In advanced hepatocellular carcinoma unsuitable for or progressing after locoregional therapy, does sorafenib improve survival compared with placebo? [SHARP]
In advanced hepatocellular carcinoma unsuitable for or progressing after locoregional therapy, does sorafenib improve survival compared with placebo?
Absolute Effect
Median OS was 10.7 vs 7.9 months; HR 0.69 (95% CI 0.55–0.87), P<.001. One-year OS was 44% vs 33%.
Absolute effect: One-year OS improved by 11 percentage points (44% vs 33%). Radiologic progression occurred later: median 5.5 vs 2.8 months, P<.001.
NNT: 10, based on 1-year overall survival (absolute improvement 11 percentage points).
NNH: 13, based on grade 3 hand–foot skin reaction (8% vs <1%; using the reported <1% comparator rate gives an approximate NNH of about 13–15 rather than a falsely precise integer).
Follow-up: The trial was stopped early at the second planned interim analysis after 321 deaths because the prespecified survival boundary was crossed.
Clinical results and treatment burden
- Intervention: Sorafenib 400 mg orally twice daily continuously until progression or unacceptable toxicity versus matching placebo.
- Principal toxicity: Drug-related adverse events were predominantly grade 1–2 gastrointestinal, constitutional and dermatologic effects. Grade 3 diarrhea was 8% vs 2%, and grade 3 hand–foot skin reaction 8% vs <1%. Dose reduction occurred in 26% vs 7%; discontinuation due to adverse events was 38% vs 37%.
- Other efficacy/recurrence findings: Symptomatic progression, one of the co-primary endpoints, was not significantly different (median 4.1 vs 4.9 months; P=.77). This distinction matters: the survival benefit was driven despite no significant improvement in that co-primary symptom endpoint.
- Quality of life: QoL was not the primary endpoint; treatment burden was reflected by dose modifications and characteristic toxicities.
Eligibility and clinical context
602 patients with advanced HCC not amenable to curative or locoregional therapy, predominantly Child-Pugh A and ECOG 0–2, without previous systemic treatment.
Limitations and maturity: The population was highly selected for liver function and performance status, and sorafenib is no longer the contemporary first-line standard in many patients. The trial remains foundational for proving that systemic therapy can extend survival in advanced HCC.