25% reduction in the risk of death in patients with nmCRPC treated with apalutamide

The second interim analysis of the randomised, phase 3 SPARTAN trial showed that apalutamide continued to offer a metastasis-free survival (MFS) benefit over placebo for patients with non-metastatic (M0) castration-resistant prostate cancer (CRPC) with higher risk (PSA doubling time ≤10 months prior to trial entry), and reduced the risk of death by 25% [1]. These findings were simultaneously published in the Annals of Oncology [2].

Prof. Matthew Smith (Massachusetts General Hospital, Boston, USA) presented the final MFS analysis and the second interim analysis for overall survival. Not surprisingly, the MFS benefit was sustained.  The fist interim analysis was reported last year at ESMO 2018. In this year’s longer median follow-up of 41 months, 4-year overall survival (OS) rates were 72.1% for patients treated with apalutamide and 64.7% for patients treated with placebo, but this was not quite significant. Overall, a 25% reduction in the risk of death was observed for patients receiving apalutamide compared with placebo (HR 0.75; 95% CI 0.59-0.96; P=0.0197; to reach statistical significance in their model, a P-value of P<0.0121 was predetermined as the the O’Brien-Fleming boundary). The OS benefit of apalutamide was consistent across baseline subgroups, including race, prior treatments, baseline PSA and performance status.

This current interim analysis took place when 67% of the required OS events had been observed, as opposed to last year when only 24% of required OS events had occurred (HR 0.70; 95% CI 0.47-1.04; P=0.07). After unblinding of the study and prior to the second interim analysis, 76 non-progressing patients in the placebo group (19% of the placebo arm) crossed over to open-label apalutamide; the OS rates in the placebo group included those patients who crossed-over to apalutamide treatment. The third and final OS analysis will occur in 2022 at 427 (100%) events.

The rates of treatment-emergent adverse events for apalutamide at the second interim analysis were consistent with rates previously reported. The most common adverse events (≥10%) were fatigue, hypertension, rash, diarrhoea, nausea, weight loss, arthralgia, falls, hot flush, decreased appetite, fracture, and peripheral oedema.

The exploratory progression-free survival 2 (PFS2) analysis, where patients were followed from randomisation beyond the initial progression on either apalutamide or placebo until the second progression, confirmed a clinical benefit (HR 0.55; 95% CI 0.45-0.68; P<0.0001, see Figure).

Figure. Results of time to second objective disease progression (PFS2) from the SPARTAN study.



(provided by ESMO)

In summary, although the OS data is still not statistically significant at this time, the study will continue to follow the patients on the trial.  Regardless of the ultimate results from the future final OS analysis, this data supports treating patients with high risk M0 CRPC with apalutamide, given the confirmed MFS benefit from the primary endpoint analysis.

1. Smith MR et al. ESMO Congress 2019. Abstract 8430.
2. Small EJ et al. Ann Oncol. 2019 Sep 27.

Posted on 26 November, 201918 March, 2021