177Lu-PSMA-617: A new class of effective therapy

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains invariably fatal. The VISION study showed for men with advanced-stage prostate-specific membrane antigen (PSMA)-positive mCRPC after androgen receptor pathway inhibition and chemotherapy, adding ¹⁷⁷Lu-PSMA-617 to standard-of-care treatment extended both overall survival (OS) and radiographic progression-free survival (rPFS). In addition, ¹⁷⁷Lu-PSMA-617 was well tolerated.

PSMA is highly expressed in many but not all prostate cancer cells. ¹⁷⁷Lu-PSMA-617 is a targeted radioligand therapy that delivers β-particle radiation, which induces DNA damage and double-strand breaks, to PSMA-expressing cells and surrounding microenvironment, destroying cancer cells.

VISION

In the phase 3 VISION trial (NCT03511664), 831 patients were randomised 2:1 to receive ¹⁷⁷Lu-PSMA-617 in combination with standard of care (SOC) or SOC alone. SOC was investigator-determined but excluded cytotoxic chemotherapy and radium-223. The 2 treatment arms were well balanced in terms of demographics and baseline characteristics.

The median study follow-up was 20.9 months. The trial met its prespecified endpoint of rPFS. ¹⁷⁷Lu-PSMA-617 plus SOC significantly improved rPFS versus SOC alone (median rPFS 8.7 vs 3.4 months; HR 0.40; one-sided P<0.001; see Figure). The alternate primary endpoint of OS was also significantly improved for ¹⁷⁷Lu-PSMA-617 plus SOC versus SOC alone (median OS 15.3 vs 11.3 months; HR 0.62; one-sided P<0.001; see Figure). According to Prof. Johann de Bono (The Institute of Cancer Research, London, UK), these findings support the adoption of ¹⁷⁷Lu-PSMA-617 as a new treatment modality in patients with mCRPC [1].

Figure: Primary endpoints of OS and rPFS in VISION [1]



CI, confidence interval; rPFS, radiographic progression-free survival; OS, overall survival; PSMA, prostate-specific membrane antigen; SOC, standard-of-care.
Figure kindly provided by Prof. De Bono.

TheraP

The investigator-initiated, phase 2 TheraP trial (NCT03392428) aimed to determine the activity and safety of ¹⁷⁷Lu-PSMA-617 in patients with mCRPC who had progressed after docetaxel. Prof. Michael Hofman (Peter MacCallum Cancer Centre, Melbourne, Australia) explained that patient characteristics of TheraP and VISION were comparable. Prior to randomisation, all patients (n=200) underwent ⁶⁸Ga-PSMA PET-CT and ¹⁸F-FDG PET-CT. The participants were randomised to ¹⁷⁷Lu-PSMA-617 or cabazitaxel [2].

The primary endpoint was a PSA response of ≥50% from baseline. PSA responses were significantly higher among men who received ¹⁷⁷Lu-PSMA-617 compared with those receiving cabazitaxel (66% vs 37%; P<0.0001). In addition, ¹⁷⁷Lu-PSMA-617 delayed progression when measured with PSA or rPFS at 12 months: PFS was 3% in the cabazitaxel arm versus 19% in the ¹⁷⁷Lu-PSMA-617 arm (HR 0.63; 95% CI 0.46–0.86; P=0.0028). The observed PFS benefit was similar when measured radiographically (rPFS; HR 0.64; P=0.007) or based on PSA (PSA-PFS; HR 0.60; P=0.002). Among 78 men with measurable disease, objective response rates were significantly greater in the ¹⁷⁷Lu-PSMA-617 arm (49%) versus the cabazitaxel arm (24%; RR 2.1; P=0.019). The OS analysis has not yet been performed for TheraP.

With respect to grade 3–4 AEs, the incidence of thrombocytopenia was higher in the ¹⁷⁷Lu-PSMA-617 arm (11% vs 0%), whereas more neutropenic events with or without fever occurred in the cabazitaxel arm (13% vs 4%).

Patient-reported outcomes demonstrated improved quality of life in several domains for ¹⁷⁷Lu-PSMA-617 versus cabazitaxel, particularly those related to chemotherapy side effects, such as skin rash, palmar/plantar soreness, hair loss, altered taste, dizziness, urinary symptoms, and diarrhoea. Those do not occur with ¹⁷⁷Lu-PSMA-617 but can be problematic with cabazitaxel. Overall, quality of life was similar between the 2 arms.

The deterioration-free survival, defined as the time to ≥10-point decrease in QLQ-C30 global health status, progression, death, or treatment discontinuation, favoured the ¹⁷⁷Lu-PSMA-617 arm at all time points.

TheraP versus VISION

Next, Prof. Hofman compared the TheraP and VISION trials: “VISION is a phase 3 registration study, providing definitive evidence of an improvement in OS. TheraP perhaps takes this treatment one step earlier by comparing ¹⁷⁷Lu-PSMA-617 directly with cabazitaxel instead of initiating after cabazitaxel.”

The treatment schedules were very similar, with a median of 5 cycles of ¹⁷⁷Lu-PSMA-617 in both studies. There were differences in the percentage of patients excluded from the trial (28% for TheraP vs 12% for VISION) and in the PSA response rate of ≥50% (66% for TheraP vs 46% for VISION).

Prof. Hofman concluded that the combined results of TheraP and VISION showed that ¹⁷⁷Lu-PSMA-617 is a new class of effective therapy. “¹⁷⁷Lu-PSMA-617 improves outcomes in men with mCRPC following docetaxel and androgen receptor directed therapies. The TheraP study provided some information on activity compared with cabazitaxel, where ¹⁷⁷Lu-PSMA-617 appears superior with fewer grade 3–4 AEs and improved quality of life. Optimal patient selection, sequencing, and monitoring of ¹⁷⁷Lu-PSMA-617 will continue to evolve.”

1. De Bono J. Phase 3 study of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). Game changing session 5, EAU21 Virtual, 8–12 July 2021.


2. Hofman M. TheraP Phase 2 trial of Lu-PSMA-617 versus cabazitaxel: Results and contrasts to VISION. Game changing session 5, EAU21 Virtual, 8–12 July 2021.

 

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Posted on 31 August, 202131 August, 2021