Apalutamide and Overall Survival in Prostate Cancer

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TAKE-HOME MESSAGE

The recent SPARTAN study reported apalutamide to improve metastasis-free survival by 2 years in nonmetastatic castration-resistant prostate cancer (nmCRPC), but overall survival data were immature. This study follow-up provided a longer-term to evaluate overall survival. A total of 1207 patients with nmCRPC (diagnosed by conventional imaging) were randomized 2:1 to apalutamide or placebo plus ongoing androgen-deprivation therapy. Of note, 19% of patients still receiving placebo crossed over to apalutamide during unblinding. At median 52-months' follow-up, the authors found that overall survival was markedly longer with apalutamide versus placebo (73.9 vs 59.9 months; HR, 0.78). Apalutamide also lengthened the time to chemotherapy compared with placebo.

The authors concluded that apalutamide in nmCRPC confers a 22% reduction in the hazard of death (despite 19% crossover). These findings support the value of apalutamide as a treatment option for nmCRPC.

– Gautam Jayram, MD

Urology

Written by Emmanuel S Antonarakis MD

This study represents the mature analysis of overall survival from the SPARTAN study, a randomized trial of apalutamide versus placebo for nonmetastatic CRPC. The current analysis shows that, in addition to improving metastasis-free survival, there are now compelling data for an overall survival improvement using apalutamide for CRPC patients before the onset of metastatic disease. Taken together with the results of the PROSPER trial (enzalutamide vs placebo) and the ARAMIS trial (darolutamide vs placebo), both of which also showed a survival advantage with the use of novel antiandrogen therapy in the nonmetastatic CRPC setting, there is now substantial evidence of significant clinical benefit when using all three agents before the onset of metastatic disease. However, the question that is not answered by any of these trials is whether androgen-deprivation therapy should be started in the first place for nonmetastatic biochemically recurrent prostate cancers or what triggers should be used to decide when to start androgen-deprivation therapy in biochemically recurrent patients.

BACKGROUND

The phase 3 SPARTAN study evaluated apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and prostate-specific antigen doubling time of ≤10 mo. At primary analysis, apalutamide improved median metastasis-free survival (MFS) by 2 yr and overall survival (OS) data were immature.

OBJECTIVE

We report the prespecified event-driven final analysis for OS.

DESIGN, SETTING, AND PARTICIPANTS

A total of 1207 patients with nmCRPC (diagnosed by conventional imaging) were randomised 2:1 to apalutamide (240mg/d) or placebo, plus on-going androgen deprivation therapy. After MFS was met and the study was unblinded, 76 (19%) patients still receiving placebo crossed over to apalutamide.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

OS and time to cytotoxic chemotherapy (TTChemo) were analysed by group-sequential testing with O'Brien-Fleming-type alpha spending function.

RESULTS AND LIMITATIONS

At median 52-mo follow-up, 428 deaths had occurred. The median treatment duration was 32.9 mo for apalutamide group and 11.5 mo for placebo group. Median OS was markedly longer with apalutamide versus placebo, reaching prespecified statistical significance (73.9 vs 59.9 mo, hazard ratio [HR]: 0.78 [95% confidence interval {CI}, 0.64-0.96]; p=0.016). Apalutamide also lengthened TTChemo versus placebo (HR: 0.63 [95% CI, 0.49-0.81]; p=0.0002). Discontinuation rates in apalutamide and placebo groups due to progressive disease were 43% and 74%, and due to adverse events 15% and 8.4%, respectively. Subsequent life-prolonging therapy was received by 371 (46%) patients in the apalutamide arm and by 338 (84%) patients in the placebo arm including 59 patients who received apalutamide after crossover. Safety was consistent with previous reports; when adverse events were adjusted for treatment exposure, rash had the greatest difference of incidence between the apalutamide and placebo groups.

CONCLUSIONS

Extension of OS with apalutamide compared with placebo conferred impactful benefit in patients with nmCRPC. There was a 22% reduction in the hazard of death in the apalutamide group despite 19% crossover (placebo to apalutamide) and higher rates of subsequent therapy in the placebo group.

PATIENT SUMMARY

With data presented herein, all primary and secondary study end points of SPARTAN were met; findings demonstrate the value of apalutamide as a treatment option for nonmetastatic castration-resistant prostate cancer.

European Urology

Apalutamide and Overall Survival in Prostate Cancer

Eur Urol 2020 Sep 06;[EPub Ahead of Print], MR Smith, F Saad, S Chowdhury, S Oudard, BA Hadaschik, JN Graff, D Olmos, PN Mainwaring, JY Lee, H Uemura, P De Porre, AA Smith, SD Brookman-May, S Li, K Zhang, B Rooney, A Lopez-Gitlitz, EJ Small

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.