Apalutamide and Overall Survival in Prostate Cancer
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
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.
Additional Info
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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 SmallFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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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.
Apalutamide has previously been demonstrated to have an overall survival benefit for those with metastatic castrate-sensitive cancer, and here there is additional follow-up that demonstrates an overall survival benefit, despite crossover in patients with nonmetastatic CRPC. The study design has previously been covered; but, importantly, noting that no molecular imaging was utilized. Just conventional CAT scans and bone scans were used to define eligibility for the study.
In addition, the PSA doubling time was restricted to those individuals with 10 months or less. In evaluating this population, there was a clear benefit in terms of overall survival, and the hazard ratio in the intent to treat, they want to get this right. In the intent to treat analysis was 0.78 with a P value of .046. There was a considerable number of patients who crossed over in this study, and, taking them into account, there was a larger overall survival benefit, with hazard ratio of 0.69, with a P value of .0002.
The analysis evaluated a number of subsets, and even though the number of patients aged less than 65 years was relatively low, there did appear to be a particular benefit in those men under the age of 65 years. Mature data were also presented on the time to PSA progression, which is an endpoint of interest for many, and the time to placebo PSA progression was 3.7 months, with an apalutamide median of 40.5. Obviously, quite a large difference in the time to PSA progression.