PSA Decline After Lutetium Lu 177 Vipivotide Tetraxetan Treatment Prolongs Survival in PSMA-Positive mCRPC

Andrew J. Armstrong, MD, MSc

The decline of prostate-specific antigen (PSA) at 12 weeks following treatment with lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) plus standard of care (SOC) was linked with prolonged radiographic progression-free survival (rPFS) and overall survival (OS) in patients with progressive prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC), according to data from a post hoc analysis of the phase 3 VISION trial (NCT03511664).¹

Findings presented at the ESMO 2022 Congress showed that patients who had a PSA decline of more than 90% (n = 83) at 12 weeks achieved a median rPFS of 20.3 months (95% CI, 16.2–not estimable [NE]). The median rPFS was 3.6 months (95% CI, 2.6-4.4) for patients who had no decline in PSA at 12 weeks (n = 161; HR, 0.11; 95% CI, 0.07-0.19).

Patients who had a PSA decline of more than 50% and no more than 90% (n = 152) at 12 weeks had a median rPFS of 11.1 months (95% CI, 9.8-11.8). This translates into a 73% reduction in the risk of radiographic progression or death vs the no decline subgroup (HR, 0.27; 95% CI, 0.19-0.37).

Those with a 12-week PSA decline of more than 0 and no more than 50% (n = 95) achieved a median rPFS of 8.3 months (95% CI, 6.0-10.4). This translates into a 54% reduction in the risk of radiographic progression or death vs the no PSA decline subgroup (HR, 0.46; 95% CI, 0.32-0.67).

The 6-month rPFS rates in the no decline, 0 to ≤ 50%, > 50% to ≤ 90%, and > 90% subgroups at 12 weeks were 26.8%, 64.6%, 84.8%, and 97.8%, respectively. The 12-month rPFS rates in those groups were 5.7%, 18.8%, 39.6%, and 69.6%, respectively, and the 18-month rPFS rates were 4.3%, 10.7%, 19.1%, and 59.0%, respectively.

“These findings suggest that PSA decline is of prognostic importance for clinical outcomes during radioligand therapy with [lutetium Lu 177 vipivotide tetraxetan] in patients with PSMA-positive mCRPC,” lead study author Andrew J. Armstrong, MD, MSc, a medical oncologist at Duke Cancer Institute Center for Prostate or Urologic Cancers, and colleagues, wrote in a poster presentation of the data.

Prior data from the VISION trial showed that the combination of lutetium Lu 177 vipivotide tetraxetan and SOC prolonged rPFS and OS compared with SOC alone in patients with progressive, PSMA-positive mCRPC who received prior treatment with at least 1 androgen receptor (AR) pathway inhibitor and 1 to 2 taxane regimens, meeting the primary end points of the study.

In March 2022, the FDA approved lutetium Lu 177 vipivotide tetraxetan for the treatment of adult patients with PSMA-positive mCRPC who have previously received other anticancer therapies, such as AR pathway inhibition and taxane-based chemotherapy, based on data from VISION.²

Prior results also showed that PSA response, which was a secondary end point, was higher in the experiential arm vs the control arm at 46% and 7.1%, respectively (odds ratio, 11.19; 95% CI, 6.25-20.04).

This post hoc analysis evaluated the outcomes of patients treated with lutetium Lu 177 vipivotide tetraxetan to investigate the relationship between the magnitude of PSA decline from baseline and clinical outcomes. Patients enrolled in VISION were randomly assigned 2:1 to receive intravenous infusions of lutetium Lu 177 vipivotide tetraxetan at 7.4 GBq every 6 weeks for up to 6 cycles plus SOC, or SOC alone.

Investigators assessed PSA levels at baseline and at the start of each treatment cycle. Patients were classified into 4 subgroups, based on PSA decline from baseline to week 12, plus best overall PSA decline from baseline. Health-related quality of life (HRQoL) was also assessed by the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire.

Of the 551 evaluable patients treated with lutetium Lu 177 vipivotide tetraxetan, 28% had a best overall PSA decline of more than 90%, 20% experienced a best overall PSA decline of more than 50% and no more than 90%, 14% had a best overall PSA decline of more than 0 to no more than 50%, and 27% had no PSA decline overall.

For patients who had a best overall PSA decline of more than 90%, the median rPFS was 19.7 months (95% CI, 17.0-20.6), compared with 3.0 months (95% CI, 2.4-3.7) for patients who had no PSA decline overall (HR, 0.04; 95% CI, 0.02-0.08).

Patients with a best overall PSA decline of more than 50% to no more than 90% experienced a median rPFS of 8.8 months (95% CI, 8.5-10.8) for an 80% reduction in risk of radiographic progression or death vs no decline in PSA (HR, 0.20; 95% CI, 0.14-0.30). Those who had a best overall PSA decline of more than 0 to no more than 50% achieved a median rPFS of 6.0 months (95% CI, 4.2-8.6) for a 60% reduction in risk of radiographic progression or death vs no decline in PSA (HR, 0.40; 95% CI, 0.26-0.60).

Among patients who had a more than 90% decline in PSA at 12 weeks, the median OS was NE (95% CI, 20.9-NE). In comparison, the median OS was 9.3 months (95% CI, 8.2-11.2) in patients who had no decline at 12 weeks (HR, 0.15; 95% CI, 0.10-0.24).

Patients who saw a PSA decline of more than 50% and no more than 90% at 12 weeks experienced a median OS of 18.3 months (95% CI, 16.2-21.4) for a 63% reduction in risk of radiographic progression or death vs no decline in PSA (HR, 0.37; 95% CI, 0.28-0.49). Additionally, those who had a PSA decline of more than 0 to no more than 50% at 12 weeks achieved a median OS of 14.0 months (95% CI, 11.5-15.3) for a 41% reduction in risk of radiographic progression or death vs no decline in PSA (HR, 0.59; 95% CI, 0.44-0.80).

The 6-month OS rates in the no decline, 0 to ≤ 50%, > 50% to ≤ 90%, and > 90% groups at 12 weeks were 69.3%, 93.7%, 98.7%, and 98.8%, respectively. The 12-month OS rates in those groups were 38.7%, 56.8%, 75.0%, and 95.0%, respectively, and the 18-month rPFS rates were 21.4%, 36.2%, 54.6%, and 76.4%, respectively.

For patients with a best overall PSA decline of more than 90%, the median OS was NE (95% CI, 26.8-NE), vs 8.4 months (95% CI, 7.3-9.5) for patients who had no PSA decline overall (HR, 0.10; 95% CI, 0.07-0.15).

Patients with a best overall PSA decline of more than 50% and no more than 90% achieved a median OS of 15.0 months (95% CI, 13.9-17.8) for a 58% reduction in risk for radiographic progression or death vs the no PSA decline overall subgroup (HR, 0.42; 95% CI, 0.32-0.56). Furthermore, patients who had a best overall PSA decline of more than 0 to no more than 50% experienced a median OS of 12.0 months (95% CI , 10.3-14.0) for a 42% reduction in risk for radiographic progression or death vs the no PSA decline overall subgroup (HR, 0.58; 95% CI, 0.43-0.79).

Additionally, declines in PSA were associated with delayed worsening of HRQoL. In patients who had a 12-week PSA decline of more than 90%, the median time to worsening (TTW) of FACT-P score was 11.3 months (95% CI, 6.9-15.6), compared with 3.3 months (95% CI, 2.5-3.9) in the no PSA decline subgroup. The median TTW of FACT-P score was 8.0 months (95% CI, 6.4-10.7) and 6.2 months (95% CI, 4.6-7.9) in the > 50% to ≤ 90% and 0 to ≤ 50% PSA decline subgroups, respectively.

References

1. Armstrong AJ, Sartor O, Saad F, et al. Association between prostate-specific antigen decline and clinical outcomes in patients with metastatic castration-resistant prostate cancer in the VISION trial. Ann Oncol. 2022;33(suppl 7):S616-S652. doi:10.1016/annonc/annonc1070
2. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. News release. FDA; March 23, 2022. Accessed September 13, 2022. https://bit.ly/3LaWA8w