SPLASH: Comparative Outcomes of PSMA Radioligand Therapy Versus ARPI Switch in mCRPC

The SPLASH trial enrolled patients with metastatic castrate-resistant prostate cancer (mCRPC) who progressed on previous treatment with one androgen receptor pathway inhibitor (ARPI) and had a PSMA-avid PET. Of note, patients who received taxane chemotherapy in the castrate-sensitive state were allowed enrollment if the chemotherapy was given more than one year prior to consent. Patients were randomized to Lu-PNT2002, also known as Lu-I&T, at a dose of 6.8 GBq every 8 weeks for up to 4 cycles versus the control arm of an alternate ARPI (enzalutamide or abiraterone).

One critique of this control arm is that patients who may be eligible for taxane chemotherapy should receive this prior to ARPI switch given lower response rates with subsequent ARPI therapy. Crossover was permitted on the ARPI switch control arm.

Regarding baseline patient characteristics, the median age was 72 years, most patients were White, with 11.6% African American on the Lu-I&T arm and 5.9% on the control arm. A minority of patients had received a prior taxane in the castration-sensitive stage (17.8% in the Lu-I&T arm and 16.9% in the control arm).

SPLASH met its primary endpoint, reducing the risk of radiographic progression (rPFS) or death by 29% versus APRI switch with an HR of 0.71 (95% CI: 0.55-0.92; P=.0088). The median rPFS was 9.5 months for Lu-I&T versus 6.0 months for ARPI switch. The overall survival (OS) data is still immature. Other secondary endpoints were met, including overall response rate (ORR), PSA50 response, and health-related quality of life (HRQOL) scores.

Adverse events (AEs) were comparable in the treatment and control arms. The most common AEs for Lu-I&T were dry mouth (37.2%), nausea (31.2%), arthralgias (28.3%), back pain (20.8%), and constipation (20.1%).

This study was presented right after updates on the UpfrontPSMA trial, which has a similar study design and evaluated Lu-PSMA-617 at a dose of 7.4 GBq every six weeks for up to 6 cycles, which is a higher cumulative dose than given in SPLASH. Although both urea-based small molecules Lu-PSMA and Lu-I&T have similar uptake, Lu-I&T has been shown to have increased kidney uptake compared to Lu-PSMA-617, but diminished lacrimal gland absorption.

In summary, the results from SPLASH continue to show benefit for PSMA radioligand therapy with Lu-I&T in the mCRPC setting and increase the data available to consider this in the pre-chemotherapy setting for patients with mCRPC who chose to forgo or cannot receive chemotherapy.

The optimal dosing and timing of Lu-PSMA therapy remains an open question, and tailoring therapy cycles to growth rates, as well as individualized dosimetry, may help to improve response and limit toxicity.