New study below [1].
"5. Conclusions"
"The final analysis of SPARTAN demonstrated that, in addition to improved MFS and time to symptomatic progression reported previously [12], the addition of apalutamide to ADT improves OS and lengthens time before initiation of cytotoxic chemotherapy in patients with nmCRPC; all primary and secondary end points were improved with apalutamide. With longer follow-up, the safety profile of apalutamide was similar to that shown in earlier reports."
"4. Discussion"
"In this prespecified, event-driven final analysis of SPARTAN, apalutamide improved OS compared with placebo in patients with nmCRPC reaching prespecified statistical significance, with 22% reduction in the hazard of death and a 14-mo increase in median OS. The survival benefit of apalutamide added to on-going ADT was observed despite the crossover of 19% of placebo-treated patients to apalutamide and the frequent use of subsequent life-prolonging therapy for metastatic prostate cancer in the placebo group (84%). Moreover, after crossover from placebo to apalutamide, the median treatment duration with apalutamide exceeded 2 yr (26.1 m), which is approximately double the median time on treatment reported for crossover patients in other studies in nmCRPC (ie, 14.5 mo in PROSPER and 11.0 mo in ARAMIS) [17], [18], [19]. In our study, two sensitivity analyses using independent methods (naive censoring and IPCW), to account for the patients receiving placebo crossing over to apalutamide, demonstrated consistent results and a 21-mo increase in median OS. These analyses delineated the impact of crossover treatment in the placebo arm. The treatment effect of apalutamide on survival was generally observed in the subpopulations evaluated, with exceptions in those with small numbers of patients. Additionally, treatment with apalutamide decreased the hazard of initiating cytotoxic chemotherapy by 37% compared with placebo.
"Taken together with data from the primary analysis, all end points in the SPARTAN study favoured treatment of patients with nmCRPC using apalutamide. This includes MFS, the primary end point, all secondary end points (time to metastasis, PFS, time to symptomatic progression, OS, and time to initiation of cytotoxic chemotherapy), as well as all exploratory end points (PFS2, PSA responses, and hazard of PSA progression), while preserving patient health-related quality of life [8], [12], [13].
"In SPARTAN, patients who progressed to metastatic disease were offered treatment with abiraterone acetate plus prednisone; >70% of patients in either arm received study-sponsored abiraterone acetate plus prednisone as the first subsequent therapy after progression (Supplementary Table 3). Among these patients, approximately half of the men progressing in either group received taxane chemotherapy. Of note, in terms of survival after metastasis in the apalutamide arm, the difference between median MFS and OS is 33.4 mo, which is similar to the previously reported median OS of 34.7 mo for the abiraterone acetate plus prednisone arm in the COU-AA-302 study of first-line treatment for metastatic CRPC [20]. In addition, the difference between median MFS and PFS2 in SPARTAN is 15.1 mo, which is close to the median radiographic PFS of 16.5 mo reported in COU-AA-302 [21]. Thus, early treatment of nmCRPC with apalutamide delays metastasis and, as shown by PFS2 and OS, lays the foundation for long-term clinical benefits. Baseline characteristics and biology of patients progressing after treatment with apalutamide who received abiraterone acetate plus prednisone as the first subsequent therapy in SPARTAN certainly have significant differences compared with baseline characteristics of patients included in the COU-AA-302 study, who had prior exposure to ADT alone. To understand continued benefit from different treatments, further investigations of cross-resistance mechanisms of androgen signalling inhibitors are needed. Recent in vitro studies highlighted potential cross-resistance in cells with high expression of androgen receptor variant 7 (ARv7) and aldo-keto reductase family 1 member C3 (AKR1C3) [22]. Preliminary results of the assessment of end-of-study-treatment patient samples from the apalutamide and placebo groups in SPARTAN demonstrated that in vivo rates of ARv7 expression in circulating free RNA were similar for apalutamide and placebo groups. No difference was observed between groups with respect to any other androgen receptor anomalies tested [23], [24]. Further research on resistance mechanisms to apalutamide is under way.
"At 52 mo of median follow-up, the safety profile of apalutamide remained consistent with that in prior reports [12], [13]. Rates of AEs leading to permanent treatment discontinuation were low, and disease progression was the most common reason for discontinuation in both groups. Although the median duration of treatment on study was almost three times longer (32.9 vs 11.5 mo) in the apalutamide group than in the placebo group, the rate of exposure-adjusted AEs in the apalutamide group (event rates/100 patient-years) did not change substantially. No new safety signals were detected with additional follow-up. These results suggest that early use of apalutamide before development of distant metastases on conventional imaging confers an overall advantage in oncologic outcome and extends survival. Conventional imaging is less sensitive than newer approaches such as prostate-specific membrane antigen ligand positron-emission tomography (PSMA-PET). Therefore, it is possible that some patients in SPARTAN whose disease was classified as nmCRPC by conventional imaging could have had low-volume metastatic disease. In a study by Fendler et al [25], a retrospective analysis of PSMA-PET imaging conducted in 200 patients diagnosed with nmCRPC by conventional imaging showed that 55% had M1 disease, based on a PSMA-PET assessment. Therefore, given the favourable outcomes for SPARTAN patients, and as also suggested in a recent editorial by van der Poel [26], apalutamide may also likely improve outcomes for patients with early M1 disease detectable with sensitive next-generation imaging techniques.
"The SPARTAN results, corroborated by other data from PROSPER (enzalutamide) and ARAMIS (darolutamide), show the benefit of adding an androgen signalling inhibitor to ADT for patients with nmCRPC and represent a major advance in treatment [12], [27], [28]. SPARTAN, PROSPER, and ARAMIS all met their primary end point of MFS. Each of the three studies also assessed the secondary end point of OS with longer follow-up recently [17], [18], [19]. Based on the results of these large randomised prospective studies and the maturation rate of data for MFS (earlier) versus OS (later), MFS appears to be relevant as an early indicator of long-term outcome in patients with nmCRPC. The findings support the US Food and Drug Administration's guidance on the use of MFS as a study end point [29]. A retrospective analysis of the relationship between MFS and OS in high-risk patients with nmCRPC concluded that metastasis development, regardless of time, is associated with a significantly greater hazard of death, and hence, MFS is predictive of OS [30]."
-Patrick
[1] sciencedirect.com/science/a...
Abstract
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 (240 mg/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.
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Abiraterone Acetate Plus Prednisone in Newly Diagnosed High-Risk Metastatic Castration-Sensitive Prostate Cancer: Final OS Results
Apalutamide for Metastatic Castration-Sensitive Prostate Cancer
