Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial

PURPOSE

In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. We report overall survival (OS) after a 7-year follow-up, a clinically relevant time point and the longest follow-up for any poly(ADP-ribose) polymerase inhibitor in the first-line setting.

METHODS

This double-blind phase III trial randomly assigned patients with newly diagnosed advanced ovarian cancer and a BRCA mutation in clinical response to platinum-based chemotherapy to maintenance olaparib (n = 260) or placebo (n = 131) for up to 2 years. A prespecified descriptive analysis of OS, a secondary end point, was conducted after a 7-year follow-up.

RESULTS

The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, and the median follow-up was 88.9 and 87.4 months, respectively. The hazard ratio for OS was 0.55 (95% CI, 0.40 to 0.76; P = .0004 [P < .0001 required to declare statistical significance]). At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups.

CONCLUSION

Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.

INTRODUCTION

The ultimate goal of treatment in women newly diagnosed with ovarian cancer is cure. However, disease is often advanced at the time of diagnosis and approximately 70% of patients who receive cytoreductive surgery followed by first-line platinum-based chemotherapy will relapse within 3 years,¹ with a 10-year survival of 17% in patients with advanced epithelial ovarian cancer.² Relapsed advanced ovarian cancer is typically incurable, highlighting the need for effective first-line treatments that delay relapse, prolong survival, and enhance the potential for cure.

CONTEXT

• Key Objective

• No overall survival (OS) benefit has yet been reported for poly(ADP-ribose) polymerase inhibitor maintenance therapy in women with newly diagnosed advanced ovarian cancer. The authors here report OS with maintenance olaparib in SOLO1 patients with newly diagnosed advanced BRCA-mutated ovarian cancer after a 7-year follow-up.

• Knowledge Generated

• Results indicate a clinically meaningful, albeit not statistically significant, improvement in OS with maintenance olaparib versus placebo, with two thirds of olaparib patients, versus fewer than half of placebo patients, alive at 7 years. No new safety signals were observed.

• Relevance (G. Fleming)

• The SOLO1 data support the use of maintenance olaparib therapy in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation.*

  *Relevance section written by JCO Associate Editor Gini Fleming, MD.

The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib represents the new standard of care in the management of patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. In the pivotal SOLO1/GOG 3004 trial, maintenance olaparib provided a sustained progression-free survival (PFS) benefit beyond the end of treatment, which was capped at 2 years, in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation.^3,4 In the primary analysis (data cutoff [DCO]: May 17, 2018), maintenance olaparib provided a significant PFS benefit compared with placebo (hazard ratio [HR], 0.30; 95% CI, 0.23 to 0.41; P < .001).³ In an updated PFS analysis conducted after a 5-year follow-up (DCO: March 5, 2020), the median PFS was 56.0 months in the olaparib group compared with 13.8 months in the placebo group (HR, 0.33; 95% CI, 0.25 to 0.43).⁴ On the basis of Kaplan-Meier estimates, 48.3% versus 20.5% of patients, respectively, were progression-free at 5 years; overall survival (OS) data were immature.⁴

We report a descriptive analysis of OS after a 7-year follow-up in SOLO1. To our knowledge, this is the longest follow-up for any PARP inhibitor in newly diagnosed advanced ovarian cancer and the first report of long-term OS data for any PARP inhibitor in this setting. Seven years is considered a clinically relevant time point for survivorship, as modeling indicates that most ovarian cancer–related deaths occur within 7 years of diagnosis, with mortality approaching that of women in the general population after a 9-year follow-up.⁵

METHODS

Study Design and Patients

The design of the randomized, double-blind, placebo-controlled, international, phase III SOLO1/GOG 3004 study has been reported previously.³ In brief, eligible patients had newly diagnosed, histologically confirmed advanced (International Federation of Gynaecology and Obstetrics [FIGO] stage III or IV) high-grade serous or endometrioid ovarian, primary peritoneal, and/or fallopian tube cancer.

Patients were eligible for SOLO1 regardless of the timing of cytoreductive surgery or surgical outcome. Patients with FIGO stage III disease had undergone an attempt at optimal upfront or interval cytoreductive surgery, and those with FIGO stage IV disease had undergone a biopsy and/or upfront or interval cytoreductive surgery. Patients had a germline or somatic BRCA1 and/or BRCA2 mutation on local or central testing and were in clinical complete or partial response after first-line platinum-based chemotherapy (without bevacizumab). Patients who had received prior PARP inhibitor therapy or who had a history or myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) were ineligible. Full eligibility criteria are given in the Data Supplement (online only).

The study Protocol (online only) was approved by the ethics committees at each participating site and performed in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and the AstraZeneca policy on bioethics.⁶ All patients provided written informed consent.

Treatment

Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg twice daily) or placebo within 8 weeks of receiving their last dose of chemotherapy. Random assignment was stratified according to clinical response (complete or partial) after platinum-based chemotherapy. Patients received treatment for up to 2 years or until investigator-assessed objective radiologic disease progression (according to modified RECIST, version 1.1), whichever occurred first, or treatment was stopped if other discontinuation criteria were met (Data Supplement). Patients with no evidence of disease at 2 years stopped receiving study treatment, but patients with evidence of disease at 2 years could continue to receive study treatment in a blinded manner if, in the opinion of the investigator, this was in the patient's best interest. Within the study, crossover between the treatment groups was not permitted. After study treatment discontinuation, patients could receive subsequent therapies at the investigators' discretion.

Outcomes

Secondary end points reported in this analysis are OS (defined as the time from random assignment to death because of any cause), time from random assignment to first subsequent therapy or death (TFST), time from random assignment to second subsequent therapy or death (TSST), time from random assignment to discontinuation of study treatment or death (TDT), and safety and tolerability. Adverse events (AEs) were monitored using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.0) throughout the treatment period and for 30 days after discontinuation of study treatment. In addition, patients were proactively followed for MDS/AML and new primary malignancies beyond the 30-day post-treatment safety follow-up period.

Investigator-assessed PFS, the primary end point,^3,4 and additional end points^3,4,7,8 have been reported previously.

Statistical Analysis

Efficacy was analyzed in all randomly assigned patients (full analysis set), and safety was analyzed in all patients who received at least one dose of randomized treatment.

This prespecified descriptive OS analysis was conducted 7 years after the last patient was randomly assigned (DCO: March 7, 2022). A final OS analysis is currently planned to be conducted at approximately 60% data maturity as prespecified in the study Protocol.³ OS was analyzed using a log-rank test stratified by response to first-line platinum-based chemotherapy, with HRs and 95% Cls estimated using a Cox proportional hazards model, including the stratification variable as a covariate. OS was not adjusted for subsequent PARP inhibitor therapy. A two-sided P value of < .0001 was required to declare statistical significance (Haybittle-Peto α = .0001). Kaplan-Meier methods were used to generate time-to-event curves, from which medians and survival proportions were calculated.

Analyses of TFST, TSST, and TDT were performed using a method similar to that used for the analysis of OS.

All statistical analyses were performed using SAS software version 9.4 (SAS Institute Inc, Cary, NC).

RESULTS

All 260 patients randomly assigned to olaparib and 130 of the 131 patients randomly assigned to placebo received study treatment (one patient assigned to placebo withdrew before receiving the intervention; Fig 1). Baseline characteristics were well balanced between the treatment groups (Data Supplement).

FIG 1.

CONSORT diagram of patients. AE, adverse event; DCO, data cutoff.

For this descriptive OS analysis, DCO (March 7, 2022) took place 7 years after the last patient was randomly assigned, with a median (interquartile range) duration of follow-up for OS of 88.9 (85.7-93.6) months in the olaparib group and 87.4 (84.3-91.7) months in the placebo group. The median (range) duration of treatment in the safety analysis set was 24.6 (0.0-97.5) months in the olaparib group, consistent with the 2-year treatment cap, and 13.9 (0.2-60.9) months in the placebo group. Study treatment was completed at 2 years, per the study Protocol, in 123 olaparib patients (47.3%) and 35 placebo patients (26.9%; Fig 1); 111 patients (42.7%) and 92 patients (70.8%), respectively, discontinued study treatment before 2 years, and 26 patients (10.0%) and three patients (2.3%), respectively, continued study treatment beyond 2 years. Seven of the 13 patients who were receiving olaparib at the primary DCO (May 17, 2018)³ were still receiving olaparib at the current DCO.

At DCO (March 7, 2022), 149 of 391 patients had died (data maturity 38.1%). The median OS was not reached (95% CI, not reached to not reached) in the olaparib group compared with 75.2 months (95% CI, 65.4 to not reached) in the placebo group, with an HR of 0.55 (95% CI, 0.40 to 0.76; P = .0004 [P < .0001 required to declare statistical significance]; Fig 2). This analysis was unadjusted for subsequent therapy, and the OS benefit was achieved despite 44.3% of patients in the placebo group having received a PARP inhibitor in a subsequent line of therapy (Table 1). Of the 122 olaparib patients and 97 placebo patients who received any subsequent therapy (Data Supplement), 31.1% and 59.8%, respectively, received a PARP inhibitor. On the basis of Kaplan-Meier estimates, 67.0% of olaparib patients versus 46.5% of placebo patients were alive 7 years after random assignment.

FIG 2.

Kaplan-Meier estimates of OS. HR, hazard ratio; NR, not reached; OS, overall survival.

TABLE 1.

Subsequent PARP Inhibitor Therapy

The median TFST (data maturity 59.6%) was 64.0 months (95% CI, 47.7 to 93.2) with olaparib compared with 15.1 months (95% CI, 12.7 to 20.5) with placebo, with an HR of 0.37 (95% CI, 0.28 to 0.48; Fig 3A). On the basis of Kaplan-Meier estimates, 45.3% of olaparib patients versus 20.6% of placebo patients were alive and had not received a first subsequent treatment after a 7-year follow-up. At the time of DCO, 122 (46.9%) patients in the olaparib group and 95 (72.5%) in the placebo group had received a first subsequent therapy (Data Supplement).

FIG 3.

Kaplan-Meier estimates of (A) TFST and (B) TSST. HR, hazard ratio; TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death.

The median TSST (data maturity 48.6%) was 93.2 months (95% CI, 84.2 to not reached) with olaparib compared with 40.7 months (95% CI, 32.9 to 54.4) with placebo, with an HR of 0.50 (95% CI, 0.37 to 0.67; Fig 3B). On the basis of Kaplan-Meier estimates, 56.9% of olaparib patients versus 32.5% of placebo patients were alive and had not received a second subsequent treatment after a 7-year follow-up. At the time of DCO, 68 (26.2%) patients in the olaparib group and 59 (45.0%) in the placebo group had received a second subsequent therapy (Data Supplement).

Consistent with the results reported previously,⁴ the median TDT (data maturity 98.2%) was 24.6 months (95% CI, 24.0 to 24.8) in the olaparib group compared with 13.8 months (95% CI, 11.2 to 16.4) in the placebo group, with an HR of 0.63 (95% CI, 0.51 to 0.78; Data Supplement).

After a 7-year follow-up, the safety profile of maintenance olaparib was consistent with that reported at previous DCOs.^3,4 The most common AEs of any grade reported in olaparib patients were nausea, fatigue/asthenia, vomiting, and anemia, and the most common grade ≥ 3 AE was anemia (Table 2). Serious AEs occurred in 21.2% of olaparib patients and 13.8% of placebo patients. The most commonly reported serious AEs were anemia (7.3% of olaparib patients v 0.0% of placebo patients) and neutropenia (1.5% v 0.0%).

TABLE 2.

Summary of AEs^a

Data on MDS/AML and new primary malignancies were collected both during study treatment and after discontinuation of study treatment up to the time of DCO (March 7, 2022). Since the primary DCO (May 17, 2018), one (0.4%) new case of MDS has been reported in the olaparib group and one (0.8%) new case of acute myelomonocytic leukemia has been reported in the placebo group. In total, after a 7-year follow-up, four (1.5%) cases of MDS/AML were reported in the olaparib group and one (0.8%) case of MDS/AML was reported in the placebo group. In total, after a 7-year follow-up, new primary malignancies were reported in 14 (5.4%) olaparib patients (breast cancer [n = 10], lip and/or oral cavity cancer [n = 1], thyroid cancer [n = 1], pancreatic adenocarcinoma [n = 1], and gall bladder adenocarcinoma [n = 1]) and eight (6.2%) placebo patients (breast cancer [n = 5], lung adenocarcinoma [n = 1], squamous cell carcinoma of the tongue [n = 1], and chronic myeloid leukemia [n = 1]). Six (2.3%) new primary malignancies occurred in olaparib patients, and three (2.3%) occurred in placebo patients since the March 5, 2020, DCO.

AEs were usually managed by dose interruption or reduction, with few patients (11.9% of olaparib patients and 3.1% of placebo patients) requiring treatment discontinuation because of AEs (Table 2).

DISCUSSION

The median duration of follow-up of approximately 88 months reported in this descriptive SOLO1 analysis represents the longest follow-up for any PARP inhibitor in newly diagnosed advanced ovarian cancer. With an HR for OS of 0.55 (95% CI, 0.40 to 0.76) observed with maintenance olaparib (administered for ≤ 2 years in most patients) versus placebo and 67.0% of olaparib patients (v 46.5% of placebo patients) alive at 7 years, SOLO1 is the first study to indicate a clinically meaningful improvement in OS with PARP inhibitor maintenance therapy in the first-line setting.

Data maturity for OS was 38.1% in the current analysis, and the SOLO1 final OS analysis is currently planned to be conducted once data maturity reaches approximately 60%.³ Given that the event rate for OS is slower than that anticipated at the onset of the study and it may be many years before the threshold to conduct the final OS analysis is met, performing a descriptive OS analysis at 7 years, a clinically relevant time point, was important to help inform treatment decisions. The Haybittle-Peto α spending function required a P < .0001 to show statistical significance in the current descriptive analysis (administrative α spending), allowing the statistical power of the final OS analysis to be preserved. Although not reaching the threshold for statistical significance, we consider the OS benefit shown in this 7-year descriptive analysis to be clinically meaningful. Given the 5-year survival rate of 38.1% previously reported in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation,⁹ the 5-year and 7-year OS rates of 73.1% and 67.0%, respectively, seen in SOLO1 patients receiving maintenance olaparib represent an important advance; it should be noted that OS rates in SOLO1 were calculated from the time of random assignment rather than from the time of diagnosis.

It is difficult to demonstrate improvements in OS in ovarian cancer trials because of the number and variety of uncontrolled postprogression treatment options including experimental agents.^10,11 In this descriptive OS analysis, more than 40% of placebo patients (v 14.6% of olaparib patients) received subsequent therapy with a PARP inhibitor (and 59.8% of placebo patients v 31.1% of olaparib patients who received any subsequent therapy received a PARP inhibitor); this is likely to have affected the OS results, which were unadjusted for subsequent PARP inhibitor therapy. Subsequent treatment with a PARP inhibitor may also partly explain the relatively long median OS of 75.2 months observed in the placebo arm. This compares with a median OS of 58.3 months in patients, irrespective of biomarker status, who were in clinical complete response after first-line platinum-based chemotherapy and enrolled in the surveillance arm of the phase III GOG 0212 trial; < 20% of patients were alive and progression-free after a median follow-up in the overall patient population of 8.1 years.¹² BRCA-mutated patients in the placebo arm of the phase III GOG 0218 trial had a median OS of 61.2 months¹³; it should be noted that compared with SOLO1, patients in GOG 0218 had a worse prognosis (patients with FIGO stage III disease and complete resection after cytoreductive surgery were excluded), and random assignment in GOG 0218 occurred before the start of chemotherapy. Advances in the management of relapsed ovarian cancer, including improvements in the sequencing of therapies and supportive care, might have also contributed to the median OS seen in placebo patients in SOLO1. OS results from other ongoing trials evaluating PARP inhibitor maintenance therapy in the newly diagnosed setting (eg, combination maintenance therapy with olaparib plus bevacizumab in PAOLA-1,¹⁴ maintenance niraparib in PRIMA,¹⁵ and maintenance rucaparib in ATHENA-MONO¹⁶) are awaited with interest.

The results of SOLO1 emphasize the importance of both testing for both germline and somatic BRCA mutations and providing PARP inhibitor maintenance therapy to all BRCA-mutated patients with advanced disease in the first-line setting, rather than delaying the introduction of PARP inhibitors until patients have experienced relapse. On the basis of the results of SOLO1, maintenance therapy with olaparib is capped at 2 years in the first-line setting although patients with evidence of disease at this time point can be treated beyond 2 years.^17,18 This descriptive OS analysis (DCO March 7, 2022) confirms findings from earlier PFS analyses in SOLO1 (DCO May 17, 2018,³ and March 5, 2020⁴) that the benefit of maintenance olaparib extends well beyond its 2-year treatment cap in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation. Indeed, the SOLO1 OS data support the use of maintenance olaparib to achieve long-term remission in BRCA-mutated patients with newly diagnosed advanced ovarian cancer.

It is noteworthy that for a considerable proportion of olaparib patients, the SOLO1 OS data reflect disease-free survival. Although updated PFS data are not available, TFST was evaluated as a proxy for PFS.¹⁹ TFST data showed a substantial delay with maintenance olaparib versus placebo in the time between random assignment and the first subsequent treatment, with 45.3% of olaparib patients (v 20.6% of placebo patients) alive and still to receive a first subsequent therapy after a 7-year follow-up. These data suggest that maintenance olaparib might enhance the potential for cure although longer follow-up is needed for a more definitive evaluation of cure. Modeling data suggest that 10-year survival appears to be an appropriate surrogate of cure in this setting.⁵

TSST data are also consistent with the previously reported PFS benefit^3,4 and indicate that the benefit of maintenance olaparib persists beyond the first subsequent therapy.¹⁹

After a 7-year follow-up, the safety profile of maintenance olaparib was consistent with that reported at earlier DCOs (May 17, 2018,³ and March 5, 2020⁴), with no new safety signals detected. It is reassuring that the incidence of MDS/AML remained low and the incidence of new primary malignancies remained balanced between the treatment arms after 7 years of active follow-up for these events in SOLO1. Only one new case of MDS/AML has been reported in the olaparib arm since the primary DCO on May 17, 2018. The low risk of MDS/AML observed in SOLO1 is consistent with that reported in other PARP inhibitor maintenance therapy trials in the newly diagnosed setting.^14-16 A higher incidence of MDS/AML has been observed in PARP inhibitor maintenance therapy trials in patients with relapsed ovarian cancer.^20,21 The incidence of MDS/AML in the relapsed disease setting should be considered in the context of potential baseline risk factors for MDS/AML (eg, prior chemotherapy with DNA-damaging agents) and the long latency of these events. A contributing role for PARP inhibitors cannot be excluded, and long-term active surveillance for MDS/AML events after discontinuation of PARP inhibitor maintenance therapy is prudent.

In conclusion, after a 7-year follow-up, results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib versus placebo in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation. These data support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced.

APPENDIX

TABLE A1.

List of SOLO1 Principal Investigators for Each Site That Randomly Assigned Patients in the Study

DATA SHARING STATEMENT

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

AUTHOR CONTRIBUTIONS

Conception and design: Paul DiSilvestro, Giovanni Scambia, Gabe S. Sonke, Amit Oza, Elizabeth S. Lowe, Kathleen N. Moore

Administrative support: John McNamara

Provision of study materials or patients: Susana Banerjee, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Michael Friedlander, Alla Lisyanskaya, Anne Floquet, Alexandra Leary, Gabe S. Sonke, Charlie Gourley, Amit Oza, Antonio González-Martín, Carol Aghajanian, William Bradley, Cara Mathews, Joyce Liu, Kathleen N. Moore

Collection and assembly of data: Susana Banerjee, Nicoletta Colombo, Giovanni Scambia, Byoung-Gie Kim, Ana Oaknin, Michael Friedlander, Alla Lisyanskaya, Anne Floquet, Alexandra Leary, Gabe S. Sonke, Charlie Gourley, Amit Oza, Antonio González-Martín, Carol Aghajanian, William Bradley, Cara Mathews, Joyce Liu, John McNamara, Elizabeth S. Lowe, Mei-Lin Ah-See, Kathleen N. Moore

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial

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