Introduction

Olaparib is a PARP inhibitor is approved for advanced ovarian cancer with germline BRCA mutations after ≥3 prior chemotherapy lines. 

Aim 

SOLO 3  evaluated the efficacy & safety of olaparib monotherapy compared with physician’s choice of single-agent nonplatinum chemotherapy in patients with germline BRCA-mutated, platinum-sensitive relapsed ovarian cancer who had received at least two prior platinum-based chemotherapy lines

Patient Profile

• Adults (≥18 years) with platinum-sensitive relapsed high-grade serous or endometrioid ovarian cancer (including primary peritoneal cancer and/or fallopian tube cancer)
• Germline BRCA mutation (BRCA1/2), ≥2 prior platinum-based chemotherapy lines, measurable or assessable disease.

Methods

• Phase III, randomized, controlled, open-label trial 
• 266 patients were randomized in 2:1 ratio
  1. 178 patients received Olaparib tablets (300 mg twice daily)
  2. 88 patients received physician’s choice of single agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan)

Endpoints

• Primary: Objective Response Rate .
• Secondary: Progression-Free Survival , Overall Survival, safety, and exploratory BRCA reversion mutation analysis.

Follow-up Duration 

• Olaparib arm: 48.9 months 
• Chemotherapy arm: 25.4 months

Results 

Treatment Exposure

Survival Outcomes

• Olaparib improved objective response rate (ORR) ORR 72.2% vs 51.4% (OR 2.53; P = .002); PFS HR 0.62; median 13.4 vs 9.2 months (P = .01).
• Overall Survival was Similar between groups: HR = 1.07; median OS: 34.9 months (olaparib) vs 32.9 months (chemotherapy).
• Progression-Free Survival favoured olaparib: HR = 0.62; median PFS: 13.4 vs 9.2 months.

Figure 1: Overall Outcomes

 

• Olaparib improved Objective Response Rate 72.2% vs Chemotherapy: 51.4%. ( OR 2.53, P = .002)
• Subgroup Analysis Outcomes by Number of Prior Chemotherapy Lines
• In patients with two previous lines of treatment, olaparib improved  OS and PFS 
• In patients with ≥3 previous lines of treatment,  OS was better with chemotherapy whereas PFS and ORR still favoured olaparib.

Table 1: Study Outcomes by Number of Prior Chemotherapy Lines (Post Hoc)

Subgroup	ORR (%) Olaparib vs Chemotherapy	PFS median (mo) Olaparib vs Chemotherapy	OS median (mo) Olaparib vs Chemotherapy
2 previous lines	85.5 vs 60.5 (HR=3.85)	16.4 vs 9.0 (HR 0.46)	37.9 vs 28.8 (HR=0.83)
3 previous lines	67.6 vs 31.8 (HR=4.46)	11.1 vs 7.4 (HR 0.43)	25.2 vs 32.9 (HR=1.20)
≥3 previous lines	58.7 vs 41.2 (HR=2.03)	9.4 vs 9.2	29.9 vs 39.4 (HR=1.33)
≥4 previous lines	50.0 vs 58.3 (HR=0.71)	7.4 vs NC	30.2 vs 43.2 (HR=1.58)

Objective Response Rate (ORR);Progression-Free Survival (PFS);Overall Survival (OS)

Impact of BRCA Reversion Mutations

1. Baseline BRCA reversion mutations detected in 3.5% of olaparib patients was mostly in those with ≥4 prior lines.
2. No objective responses in patients with BRCA reversion mutations.

Safety 

1. Long-term olaparib safety remained consistent with prior analyses; no new safety signals were identified.
2. Disease progression was the most common reason for treatment discontinuations; withdrawals before death were lower with olaparib (10.7%) vs chemotherapy (25%).

Conclusion

• Final overall survival (OS) in the SOLO3 trial was comparable between olaparib and nonplatinum chemotherapy. 
• OS outcomes favoured olaparib in patients with two prior chemotherapy lines, whereas a potential detrimental effect was observed in those with three or more lines (post hoc analysis). 
• Baseline BRCA reversion mutations may influence subsequent treatment response and likely contributed to later-line OS findings.

Reference

J Clin Oncol 43:1408-1416