Çağatay Arslan

Importance: Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. Objective: To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. Design, Setting, and Participants: This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Interventions: Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. Main Outcomes and Measures: The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Results: Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Conclusions and Relevance: Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT04063163.

BACKGROUND: Preclinical studies and results of a phase 2 trial of abiraterone and olaparib suggest a combined antitumor effect when the poly(adenosine diphosphate[ADP]-ribose) polymerase inhibitor olaparib is combined with next-generation hormonal agent abiraterone to treat metastatic castration-resistant prostate cancer (mCRPC). METHODS: We conducted a double-blind, phase 3 trial of abiraterone and olaparib versus abiraterone and placebo in patients with mCRPC in the first-line setting. Patients were enrolled regardless of homologous recombination repair gene mutation (HRRm) status. HRRm status was determined following enrollment by tumor tissue and circulating tumor DNA tests. Patients were randomly assigned (1:1) to receive abiraterone (1000 mg once daily) plus prednisone or prednisolone with either olaparib (300 mg twice daily) or placebo. The primary end point was imaging-based progression-free survival (ibPFS) by investigator assessment. Overall survival was among the secondary end points. RESULTS: At this planned primary analysis at the first data cutoff, median ibPFS was significantly longer in the abiraterone and olaparib arm than in the abiraterone and placebo arm (24.8 vs. 16.6 months; hazard ratio, 0.66; 95% confidence interval [CI], 0.54 to 0.81; P<0.001) and was consistent with blinded independent central review (hazard ratio, 0.61; 95% CI, 0.49 to 0.74). At this data cutoff, overall survival data were immature (28.6% maturity; hazard ratio, 0.86; 95% CI, 0.66 to 1.12; P=0.29). The safety profile of olaparib and abiraterone was consistent with the known safety profiles of the individual drugs. The most common adverse events in the abiraterone and olaparib arm were anemia, fatigue/asthenia, and nausea. CONCLUSIONS: At primary analysis at this first data cutoff, abiraterone combined with olaparib significantly prolonged ibPFS compared with abiraterone and placebo as first-line treatment for patients with mCRPC enrolled irrespective of HRRm status. (Funded by AstraZeneca and Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; ClinicalTrials.gov number, NCT03732820.)

11 Background: Preclinical studies have shown combined anti-tumor effect through interactions between poly(adenosine diphosphate–ribose) polymerase and androgen receptor signaling pathways. A Phase II trial (NCT01972217) in pts with mCRPC unselected by homologous recombination repair (HRR) status who previously received docetaxel demonstrated improved radiographic progression-free survival (rPFS) for pts treated with ola + abi vs pbo + abi (Clarke N, 2018). The Phase III PROpel study (NCT03732820) evaluates the efficacy and safety of ola + abi in the 1L mCRPC setting. Methods: PROpel is a randomized, double-blind, placebo-controlled Phase III trial in pts with mCRPC undergoing 1L treatment after failure of primary androgen deprivation therapy, enrolled independent of HRR status. Pts were randomized 1:1 to receive ola (300 mg twice daily [bid]) or pbo, and abi (1000 mg once daily) + prednisone or prednisolone (5 mg bid). The primary endpoint was investigator-assessed rPFS with multiple secondary endpoints, including overall survival (OS). Results:796 pts were randomized to ola + abi (n=399) or pbo + abi (n=397).In this planned interim analysis, 1L treatment with ola + abi significantly prolonged rPFS vs pbo + abi in pts with mCRPC irrespective of HRR status (24.8 vs 16.6 months; hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P &lt;0.0001). Predefined subgroup analyses showed rPFS improvement across all subgroups, including pts with (HR 0.54, 95% CI 0.36–0.79) and without (HR 0.76, 95% CI 0.59–0.97) HRR mutations detected by circulating tumor DNA testing. A sensitivity analysis of rPFS by blinded independent central review was consistent with the primary analysis (HR 0.61, 95% CI 0.49–0.74; P=0.004). OS is currently immature with 228 deaths (28.6%). A trend in OS favoring ola + abi was observed (HR 0.86, 95% CI 0.66–1.12). Secondary endpoints of time to first subsequent treatment (HR 0.74, 95% CI 0.61–0.90) and time to second progression-free survival or death (HR 0.69, 95% CI 0.51–0.94) were supportive of long-term benefits. The most common grade ≥3 adverse event (AE) reported was anemia (15.1 vs 3.3%) for ola + abi vs pbo + abi; 13.8 vs 7.8% pts, respectively, discontinued ola/pbo because of an AE. The rate of AEs leading to abi discontinuation were similar in both arms (8.5 vs 8.8%). Conclusions: At interim analysis, PROpel met its primary objective, demonstrating significant improvement in rPFS for ola + abi vs pbo + abi in pts with newly detected mCRPC who had not received prior 1L therapy, irrespective of HRR status. The safety and tolerability profile of ola + abi was consistent with the known safety profiles of the individual drugs. These results demonstrate the benefit of ola + abi without the need for HRR stratification in 1L treatment of mCRPC. Pt follow-up is ongoing for the planned OS analysis. Clinical trial information: NCT03732820.