Brown Spotlights Key ASCO Highlights in Gynecologic Malignancies

Jubilee Brown, MD

The field of gynecologic oncology gained a number of important updates at the 2020 ASCO Virtual Scientific Program. As part of the 2020 ASCO Direct Highlights^TM webcast, a program developed by Physicians’ Education Resource^®(PER^®), LLC., Jubilee Brown, MD, a professor of gynecologic oncology and the associate director of Gynecologic Oncology at Levine Cancer Institute, Atrium Health, provided insight on key trials that were presented at the program.

“This [is] an incredible time for [gynecologic] oncology,” said Brown. “It is a great time to take care of patients because we have so many options.”

PARP Inhibitors in Platinum-Sensitive Ovarian Cancer

One of the most notable trials that was presented in the platinum-sensitive setting was the phase 3 SOLO2/ENGOT-ov21 study, which showed a 12.9-month improvement in median overall survival (OS) with maintenance olaparib (Lynparza) compared with placebo in patients with BRCA-mutated platinum-sensitive, relapsed ovarian cancer.1 The median OS was 51.7 months with olaparib versus 38.8 months with placebo (HR, 0.74; 95% CI, 0.54-1.00; P = .0537).

Notably, a survival advantage was seen with olaparib despite the fact that 38% of patients who received placebo went on to receive subsequent PARP inhibitor therapy. The median OS adjusted for subsequent PARP inhibitor therapy was 51.7 months with olaparib versus 35.4 months with placebo (HR, 0.56; 95% CI, 0.35-0.97).

The study randomized patients 2:1 to receive 300 mg of olaparib twice daily or placebo until disease progression. The majority of patients in both groups had their primary tumor located in the ovary, had serous histology, and had an ECOG performance score of 0.

In the olaparib arm, 67% and 30% of patients had germline BRCA1 and BRCA2 mutations according to the BRACAnalysis CDx® diagnostic test from Myriad. Three percent of patients had a germline BRCA mutation that was confirmed by local testing that went without confirmation in the trial. In the placebo arm, these rates were 62%, 35%, and 3%, respectively.

At 5 years, the median time to first subsequent therapy was 27.4 months with olaparib (n = 196) and 7.2 months with placebo (n = 99). Moreover, 28% and 13% of patients were alive and had not received subsequent therapy, respectively.

Additionally, olaparib was found to be beneficial and tolerable in this patient population as 22% of patients who received olaparib remained on treatment for at least 5 years.

Regarding safety in this analysis, serious treatment-emergent adverse effects (TEAEs) were observed in 26% of patients treated with olaparib versus 8% of patients treated with placebo.

“Incredibly, maintenance olaparib provided a clinically meaningful prolongation of median OS…over placebo,” said Brown. “This is really a home run.”

Olaparib was also evaluated with or without the investigational VEGF inhibitor cediranib versus standard platinum-based chemotherapy in women with recurrent platinum-sensitive ovarian cancer as part of the phase 3 NRG Oncology GY004 trial (NCT02446600).²

The median progression-free survival (PFS) was 10.3 months with chemotherapy. In comparison with chemotherapy, the median PFS was 10.4 months with olaparib/cediranib (HR, 0.856, 95% CI, 0.663-1.105; P = .077) and 8.2 months with olaparib monotherapy (HR, 1.20; 95% CI, 0.933-1.54).

Additionally, in the intention-to-treat (ITT) patient population, the median OS was 31.3 months, 30.5 months, and 29.2 months, respectively.

Patients enrolled were randomized 1:1:1 to receive investigator’s choice of platinum-based chemotherapy with either carboplatin/paclitaxel, carboplatin/gemcitabine, or carboplatin/liposomal doxorubicin, 300 mg of twice daily olaparib, or 200 mg of olaparib twice daily plus 30 mg of cediranib daily. Patients received therapy until progression.

Patients’ performance status, number of prior lines of therapy, disease histology, germline BRCA status, ­platinum-free intervals, and prior antiangiogenic therapy were similar between arms, said Brown.

The objective response rates (ORR) were 71.3% in the chemotherapy arm (n = 143), 69.4% in the combination arm (n = 157), and 52.4% in the olaparib-alone arm (n = 160).

In a prespecified subset analysis of patients with a germline BRCA1/2 mutation, the ORRs were 71% with chemotherapy, 89% with the combination, and 90% with olaparib alone. Moreover, 32.3%, 27.8%, and 30% of patients had complete responses (CRs), respectively.

For patients without BRCA1/2 mutations, the ORRs were 72% with chemotherapy, 64% with cediranib/olaparib, and 40% with olaparib alone. The CR rates were 12.8%, 9.9%, and 8.3%, respectively.

Notably, there were no cases of grade 3 or higher peripheral sensory neuropathy in the combination and olaparib-alone arms. All-grade fatigue, nausea, diarrhea, and hypertension, among other AEs, were higher with the combination versus single-agent olaparib or chemotherapy.

Treatment discontinuation due to AEs were observed in 15% of patients on chemotherapy, 21.2% of patients on the combination regimen, and 8.5% of patients on olaparib monotherapy.

Although the combination of cediranib and olaparib did not meet the primary end point of improved PFS compared with chemotherapy, the comparable clinical activity noted with the regimen warrants further studies with non-platinum–based therapies, said Brown.

Secondary Cytoreductive Surgery

Surgery and systemic therapy are standards of care in the treatment of women with ovarian cancer. However, whether patients who experience disease recurrence could benefit from secondary cytoreductive surgery had been undefined.

The phase 3 AGO DESKTOP III/ENGOT-ov20 study³ was designed to evaluate the role of secondary cytoreductive surgery by randomizing patients with platinum-sensitive recurrent ovarian cancer to cytoreductive surgery followed by platinum-based chemotherapy versus up-front platinum-based chemotherapy.

In order to be eligible for enrollment, patients had to be in first relapse and have a positive AGO score. The median age of patients who did not undergo surgery (n = 201) was 62.2 years compared with 60.8 years in patients who underwent surgery (n = 206; P = .37). Initially, 73.1% and 75.6% of patients had stage IIB to IV disease, according to the International Federation of Gynecology and Obstetrics grading system, respectively (P = .57). Additionally, 77.1% and 84% of patients had grade 2/3 serous histology, respectively (P = .08).

In both subgroups, 99% of patients had received prior platinum-based chemotherapy (P = .98). Moreover, 75.1% of patients in the non-surgery cohort and 75.2% in the surgery cohort had a platinum-free interval of greater than 12 months (P = .99). Median platinum-free intervals were 18.7 months and 21.1 months, respectively (P = .40). Additionally, the majority of patients in both arms had received prior taxane (P = .13).

Eight patients who were randomized to surgery and 14 patients who were not were not compliant with their randomization (P = .21). The majority of patients received platinum-containing treatment (90% versus 88.8%, respectively). Additional post-randomization therapies included bevacizumab (Avastin) and PARP inhibitors.

The macroscopic complete resection rate was 74.2% among patients who underwent secondary cytoreductive surgery.

The median OS in the 407 evaluable patients who were included in the ITT population was 53.7 months with surgery compared with 46 months with chemotherapy alone (HR, 0.75; 95% CI, 0.58-0.96; P = .02). Median PFS was 18.4 months versus 14 months, respectively (HR, 0.66; 95% CI, 0.54-0.82; P <.001).

A post-hoc analysis of the surgical arm revealed that the median OS in patients with residual disease was 28.8 months compared with 61.9 months in patients who achieved complete resection (P <.001). Moreover, with the incomplete resection cohort excluded, the median OS for patients who did not undergo surgery was 46 months versus 61.9 months for patients who achieved complete resection (P <.001).

DESKTOP III/ENGOT-ov21 is the first prospective, randomized clinical trial to demonstrate an OS benefit with debulking surgery in this patient population and suggests that patient selection is critical to ensure the maximum OS and PFS benefit is possible, said Brown.

Sentinel Lymph Node (SLN) Biopsy in Cervical Cancer

In cervical cancer, systematic pelvic lymphadenectomy (PLN) remains the standard lymph node staging method while SLN biopsy alone is not utilized outside of clinical trials, explained Brown.

However, long-term data from an ancillary analysis of the prospective SENTICOL I and SENTICOL II trials revealed that patients with early-stage cervical cancer who underwent SLN biopsy had similar survival compared with patients who underwent SLN biopsy and PLN.⁴

Patients characteristics were essentially equivalent between groups, said Brown. The majority of patients in both groups had a squamous cell carcinoma subtype (63.2% vs 69.2%), followed by adenocarcinoma (33.3% vs 27.9%; P = .63). Likewise, the majority of patients in both groups had grade 1 differentiation (56.1% vs 39.3%), followed by grade 2 (29.8% vs 41%), grade 3 (14% vs 19.7%), and not specified (P = .11).

At a median follow-up of 53 months in the SLN biopsy group (n = 87) and 46 months in the PLN group (n = 172), disease-free survival (DFS) was 85.1% and 80.4%, respectively (HR, 1.67; 95% CI, 0.71-3.94; P = .24). Median time to recurrence was 22 months and 26 months, respectively.

The disease-specific survival (DSS) was 90.8% in women who underwent SLN versus 97.2% in those who underwent PLN and SLN (HR, 2.24; 95% CI, 0.60-8.39; P = .22). Median time to DSS was 36 months and 37 months, respectively.

Regarding previous treatment, 95.4% of patients in the SLN group and 92.4% in the PLN group underwent minimally invasive surgery (P = .36). Additionally, 81.2% and 82.4% of patients did not receive adjuvant treatment, respectively (P = .17).

In the SLN cohort, 82.8%, 8%, and 9.2% of patients had pathologic risk levels of low, intermediate, and high, respectively, as defined by the Sedlis criteria. In the PLN cohort, these rates were 81.4%, 10.5%, and 8.1%, respectively (P = .80).

At follow up, the majority of patients in both groups did not experience recurrence. However, 3 patients in the SLN only group and 1 patient in the PLN group experienced nodal recurrence (P = .23).

A Novel Agent Shows Early Promise in Endometrial Cancer

Brown stated that early data from the ongoing phase 1/2 GARNET trial (NCT02715284)5 demonstrated favorable patient-reported outcomes with the investigational PD-1 inhibitor dostarlimab in women with advanced or recurrent mismatch repair deficiency or microsatellite instability–high endometrial cancer.

A 98% compliance rate was noted in 43 evaluable patients. Notably, patients reported meaningful improvements in pain, insomnia, and social and emotional functioning. Moreover, patients’ nausea, appetite, vomiting, constipation, diarrhea, and physical and role functioning were reportedly stable throughout treatment.

Although the findings are early, quality of life also appeared to be maintained with the agent.

Previously, dostarlimab had shown an ORR of 42.9% and a disease control rate of 58.6% in this patient population.⁶ 

References

1. Poveda A. Floquet A, Ledermann JA, et al. Final overall survival (OS) results from SOLO2/ENGOT-ov21: a phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation. J Clin Oncol. 2020;38(suppl 15):6002). doi:10.1200/JCO.2020.38.15_suppl.6002
2. Liu JF, Brady MF, Matulonis UA, et al. A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer. J Clin Oncol. 2020;38(suppl 15):6003. doi:10.1200/JCO.2020.38.15_suppl.6003
3. Du Bois A, Sehouli J, Vergote I, et al. Randomized phase III study to evaluate the impact of secondary cytoreductive surgery in recurrent ovarian cancer: Final analysis of AGO DESKTOP III/ENGOT-ov20. J Clin Oncol. 2020;38(suppl 15):6000. doi:10.1200/JCO.2020.38.15_suppl.6000
4. Balaya V, Guani B, Maguad L, et al. Long-term oncological safety of sentinel lymph node biopsy in early-stage cervical cancer. J Clin Oncol. 2020;38(suppl 15):6006. doi:10.1200/JCO.2020.38.15_suppl.6006
5. Kristeleit RS, Mathews CA, Redondo A, et al. Patient-reported outcomes (PRO) in the GARNET trial in patients (pts) with advanced or recurrent dMMR/MSI-H endometrial cancer (EC) treated with dostarlimab. J Clin Oncol. 2020;38(suppl 15):e18032. doi:10.1200/JCO.2020.38.15_suppl.e18032
6. Oaknin A, Duska LR, Sullivan RJ, et al. Preliminary safety, efficacy, and pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-H and MSS endometrial cancer. Presented at: 2019 SGO Annual Meeting; March 16-19, 2019; Honolulu, HI. Abstract 33.