Health-related quality of life and pain outcomes with [177Lu]Lu-PSMA-617 plus standard of care versus standard of care in patients with metastatic castration-resistant prostate cancer (VISION): a multicentre, open-label, randomised, phase 3 trial

Abstract

Background: In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [¹⁷⁷Lu]Lu-PSMA-617 (vipivotide tetraxetan) improved radiographic progression-free survival and overall survival when added to protocol-permitted standard of care in patients with metastatic castration-resistant prostate cancer. Here, we report additional health-related quality of life (HRQOL), pain, and symptomatic skeletal event results.

Methods: This multicentre, open-label, randomised, phase 3 trial was conducted at 84 cancer centres in nine countries in North America and Europe. Eligible patients were aged 18 years or older; had progressive PSMA-positive metastatic castration-resistant prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; and had previously received of at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens. Patients were randomly assigned (2:1) to receive either [¹⁷⁷Lu]Lu-PSMA-617 plus protocol-permitted standard of care ([¹⁷⁷Lu]Lu-PSMA-617 group) or standard of care alone (control group) using permuted blocks. Randomisation was stratified by baseline lactate dehydrogenase concentration, liver metastases, ECOG performance status, and androgen receptor pathway inhibitor inclusion in standard of care. Patients in the [¹⁷⁷Lu]Lu-PSMA-617 group received intravenous infusions of 7·4 gigabecquerel (GBq; 200 millicurie [mCi]) [¹⁷⁷Lu]Lu-PSMA-617 every 6 weeks for four cycles plus two optional additional cycles. Standard of care included approved hormonal treatments, bisphosphonates, and radiotherapy. The alternate primary endpoints were radiographic progression-free survival and overall survival, which have been reported. Here we report the key secondary endpoint of time to first symptomatic skeletal event, and other secondary endpoints of HRQOL assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-5L, and pain assessed with the Brief Pain Inventory-Short Form (BPI-SF). Patient-reported outcomes and symptomatic skeletal events were analysed in all patients who were randomly assigned after implementation of measures designed to reduce the dropout rate in the control group (on or after March 5, 2019), and safety was analysed according to treatment received in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, NCT03511664, and is active but not recruiting.

Findings: Between June 4, 2018, and Oct 23, 2019, 831 patients were enrolled, of whom 581 were randomly assigned to the [¹⁷⁷Lu]Lu-PSMA-617 group (n=385) or control group (n=196) on or after March 5, 2019, and were included in analyses of HRQOL, pain, and time to first symptomatic skeletal event. The median age of patients was 71 years (IQR 65-75) in the [¹⁷⁷Lu]Lu-PSMA-617 group and 72·0 years (66-76) in the control group. Median time to first symptomatic skeletal event or death was 11·5 months (95% CI 10·3-13·2) in the [¹⁷⁷Lu]Lu-PSMA-617 group and 6·8 months (5·2-8·5) in the control group (hazard ratio [HR] 0·50, 95% CI 0·40-0·62). Time to worsening was delayed in the [¹⁷⁷Lu]Lu-PSMA-617 group versus the control group for FACT-P score (HR 0·54, 0·45-0·66) and subdomains, BPI-SF pain intensity score (0·52, 0·42-0·63), and EQ-5D-5L utility score (0·65, 0·54-0·78). Grade 3 or 4 haematological adverse events included decreased haemoglobin (80 [15%] of 529 assessable patients who received [¹⁷⁷Lu]Lu-PSMA-617 plus standard of care vs 13 [6%] of 205 who received standard of care only), lymphocyte concentrations (269 [51%] vs 39 [19%]), and platelet counts (49 [9%] vs five [2%]). Treatment-related adverse events leading to death occurred in five (1%) patients who received [¹⁷⁷Lu]Lu-PSMA-617 plus standard of care (pancytopenia [n=2], bone marrow failure [n=1], subdural haematoma [n=1], and intracranial haemorrhage [n=1]) and no patients who received standard of care only.

Interpretation: [¹⁷⁷Lu]Lu-PSMA-617 plus standard of care delayed time to worsening in HRQOL and time to skeletal events compared with standard of care alone. These findings support the use of [¹⁷⁷Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer who received previous androgen receptor pathway inhibitor and taxane treatment.

Funding: Advanced Accelerator Applications (Novartis).

Figure 1:. CONSORT diagram

CT=computed tomography. PET=positron emission tomography. PSMA=prostate-specific membrane antigen. The number in parentheses indicate the numbers of patients who underwent randomisation after the enhanced trial-site education measures implemented on or after March 5, 2019, as reported in Methods.

Figure 2:. Time to worsening in FACT-P total score (A), BPI-SF pain intensity scale (B), and EQ-5D-5L utility score (C)

BPI-SF=Brief Pain Inventory – Short Form. CI=confidence interval. EQ-5D-5L=EuroQol 5-dimension 5-level. FACT-P=Functional Assessment of Cancer Therapy–Prostate. PSMA=prostate-specific membrane antigen. SoC=standard of care. Testing was two-sided using the Cox model (Wald Chi-square test). All p values are nominal, descriptive, and non-inferential. Analyses in the 581 patients randomised after measures were implemented on or after March 5, 2019. (A) Time to worsening of 10 points or greater in FACT-P total score, clinical disease progression, or death (prespecified analysis) and time to worsening of 10 points or greater in FACT-P total score (post hoc analysis); (B) Time to worsening of 30% or greater or 2 points or greater in BPI-SF pain intensity, clinical disease progression, or death (prespecified analysis) or time to worsening of 30% or greater or 2 points or greater in BPI-SF pain intensity (post hoc analysis); (C) Time to worsening in EQ-5D-5L utility score was defined as the time to the first occurrence of worsening in utility score relative to baseline (no change or any decrease).

Figure 3:. Haemoglobin (A), platelet (B), and creatinine (C) levels during randomised treatment

C=cycle. EOT=End of treatment. PSMA=prostate-specific membrane antigen. SoC=standard of care. W=week. Plot shows boxes (25th–75th percentiles) with the median as a horizontal line. The dots in the boxes and joint lines represent the mean values. Whiskers (vertical lines) extend to the 10th–90th percentiles. Values outside this range are not displayed. CxWy: Cycle x Week y Day 1. Cycle visits were scheduled every 6 weeks for the first six cycle visits and then every 12 weeks. This analysis only includes assessments up to the time point at which there are at least 10 patients in each of the treatment groups. Platelet values ≥100 000 10⁹/L at C6W5 were not converted to correct standardized units and were excluded from the analysis. Analyses in the 734 patients who received at least one dose of randomised treatment.