SOLO1 and PAOLA-1: Clinically meaningful OS benefit with first-line maintenance olaparib in BRCA- or HRD-mutated advanced ovarian cancer

Bevacizumab in combination with carboplatin and paclitaxel was approved for the first-line treatment of patients with advanced ovarian cancer,1 despite the lack of overall survival (OS) advantage over chemotherapy alone in the ICON7 and GOG-0218 trials.2,3 Recently, poly (adenoside phosphate [ADP]-ribose) polymerase (PARP) inhibitors, such as olaparib, niraparib and rucaparib, expanded the treatment landscape, with improvements in PFS when used as maintenance therapy in the first-line setting but unclear long-term benefit.4–8 At the ESMO Congress 2022, the long-awaited OS data from the placebo-controlled, phase III studies SOLO19 (olaparib) and PAOLA-110 (olaparib plus bevacizumab) were presented. Both trials included patients with newly diagnosed advanced (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV), high-grade serous or endometrioid ovarian cancer, primary peritoneal or fallopian tube cancer; while SOLO1 was restricted to patients with BRCA-mutated tumors, PAOLA-1 followed an all-comers design. SOLO-1 had a prespecified, 7-year post-last-patient-in descriptive OS analysis and a planned final analysis at ~60% data maturity, with statistical significance at p<0.0001 (two-sided).9 In PAOLA-1, a hierarchical strategy was applied, with sequential testing for progression-free survival (PFS), PFS2 and OS, and the final OS analysis was planned at 3 years after the primary PFS report or 60% data maturity, with statistical significance at p<0.05.10

At the 5-year PFS update of SOLO1, maintenance olaparib for up to 2 years resulted in a 67%-reduction in the risk of disease progression or death versus placebo (HR: 0.33 [95% CI: 0.25–0.43]).11 At this 7-year OS analysis, olaparib demonstrated a statistically non-significant but clinically meaningful improvement in OS compared with placebo (median, not reached vs 75.32 months, HR: 0.55 [95% CI: 0.40–0.76]; p=0.0004), with 7-year rates of 67.0% and 46.5%, respectively.9 The OS benefit of olaparib versus placebo became more evident over time, despite the high rate of patients who received subsequent PARP inhibitor treatment in the placebo arm (44.3% vs 14.6% in the olaparib arm). In terms of time to first subsequent therapy (TFST), a plateau was reached in the placebo arm, while only a slight drop from the 5-year analysis was observed in the olaparib arm, with 5-year rates of 22.5% and 51.2% and 7-year rates of 20.6% and 45.3%, respectively. The median TFST was 4 times longer with olaparib than placebo (64.0 months vs 15.1 months, HR: 0.37 [95% CI: 0.28–0.48]).

In PAOLA-1, patients received maintenance olaparib versus placebo for up to 2 years on top of bevacizumab after first-line platinum-taxane chemotherapy plus bevacizumab.10 With a 5-year median follow-up and 55.3% data maturity, there were no OS differences between the two treatment arms in the intention-to-treat (ITT) population (HR: 0.92; p=0.4118). However, olaparib provided a clinically meaningful OS benefit compared with placebo among patients with homologous recombination deficiency (HRD)-positive tumors (HR: 0.62 [95% CI: 0.45–0.85]); 5-year OS rates were 65.5% and 48.4%, respectively. In this subgroup, 50.8% of patients in the placebo arm received a PARP inhibitor during any subsequent therapy versus 17.3% in the olaparib arm. The updated PFS analysis showed a 26.9%-difference in the 5-year PFS rates (46.1% vs 19.2%) and a 59%-reduction in the risk of disease progression or death with olaparib versus placebo within the HRD-positive population (HR: 0.41 [95% CI: 0.32–0.54]). Of note, the benefit of bevacizumab addition to PARP inhibitor therapy is also being evaluated in the phase III ENGOT-ov57 trial on niraparib.12

With regards to long-term side effects of PARP inhibitors, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and aplastic anemia (AA) were adverse events (AEs) of special interest. With this long follow-ups, only minor differences were observed between the olaparib and placebo arms (SOLO19: 1.5% vs 0.8%; PAOLA-110: 1.7% vs 2.2%), as well as from the primary analyses (with olaparib, SOLO14: 1.2%; PAOLA-15: 1.1%), demonstrating that olaparib had a good long-term safety profile.

The importance of BRCA and HRD testing in first-line ovarian cancer

The question can be raised of how much the survival benefit was driven by the BRCA-mutated patients in the PAOLA-1 trial. In the subgroup analysis by BRCA and HRD status, OS favored olaparib over placebo in HRD-positive patients without a BRCA mutation (HR: 0.71 [95% CI: 0.45–1.13]; 50% data maturity), with comparable results for the BRCA-mutated subgroup (HR: 0.60 [95% CI: 0.39–0.93]; 36% data maturity).10 Thus, BRCA testing alone might miss patients who may potentially benefit from PARP inhibition and HRD assessment with a validated test could be valuable in clinical practice. So far, only the MyChoice CDx test from Myriad Genetics can be regarded as a validated test and was predictive in the PAOLA-1 trial; patients with HRD-negative or unknown status did not show PFS advantage (HR: 0.92).5,10 In the PRIMA trial, however, it was not predictive of response to PARP inhibition as HR-proficient patients also derived PFS benefit from niraparib therapy (HR: 0.68 [95% CI: 0.49–0.94]).13 Similarly, rucaparib showed PFS improvement in HRD-negative patients in the ATHENA-MONO trial (HR: 0.60 [95% CI: 0.40–0.89]), in which the FoundationOne CDx assay was used for HRD status determination.8 Of note, the Geneva test from the ENGOT HRD Initiative, which has been presented at the ESGO Congress 2022, represents a great opportunity for a validated, decentralized test from an academic initiative that is associated with low costs.

ARIEL4: Rucaparib did not improve OS versus chemotherapy in patients with relapsed ovarian cancer

In the phase III ARIEL4 trial, patients with recurrent ovarian cancer harboring BRCA mutations were randomized 2:1 to receive rucaparib or chemotherapy with either paclitaxel or a platinum-based regimen, depending on their platinum-sensitivity status.14 Crossover to rucaparib was permitted upon progressive disease. Despite the PFS benefit of rucaparib versus chemotherapy in the ITT (HR: 0.67 [95% CI: 0.52–0.86]; p=0.0017),14 OS favored chemotherapy in the final analysis (HR: 1.313 [95% CI: 0.999–1.725]).15 Notably, in the platinum-resistant subgroup (rucaparib, n=120; chemotherapy, n=59), the median duration of treatment in the rucaparib arm was 5.6 months but 91.1% of patients in the chemotherapy arm crossed over, with 27 of those receiving treatment for ≥6 months (median duration of crossover to rucaparib: 9.4 months). When patients who crossed over were excluded from the OS analysis (ITT), there was a positive signal for rucaparib versus placebo (median, 19.4 months vs 9.1 months; HR: 0.423 [95% CI: 0.276–0.650]). Thus, crossover and long post-progression survival could explain the discrepancy between analyses. For the time being, chemotherapy is still the preferred option for relapsed patients.

ENGOT-cx9: Second-line cemiplimab improved OS in patients with recurrent cervical cancer, regardless of PD-L1 expression

In this phase III trial, 608 patients with recurrent cervical cancer after first-line platinum-based chemotherapy were randomized 1:1 to receive either the immune checkpoint inhibitor cemiplimab or single-agent chemotherapy.16 At the second interim analysis, the trial met its primary endpoint of OS16 and similar results were observed at this final analysis at a median follow-up of 30.2 months, with a median OS in the overall population of 11.7 months with cemiplimab versus 8.5 months with chemotherapy (HR: 0.656 [95% CI: 0.545–0.790]; one-sided p<0.00001).17 The OS improvement was observed among patients with squamous cell carcinoma (HR: 0.690 [95% CI: 0.560–0.850]; p=0.0023) and those with adenocarcinoma (HR: 0.545 [95% CI: 0.365–0.814]). In addition, programmed death-ligand 1 (PD-L1) testing was available for 42% of patients in the previous analysis16 and 60% of patients in the current analysis.17 The overall PD-L1 positivity was 64% and cemiplimab prolonged OS versus chemotherapy irrespective of PD-L1 status (tumor cell PD-L1 expression <1%; HR: 0.650), indicating that PD-L1 is not a predictive biomarker.17 Interestingly, patients with tumor PD-L1 expression <1% showed no benefit of cemiplimab in the previous analysis (HR: 0.98).16

Notably, PD-L1 was a predictive biomarker in the phase III KEYNOTE-826 trial in patients with persistent, recurrent or metastatic cervical cancer.18 The addition of pembrolizumab to first-line chemotherapy, with or without bevacizumab, prolonged PFS and OS in patients with a PD-L1 combined positive score (CPS) ≥1 (HR: 0.62 and 0.64, respectively; p<0.001 for both) but not in those with CPS <1 (n=69; HR: 0.94 and 1.00).

Based on these data, PD-L1 as a biomarker should be used with care and should not drive treatment decision-making.

Encouraging results with immunotherapy in gynecologic CCC

Clinical evidence of immunotherapy activity in ovarian clear cell cancer (OCCC) was provided in subgroup analyses of four clinical trials, namely NINJA,19 KEYNOTE-100,20 IMAGYN5021 and NRG GY003.22 The AGO-OVAR 2.29 trial of atezolizumab combination treatment in recurrent ovarian cancer will likely contribute data on CCC patients.23 In advanced endometrial CCC, lenvatinib plus pembrolizumab improved PFS (HR: 0.47) and OS (HR: 0.33) versus treatment of physician’s choice (TPC) chemotherapy in the KEYNOTE-775 trial.24

In the phase II PEACOCC trial, patients with advanced recurrent clear cell gynecological cancer (CCGC) (85% with ovarian cancer) received pembrolizumab monotherapy for up to 2 years.25 The primary endpoint of PFS at 12 weeks was 43.8% and the median OS was 71 weeks. Importantly, the response rate in this patient population was 25%, with a 1-year duration of response rate of 47.7% Furthermore, preliminary results from the INOVA trial in relapsed or persistent OCCC showed an overall response rate (ORR) of 38.5% with the combination of the immune checkpoint inhibitor sintilimab and bevacizumab, hinting towards a benefit of the addition of antiangiogenic therapy.26

Overall, it is a reasonable approach to rely on histology if disease-based treatment is not possible. Related to this, basket trials such as BOUQUET investigate molecular-directed therapies in rare gynecologic tumors.27