Improved clinical outcomes with [177Lu]Lu-PSMA-617 in taxane-naïve patients with metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) poses a substantial clinical challenge, demanding the exploration of new treatment strategies. The PSMAfore trial recently demonstrated the superiority of [¹⁷⁷Lu]Lu-PSMA-617 over androgen receptor pathway inhibitor change in taxane-naïve patients with PSMA-positive mCRPC, achieving substantial improvements in radiographic progression-free survival, response rates, time to symptomatic skeletal events, and quality of life. A positive trend in overall survival further underscores its potential, supported by a favourable safety profile.

Background

[¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) is a targeted radioligand with a high affinity for prostate-specific membrane antigen (PSMA)-positive cells.  In patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC), ¹⁷⁷Lu-PSMA-617 binds to PSMA molecules on the cancer cell membrane. Upon binding, this agent undergoes internalisation in the cell through endocytosis, leading to DNA damage through the β-radiation of ¹⁷⁷Lu, ultimately inducing cell death. The PSMAfore study aimed to compare the efficacy and safety of ¹⁷⁷Lu-PSMA-617 over androgen receptor pathway inhibitor (ARPI) change in taxane-naïve mCRPC patients.

Methods

The phase III PSMAfore trial enrolled mCRPC patients with at least one PSMA-positive metastatic lesion and no exclusionary PSMA-negative lesions confirmed by [⁶⁸Ga]Ga-PSMA-11 PET/CT scans. Eligible participants had previously progressed on second-generation ARPI and were candidates for ARPI change. Most patients were taxane- naïve, and a few had received (neo)adjuvant therapy more than 12 months before. Patients eligible for poly ADP-ribose polymerase (PARP) inhibition were excluded. Patients were randomly assigned (1:1) to receive ¹⁷⁷Lu-PSMA-617 (7.4 GBq ± 10%, Q6W for six cycles) or ARPI change (abiraterone/enzalutamide). Of note, patients randomised to ARPI could crossover to ¹⁷⁷Lu-PSMA-617 following radiographic progression (rPD). The primary endpoint was radiographic progression-free survival (rPFS). Overall survival (OS) was a key secondary endpoint.

Results

In total, 468 patients were randomised to ¹⁷⁷Lu-PSMA-617 (N= 234) or ARPI change (N= 234). Of those, 51 (21.8%) patients in the ¹⁷⁷Lu-PSMA-617 arms and 146 (62.4%) in the ARPI arm discontinued treatment due to rPD. Importantly, 84.2% of patients who discontinued treatment in the ARPI arm crossed over to ¹⁷⁷Lu-PSMA-617. The primary analysis, with a median follow-up of 7.3 months, met the primary endpoint of rPFS (HR[95%CI]: 0.41[0.29-0.56]; p< 0.0001). The second interim analysis, conducted after a median follow-up of 15.9 months, confirmed these results with a median rPFS of 12.02 months for ¹⁷⁷Lu-PSMA-617 compared to 5.59 months for ARPI change (HR[95%CI]: 0.43[0.33-0.54]). This rPFS benefit was consistent across the prespecified subgroups. Moreover, ¹⁷⁷Lu-PSMA-617 demonstrated a substantial overall response rate (ORR) benefit over ARPI change (50.7% vs. 14.9%, respectively), with complete responses observed in 21.1% and 2.7% of patients. The duration of response (DoR) was longer with ¹⁷⁷Lu-PSMA-617, with a median DoR of 13.63 months in the ¹⁷⁷Lu-PSMA-617 arm and 10.5 months in ARPI change. Additionally, a prostate-specific antigen (PSA) decrease of ≥50% was observed in 57.6% vs. 20.4% of patients in the ¹⁷⁷Lu-PSMA-617 and ARPI change arms, respectively. Time to symptomatic skeletal events was not reached in either of the arms but clearly favoured ¹⁷⁷Lu-PSMA-617 (HR[95%CI]: 0.35[0.22-0.57]). Time to composite health-related quality of life (HRQoL) or pain worsening, assessed by FACT-P total score and BPI-SF pain intensity scale, also favoured ¹⁷⁷Lu-PSMA-617 (HRs of 0.59 and 0.69, respectively). The prespecified crossover-adjusted OS analysis demonstrated a median OS of 19.25 vs. 19.55 months for ¹⁷⁷Lu-PSMA-617 and ARPI change, respectively (HR[95%CI]: 0.80[0.48-1.33]).

The incidence of grade 3-4 treatment-emergent adverse events (TEAEs) was lower in the ¹⁷⁷Lu-PSMA-617 arm than in the ARPI change arm (33.9% vs. 43.1%). Similarly, serious TEAEs (20.3% vs. 28%) and AEs leading to dose adjustments (3.5% vs. 15.1%) were lower in the ¹⁷⁷Lu-PSMA-617 arm. The most common TEAEs (≥10% of patients in each arm) included dry mouth (all grades, 57.3% vs. 2.2% in the ¹⁷⁷Lu-PSMA-617 and ARPI change arms, respectively), asthenia (31.7% vs. 28.9%), nausea (31.3% vs. 12.1%), anaemia (24.2% vs. 16.8%) and fatigue (22.9% vs. 25.4%). Importantly, grade 3-5 events were infrequent.

Conclusions

The PSMAfore trial demonstrates the superiority of ¹⁷⁷Lu-PSMA-617 over ARPI change in taxane-naïve patients with PSMA-positive mCRPC, achieving significant improvements in rPFS, ORR, time to symptomatic skeletal events, and quality of life. A positive trend in OS further underscores its potential, supported by a favourable safety profile.

Reference

Sartor O. Phase III trial of [¹⁷⁷Lu]Lu-PSMA-617 in taxane-naïve patients with metastatic castration-resistant prostate cancer (PSMAfore). Presented at ESMO 2023; Abstract LBA13.