177Lu-PNT2002 Boosts rPFS in PSMA+ mCRPC Following ARPI Progression

The radioligand therapy ¹⁷⁷Lu-PNT2002 led to an improvement in radiographic progression-free survival (rPFS) vs an androgen receptor pathway inhibitor (ARPI) in patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC) following progression on an ARPI, according to data from the phase 3 SPLASH trial (NCT04647526) presented at the 2024 ESMO Congress.

Findings showed that at a median follow-up of 11.1 months (95% CI, 10.1-11.6) for the ¹⁷⁷Lu-PNT2002 arm (n = 276) and 12.9 months (95% CI, 10.2-15.9) for the ARPI arm (n = 136), the median rPFS was 9.5 months (95% CI, 7.4-10.0) for ¹⁷⁷Lu-PNT2002 compared with 6.0 months (95% CI, 4.7-7.9) in the alternate ARPI arm (HR, 0.71; 95% CI, 0.55-0.92; P = .0088).

“¹⁷⁷Lu-PNT2002 reduced the risk of radiographic progression or death by 29% and had a favorable safety profile compared with the ARPI control,” lead study author Oliver Sartor, MD, of Mayo Clinic in Rochester, Minnesota, noted in the presentation.

SPLASH Study Design

The SPLASH trial enrolled patients with mCRPC who had progressed on one ARPI. Eligible patients were required to have PSMA-positive disease confirmed via PSMA-avid PET imaging and an ECOG performance status of 0 or 1. Prior taxane treatment for castration-sensitive prostate cancer (CSPC) was permitted if administered more than 1 year prior to consent.

Once enrolled, patients were randomly assigned in a 2:1 fashion to receive either ¹⁷⁷Lu-PNT2002 at 6.8 GBq (±10%) once every 8 weeks for up to 4 cycles or an alternate ARPI, such as enzalutamide (Xtandi) or abiraterone acetate (Zytiga). The study allowed for a crossover design, where patients initially assigned to the alternate ARPI arm could switch to ¹⁷⁷Lu-PNT2002 upon radiographic progression.

Investigators stratified patients based on prior taxane treatment for CSPC (yes vs no), prior use of bisphosphonates (yes vs no), metastatic status during prior ARPI therapy (M0 vs M1), and measurable disease at study entry (yes vs no).

The primary end point of the study was rPFS; secondary endpoints included overall survival (OS), objective response rate (ORR), time to skeletal-related events, and PSA50 response. Additional assessments included biochemical PFS (bPFS), health-related quality of life (HRQOL), and the identification of adverse effects (AEs) or toxicities associated with treatment.

Baseline Patient Characteristics

The median age of patients enrolled in the SPLASH study was 72 years (range, 45-92) in the ¹⁷⁷Lu-PNT2002 arm and 72 years (range, 47-90) in the alternate ARPI arm. The majority of patients were White (¹⁷⁷Lu-PNT2002, 77.9%; alternative ARPI, 82.4%).

Additionally, 58.7% of patients in the ¹⁷⁷Lu-PNT2002 arm had an ECOG performance status of 0 compared with 55.9% in the alternate ARPI arm. The remaining patients in both arms had an ECOG performance status of 1.

The median PSA level at baseline was 13.20 µg/L (range, 0.19-1182) in the ¹⁷⁷Lu-PNT2002 arm and 18.95 µg/L (range, 0.33-1528) in the alternate ARPI arm. Median hemoglobin levels were 127 g/L (range, 83-160) in the ¹⁷⁷Lu-PNT2002 group and 129.5 g/L (range, 84-163) in the alternate ARPI group.

Regarding prior taxane treatment for CSPC, 17.8% of patients in the ¹⁷⁷Lu-PNT2002 arm and 16.9% of patients in the alternate ARPI arm had previously received this therapy. Most patients had M1 disease at the start of prior ARPI therapy in the ¹⁷⁷Lu-PNT2002 arm (89.9%) and the alternate ARPI arm (89.0%).

Additional Efficacy Findings

Evaluable patients treated with ¹⁷⁷Lu-PNT2002 (n = 97) achieved an ORR of 38.1% (95% CI, 28.5%-48.6%) compared with 12% (95% CI, 4.5%-24.3%) in patients receiving an alternate ARPI (n = 50; P = .0021). The complete response (CR) rate for ¹⁷⁷Lu-PNT2002 was 9.3%; no patients in the ARPI arm achieved a CR. The partial response rate was 28.9% in the ¹⁷⁷Lu-PNT2002 group compared with 12.0% in the ARPI arm. Patients in the ¹⁷⁷Lu-PNT2002 arm had a stable disease rate of 25.8%, whereas 54.0% of patients in the ARPI arm had stable disease. The rates of progressive disease were 35.1% in the ¹⁷⁷Lu-PNT2002 arm vs 34.0% in the ARPI arm.

The median duration of response was 9.4 months (95% CI, 5.9-13.2) for ¹⁷⁷Lu-PNT2002 vs 7.3 months (95% CI, 1.6–not evaluable) in the ARPI arm.

In the ¹⁷⁷Lu-PNT2002 arm, 35.7% of evaluable patients (n = 269) achieved at least a 50% PSA decrease from baseline. In comparison, 14.6% of patients (n = 130) in the alternate ARPI arm experienced a PSA50 response.

At a median follow—up of 9.9 months (95% CI, 9.4-10.8) in the ¹⁷⁷Lu-PNT2002 arm (n = 276) and 10.0 months (95% CI, 6.6-11.6) in the ARPI arm (n =136), the median bPFS was 7.0 months (95% CI, 4.8-9.9) for the experimental arm compared with 3.9 months (95% CI, 3.5-4.3) in the ARPI arm (HR, 0.58; 95% CI, 0.44-0.76; P < .0001).

Sartor noted that OS data continue to mature.

Safety Profile

The most common any-grade treatment-emergent AEs (TEAEs) observed across patients treated with ¹⁷⁷Lu-PNT2002 (n = 269) and an alternate ARPI (n = 130) included fatigue (¹⁷⁷Lu-PNT2002, 53.5%; alternate ARPI, 40.0%) dry mouth (37.2%; 1.5%), and nausea (31.2%; 19.2%).

Any-grade TEAEs occurred in 99.3% of patients in the experimental arm and 94.6% of patients in the control arm. The rates of grade 3 or higher TEAEs were 30.1% and 36.9%, respectively, and the respective rates of grade 3 or higher treatment-related TEAEs were 9.7% and 11.5%.

Serious TEAEs occurred in 17.1% of patients in the control arm vs 23.1% of patients in the experimental arm, including 2.2% and 3.8% who had treatment-related serious TEAEs, respectively. TEAEs led to death in 1.9% and 3.8% of patients, respectively. No deaths were reported in either arm due to treatment-related TEAEs. TEAEs led to treatment discontinuation and treatment reduction in 1.9% and 1.1% of patients in the experimental arm, respectively. These respective rates were 6.2% and 5.4% in the control arm.

Reference

Sartor O, Jiang DM, M. Smoragiewicz, et al. Efficacy of 177Lu-PNT2002 in PSMA-positive mCRPC following progression on an androgen-receptor pathway inhibitor (ARPI) (SPLASH). Ann Oncol. 2024;35(suppl 2):S1254-S1255. doi:10.1016/j.annonc.2024.08.2308

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