Nomograms predictive of outcomes with novel PSMA-targeted agent in mCRPC

A study recently published in the Lancet Oncology suggested that nomograms could predict outcomes with the PSMA-targeted agent Lutetium-177–PSMA-617 (¹⁷⁷Lu-PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC).¹

Investigators used data from 2 previous phase 2 studies (NCT03042312, ACTRN12615000912583) to retrospectively assess patients who had been treated with ¹⁷⁷Lu-PSMA for overall survival (OS) and prostate-specific antigen (PSA)–progression-free survival (PFS).

“These externally validated nomograms that are predictive of outcomes after ¹⁷⁷Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where ¹⁷⁷Lu-PSMA is introduced as a novel therapeutic option,” wrote the study investigators who were led by Andrei Gafita, MD, of the University of California Los Angeles.

This study population was comprised of 270 patients who were divided into 2 cohorts for nomogram development (n = 196) and independent validation (n = 74). Forty patients (10%) started treatment after the cutoff date, 86 (21%) were given 18F-labelled PSMA-PET, and 9 (2%) were lost to follow-up.

Of the total cohort examined, 113 patients were enrolled on a clinical trial compared with 157 patients who received ¹⁷⁷Lu-PSMA as part of a compassionate access programs. Treatment was administered for a median of 3 cycles per patient, with each cycle including a 1-time injections of ¹⁷⁷Lu-PSMA at 6.0 to 8.5 GBq every 6 to 8 weeks. Prior treatment in 257 patients included second-generation antiandrogens whereas 219 had experience with chemotherapy.

The primary end points were PSA-PFS and OS with a secondary end point of PSA decline of 50% (PSA50) or more form the baseline during treatment.

Some predictors used to assess OS were time since initial diagnosis of prostate cancer, chemotherapy status, baseline hemoglobin concentration, and characteristics of PET/CT. PSA-PFS was defined as time from treatment to PSA progression or death.

Median duration of follow-up was 21.5 months. At the last follow-up, 225 patients had died and 245 had experienced PSA progression. Median OS and PSA-PFS were similar between cohorts, with 12-month and 18-month OS rates of 54% and 34%, respectively, across all patients.

The estimated at PSA-PFS rate at 3 months was 64%, whereas at 6 months it was estimated to be 38%,

Patients in the cohorts were described as either having high- or low-risk disease and based on calculated optimal cutoff in the risk score of 197 points for the OS nomogram and 178 points for the PSA-PFS nomogram. In low-risk patients in the development cohort, median OS was 19.1 months compared with 8.4 months in high-risk patients (P <.0001). Median OS for low-risk patients in the validation cohort was 24.9 months compared with 7.4 months for high-risk (P <.0001). In the entire cohort, OS for low-risk was 19.9 months and 8.2 months for high-risk (P <.0001).

¹⁷⁷Lu-PSMA in low- and high-risk patients resulted in a median PSA-PFS of 9.4 and 3.3 months, respectively, in the development cohort (P <.0001); 6.6 months and 2.5 months in the validation cohort (P = .022); and 8.8 months versus 3.3 months in the entire cohort (P <.0001).

For the secondary end point of PSA50, the area under the curve for the validation cohort was 0.78%. Investigators used a cutoff of 41 points for stratification, resulting in a sensitivity of 94% and a specificity of 38% to determine responders or non-responders. The positive predictive value was 54% and the negative predictive value was 89%.

“Our nomograms support preclinical findings and suggest that high levels of tumor PSMA expression is a requisite for favorable outcome following ¹⁷⁷Lu-PSMA (higher PSMA expression is associated with longer overall survival and PSA-progression-free survival, and greater likelihood of PSA 50% decline),” wrote the study investigators.

Reference

1. Gafita A, Calais J, Grogan TR, et al. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study [published online ahead of July 8, 2021]. Lancet Oncol. doi:10.1016/S1470-2045(21)00274-6