177Lu-PSMA effective both in mCRPC and mHSPC

Recent results from the SPLASH and UpFrontPSMA trials showed an improved efficacy with ¹⁷⁷Lu-PSMA over standard treatments, both in metastatic castration-resistant (mCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC), respectively.

Until now, no prospective data was available concerning the Lu-PSMA radioligand ¹⁷⁷Lu-PNT2002, formerly known as ¹⁷⁷Lu-PSMA-I&T. Prof. Oliver Sartor (Tulane University, LA, USA) presented results of the phase 3 SPLASH trial (NCT04647526), which compared the efficacy and safety of ¹⁷⁷Lu-PNT2002 versus a second androgen receptor pathway inhibitor (ARPI) in patients with mCRPC who progressed on previous treatment with an ARPI [1]. The study randomised 412 participants 2:1 to ¹⁷⁷Lu-PNT2002 (up to 4 cycles) or alternate ARPI (i.e. enzalutamide or abiraterone). Upon radiographic progression, crossover from ARPI to ¹⁷⁷Lu-PNT2002 was allowed (84.6% did cross over).

The primary endpoint of radiographic progression-free survival (PFS) favoured ¹⁷⁷Lu-PNT2002 over ARPI treatment: median radiographic PFS was 9.5 versus 6.0 months, respectively (HR 0.71; 95% CI 0.55–0.92; P=0.0088). ¹⁷⁷Lu-PNT2002 treatment also came with a higher response rate: 38.1% best overall response versus 12% best response (P=0.0021). In addition, 35.7% of the participants on ¹⁷⁷Lu-PNT2002 achieved a ≥50% decrease of prostate-specific antigen (PSA), versus 14.6% in the ARPI arm (HR 0.58; 95% CI 0.44–0.76; P<0.0001).

In another presentation, Dr Arun Azad (Peter MacCallum Cancer Centre, Australia) was the first to report prospective data on the safety and efficacy of ¹⁷⁷Lu-PSMA treatment in patients with de novo, high-volume mHSPC [2]. The phase 2 UpFrontPSMA study (NCT04343885) compared the safety and efficacy of upfront ¹⁷⁷Lu-PSMA-617 versus standard docetaxel. Enrolled participants (n=130) were randomised 1:1 to 6 cycles of docetaxel or 2 cycles of ¹⁷⁷Lu-PSMA-617 followed by 6 cycles of docetaxel.

¹⁷⁷Lu-PSMA-617/docetaxel improved the rates of participants with undetectable PSA at 48 weeks over docetaxel alone: 41% versus 16% (OR 3.88; 95% CI 1.03–4.46; P=0.042). In addition, ¹⁷⁷Lu-PSMA-617 improved median PFS: 31 versus 20 months (HR 0.60; 95% CI 0.37–0.98; P=0.039).

In both trials, ¹⁷⁷Lu-PSMA did not increase adverse events, except for dry mouth.

1. Sartor AO, et al. Efficacy of 177Lu-PNT2002 in PSMA-positive mCRPC following progression on an androgen-receptor pathway inhibitor (ARPI) (SPLASH). Abstract LBA65, ESMO Congress 2024, 13–17 September, Barcelona, Spain.
2. Azad AA, et al. UpFrontPSMA: A randomised phase II study of sequential 177Lu-PSMA-617 and docetaxel (D) versus docetaxel in metastatic hormone-sensitive prostate cancer (mHSPC). Abstract LBA66, ESMO Congress 2024, 13–17 September, Barcelona, Spain.

 

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Posted on 4 November 20244 November 2024