New England Journal of Medicine DECEMBER 27, 2018

Olaparib Maintenance Monotherapy in Patients with Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation (SOLO-1)

Kathleen N. Moore, Nicoletta Colombo, Giovanni Scambia, et al.

Bottom Line

In patients with newly diagnosed advanced BRCA-mutated ovarian cancer, maintenance therapy with olaparib significantly prolonged progression-free survival compared to placebo following a clinical response to platinum-based chemotherapy.

Key Findings

1. At a median follow-up of 41 months, the risk of disease progression or death was reduced by 70% in the olaparib group compared to the placebo group (hazard ratio, 0.30; 95% CI, 0.23 to 0.41; P<0.001).

2. The 3-year progression-free survival rate was 60.4% in the olaparib arm compared to 26.9% in the placebo arm.

3. Long-term (7-year) follow-up analysis demonstrated a sustained benefit, with an overall survival hazard ratio of 0.55 (95% CI, 0.40 to 0.76), representing a 45% reduction in the risk of death.

4. Adverse events were consistent with the known profile of olaparib; common grade 3 or higher adverse events included anemia (22%) and neutropenia (8%).

Study Design

Design

RCT

Double-Blind

Sample

391

Patients

Duration

88.9 mo

Median

Setting

Multicenter, international

Population Women with newly diagnosed, FIGO stage III or IV, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian-tube cancer with a confirmed BRCA1/2 mutation who were in clinical complete or partial response following first-line platinum-based chemotherapy.

Intervention Olaparib 300 mg tablets administered orally twice daily for up to 2 years.

Comparator Matching placebo administered orally twice daily for up to 2 years.

Outcome Progression-free survival as assessed by the investigator.

Study Limitations

• The study was limited to patients with BRCA mutations, which restricts the generalizability of these findings to the broader ovarian cancer population without such mutations.

• The 2-year cap on treatment duration was a protocol decision that may not fully capture the optimal duration of therapy for all patients, despite the observed enduring benefit.

• While overall survival was a secondary endpoint, the study was not initially powered to detect a formal statistical difference in overall survival at the initial interim analysis.

Clinical Significance

The SOLO-1 trial established olaparib as a standard-of-care maintenance therapy for patients with newly diagnosed, BRCA-mutated advanced ovarian cancer who achieve a response to platinum-based chemotherapy, significantly altering the treatment paradigm by offering a substantial, durable improvement in progression-free and overall survival.

Historical Context

Prior to SOLO-1, the use of PARP inhibitors was largely limited to the recurrent setting. SOLO-1 was the first Phase 3 trial to demonstrate that move-up maintenance therapy with a PARP inhibitor could provide a landmark, long-term survival advantage in the first-line treatment setting for ovarian cancer.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Explain the concept of 'synthetic lethality' and why it makes Olaparib particularly effective in patients with BRCA1 or BRCA2 mutations.

Key Response

BRCA proteins are essential for homologous recombination repair (HRR) of double-strand DNA breaks. PARP inhibitors block base excision repair of single-strand breaks, which then convert to double-strand breaks. In BRCA-mutated cells, both repair pathways are compromised, leading to genomic instability and cell death (synthetic lethality), while normal cells with one functional BRCA allele can still repair the damage.

Resident

In a patient with newly diagnosed Stage III high-grade serous ovarian cancer who has achieved a complete response to platinum-based chemotherapy, what is the recommended duration of Olaparib maintenance according to the SOLO-1 protocol, and when should it be discontinued earlier?

Key Response

According to SOLO-1, Olaparib maintenance is administered for up to 2 years. It should be discontinued earlier if there is evidence of disease progression or unacceptable toxicity. If a patient still has evidence of disease (partial response) at 2 years, the investigator may consider continuing the treatment.

Fellow

The SOLO-1 trial demonstrated a Hazard Ratio of 0.30 for progression-free survival. Discuss how the trial's exclusion of patients with 'no evidence of disease' after surgery but prior to chemotherapy impacts the generalizability of these results to the 'R0' resection population.

Key Response

SOLO-1 required patients to have a clinical response (CR or PR) to chemotherapy. While many R0 patients (no visible residual disease after primary debulking) fall into this category, the trial specifically confirms the benefit in those who had measurable or detectable disease that responded to platinum. This reinforces the idea that PARP inhibitors are most effective when the tumor is 'platinum-sensitive,' which serves as a functional assay for HRD status.

Attending

With 7-year follow-up data showing that nearly half of the olaparib group remained progression-free compared to 20% in the placebo group, how does this study redefine the 'cure' expectations for BRCA-mutated advanced ovarian cancer?

Key Response

The plateau in the Kaplan-Meier curve suggests that a significant proportion of patients may achieve long-term remission or even a cure. This shifts the treatment paradigm from simply delaying recurrence in a chronic disease to aiming for a definitive cure in the first-line setting, emphasizing the critical importance of early germline and somatic BRCA testing.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Analyze the statistical implications of the 'median progression-free survival' not being reached in the Olaparib arm for several years. How does this affect the power of the study to detect a difference in Overall Survival (OS) given the high crossover rate and subsequent use of PARP inhibitors in the placebo arm?

Key Response

When the median is not reached, the Hazard Ratio becomes the primary driver of effect size. However, OS analysis is frequently confounded by 'post-progression' therapies (crossover). In SOLO-1, many placebo patients received PARP inhibitors upon recurrence, which can dilute the OS benefit, requiring sophisticated statistical modeling like Rank-Preserving Structural Failure Time (RPSFT) to estimate the true survival advantage.

Journal Editor

Critically appraise the use of 'investigator-assessed PFS' as the primary endpoint in SOLO-1 versus 'blinded independent central review' (BICR). What bias might this introduce in an unblinded or maintenance setting?

Key Response

While SOLO-1 was double-blinded, reducing observer bias, investigator-assessed PFS can sometimes differ from BICR due to local interpretation of imaging. However, the SOLO-1 authors performed a sensitivity analysis using BICR which showed a highly consistent HR (0.28), strengthening the internal validity and reassuring editors that the investigator assessment was robust and not overly optimistic.

Guideline Committee

Based on the SOLO-1 findings, how do current NCCN and ASCO guidelines prioritize PARP maintenance relative to Bevacizumab in BRCA-mutated patients, and is there evidence to support using both concurrently in the first-line setting?

Key Response

NCCN guidelines (Version 1.2024) strongly recommend Olaparib as a Category 1 maintenance therapy for BRCA-mutated patients. While SOLO-1 looked at Olaparib monotherapy, the PAOLA-1 trial later showed that adding Olaparib to Bevacizumab also provides significant benefit in HRD-positive/BRCAm patients. Guidelines currently suggest Olaparib monotherapy is a preferred standard for BRCAm, reserving the combination for patients who started Bevacizumab during chemotherapy.

Clinical Landscape

Noteworthy Related Trials

2019

PAOLA-1 Trial

n = 806 · NEJM

Tested

Olaparib plus bevacizumab

Population

Patients with newly diagnosed advanced ovarian cancer regardless of BRCA mutation status

Comparator

Placebo plus bevacizumab

Endpoint

Progression-free survival

Key result: The addition of olaparib to maintenance bevacizumab provided a significant progression-free survival benefit in the overall population, particularly in those with homologous recombination deficiency.

2019

PRIMA Trial

n = 733 · NEJM

Tested

Niraparib

Population

Patients with newly diagnosed advanced ovarian cancer responding to first-line platinum-based chemotherapy

Comparator

Placebo

Endpoint

Progression-free survival

Key result: Niraparib maintenance therapy significantly prolonged progression-free survival compared to placebo across all patient subgroups, including those without BRCA mutations.

2019

VELIA Trial

n = 1140 · NEJM

Tested

Veliparib plus chemotherapy followed by veliparib maintenance

Population

Patients with newly diagnosed high-grade serous ovarian carcinoma

Comparator

Chemotherapy plus placebo followed by placebo maintenance

Endpoint

Progression-free survival

Key result: The addition of veliparib to chemotherapy and continued as maintenance resulted in significantly longer progression-free survival compared to chemotherapy alone, regardless of the clinical status of BRCA mutations.

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