Third-line treatment and 177Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review

Abstract

Aims: There is a controversy as to the relative efficacy of ¹⁷⁷Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether ¹⁷⁷Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743).

Methods: The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model.

Results: Twelve studies including 669 patients reported ¹⁷⁷Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with ¹⁷⁷Lu-PSMA RLT. The treatment with ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA for imaging and therapy (I&T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. ¹⁷⁷Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). ¹⁷⁷Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ² test). Median survival was longer after ¹⁷⁷Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for ¹⁷⁷Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ² test).

Conclusions: As for patients with mCRPC, treatment with ¹⁷⁷Lu-PSMA-617 RTL and ¹⁷⁷Lu-PSMA I&T gave better effects and caused fewer adverse effects than third-line treatment.

Keywords: 177Lu-PSMA radioligand therapy; Abiraterone; Cabazitaxel; Docetaxel; Enzalutamide; Prostate cancer; Systematic review.

Fig. 1

a Flow chart of the selection process for articles with ¹⁷⁷Lu-PSMA RLT. b Flow chart of the selection process for selection of articles with third-line treatment

Fig. 2

a Funnel plot of a best PSA decline of ≥50% in articles of ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA I&T. b Funnel plot of a best PSA decline ≥50% in evaluable articles of third-line treatment

Fig. 3

Forest plot showing the frequency of a best PSA decline of ≥50% in 12 articles with ¹⁷⁷Lu-PSMA RLT, ¹⁷⁷Lu-PSMA-617, and ¹⁷⁷Lu-PSMA I&T (10 articles) gave a higher frequency of a best PSA decline of ≥50% than given by ¹⁷⁷Lu-PSMA-J591 (2 articles). The forest plot shows pooled estimates of the frequency of a best PSA decline of ≥50% with 95% confidence intervals shown as a line

Fig. 4

Forest plot regarding the frequency of a best PSA decline of ≥50% in 16 articles of third-line treatment. The frequency of a best PSA decline of ≥50% increased summarizing 3 articles with abiraterone, 5 articles with enzalutamide, and 8 articles with cabazitaxel. The forest plot shows pooled estimates of the frequency of best PSA decline of ≥50%, with the 95% confidence interval shown as a line

Fig. 5

Boxplots show effect endpoints for 177Lu-PSMA RLT and third-line treatment. a Frequency of best PSA decline of ≥50%. b Frequency of objective remission. c Overall survival. The boxes show the 5, 50, and 75% percentiles. The whiskers show the full range