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Clinical Trial
. 2019 Nov 1;30(11):1813-1820.
doi: 10.1093/annonc/mdz397.

Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer

E J Small  1 , F Saad  2 , S Chowdhury  3 , S Oudard  4 , B A Hadaschik  5 , J N Graff  6 , D Olmos  7 , P N Mainwaring  8 , J Y Lee  9 , H Uemura  10 , P De Porre  11 , A A Smith  12 , K Zhang  13 , A Lopez-Gitlitz  14 , M R Smith  15
Affiliations
Clinical Trial

Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer

E J Small et al. Ann Oncol. .

Abstract

Background: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2).

Methods: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed.

Results: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed.

Conclusion: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

Keywords: apalutamide; non-metastatic castration-resistant prostate cancer; overall survival; subsequent therapy.

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Figures

Figure 1.
Figure 1.
Overall survival (A) Kaplan–Meier estimates, (B) adjusted for patient crossover from placebo to apalutamide, and (C) forest plot subgroup analysis by baseline patient characteristics. Analyses for the Kaplan–Meier plot (Figure 1A) were stratified, and those for the forest plot were unstratified. Kaplan–Meier estimates of OS for patients (D) with prior radical prostatectomy or radiation therapy and (E) without prior radical prostatectomy or radiation therapy. For Figure 1B, inverse probability of censoring weighted (IPCW) and naive-censored Kaplan–Meier estimates of overall survival for placebo arm are presented along with the standard Kaplan–Meier estimates of overall survival for apalutamide arm and placebo arm. Patients at risk are presented for the naive-censored curve. Patients at risk for the IPCW curve are not included due to lack of clear clinical interpretation on the number of patients at risk associated with the weighted methodology.
Figure 1.
Figure 1.
Continued.
Figure 2.
Figure 2.
Kaplan–Meier estimates of (A) time to initiation of cytotoxic chemotherapy and (B) second progression-free survival.
See this image and copyright information in PMC

Comment in

References

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