lu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle [¹⁷⁷Lu]Lu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of [¹⁷⁷Lu]Lu-PSMA-617.

Discussion: This is the first prospective study to combine EBRT and ADT with [¹⁷⁷Lu]Lu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of [¹⁷⁷Lu]Lu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments.

Trial registration: ClinicalTrials, NCT05162573 . Registered 7 October 2021.

Keywords: Lu-PSMA; Node-positive; Prostate cancer.

Fig. 1

Example of response of [¹⁷⁷Lu]Lu-PSMA-617 in a patient with metastatic castration-resistant prostate cancer. On the left side you see a [⁶⁸ Ga]Ga-PSMA-11 PET maximal intensity projection (MIP) of a patient with metastatic prostate cancer in bone and lymph nodes. There is physiological accumulation in the salivary glands, kidneys, spleen, and to a much lower extent small and large bowel. On the right you also see a [⁶⁸ Ga]Ga-PSMA-11 PET MIP from the same patient after two cycles of [¹⁷⁷Lu]Lu-PSMA-617 which shows almost complete response

Fig. 2

Study design. At the start of the treatment patients receive adjuvant hormone therapy (ADT) at most one month prior to the start of external beam radiation therapy (EBRT) and will continue during EBRT. Adjuvant hormone therapy is then continued as adjuvant treatment up to the advised total duration of 3 years (provided that its toxicity remains acceptable). In week two of EBRT, patients also receive one concurrent cycle of systemic [¹⁷⁷Lu]Lu-PSMA-617 (Lu-PSMA) as part of the study procedure

Fig. 3

Example radiation field. Example of a radiation field in a patient with primary prostate cancer (indicated by a green arrow) and one lymph node metastasis in the left pelvic area (indicated by a red arrow) who is eligible for external beam radiation therapy (EBRT) and participation in the study. The delivered physical EBRT dose is 70–77 Gy to the prostate (purple area with green arrow), 60 Gy to macroscopic lymph node metastases (purple area with red arrow), and 52.5 Gy to the RTOG-based elective pelvic nodal fields expanded to include all detected nodal metastases (pink area)