New Biomarkers for Responses Are Explored in Late-Stage Ovarian Cancer

Michael Birrer, MD, PhD

The identification of appropriate biomarkers for evaluating responses to therapy would be beneficial across all stages of ovarian cancer, from early to advanced, according to Michael J. Birrer, MD, PhD.

“All ovarian cancers are treated with surgery followed by chemotherapy,” said Birrer, during a keynote lecture at the European Society for Medical Oncology’s 12th International Symposium on Advanced Ovarian Cancer in Valencia, Spain.¹ Birrer is director of the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham.

The standard of care for early-stage, high-grade epithelial ovarian cancer is the same as for its advanced counterpart, yet 10% to 20% of patients will experience recurrence despite complete resection and adjuvant chemotherapy, said Birrer.

Taking a personalized approach to adjuvant therapy, even in patients with early-stage disease, may be the best way to optimize care. Birrer noted that predictive signatures for recurrence in early-stage ovarian cancer have been developed, with the identification of important therapeutic targets for recurrent disease currently underway. Birrer focused most of his presentation on potential biomarkers in late-stage disease.

Advanced-Disease Setting

In advanced disease, the question of improving outcomes after surgery continues to challenge investigators and clinicians. Birrer said that success of cytoreduction is associated with greater median survival, according to research from Bristow and colleagues.² For each 10% increase in maximal cytoreduction, the investigators reported a 5.5% increase in median survival time. Additionally, cohorts with ≤25% maximal cytoreduction had a mean weighted median survival time of 22.7 months, whereas cohorts with more than 75% maximal cytoreduction had a mean weighted median survival time of 33.9 months, or an increase of 50%.

Birrer suggested that in patients with suboptimal debulking, hyperactivity in the transforming growth factor—β (TGF-β) pathway may contribute. Research involving TGF-β signaling inhibition may provide clinical benefits in both the postsurgical and neoadjuvant settings.

Postsurgical management of suboptimally debulked tumors leads to an increase in the chance of complete response, reduction of tumor recurrence, increase in progression-free survival (PFS), and reduction in secondary tumor dissemination.

In the neoadjuvant setting, the use of first-line platinum/taxol kills those tumors that pose an anatomical hindrance to optimal debulking and reduces tumor dissemination during the window period between adjuvant chemotherapy and surgery.

Birrer pointed out that Riester and colleagues had developed and validated 2 gene expression signatures, the first for predicting survival in advanced-stage ovarian cancer, and the second for predicting debulking status.³

Blocking TGF-β Signaling

There are also several potential pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors.

Galunisertib (LY2157299 monohydrate) is an orally administered small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, deactivating the pathway. Mouse models suggest galunisertib is a potent reagent to suppress the dissemination of ovarian cancer cells.

Another approach focuses on VEGF and angiogenesis, which are important promoters of ovarian cancer progression. Both correlate directly with the extent of disease and inversely with PFS and overall survival, often independently of known prognostic factors.

Bevacizumab (Avastin) is a humanized VEGF-neutralizing monoclonal antibody that inhibits tumor angiogenesis. The FDA has approved its use in combination with chemotherapy, followed by single-agent bevacizumab, for stage III or IV disease following initial resection and for platinum-sensitive recurrent disease. The drug also is approved in combination with chemotherapy for platinum-resistant recurrent disease after prior therapy.

Bevacizumab also has shown single-agent activity in phase II epithelial ovarian cancer trials.⁴ Investigators randomly assigned eligible patients with newly diagnosed stage III (incompletely resected) or stage IV epithelial ovarian cancer who had undergone debulking surgery to receive 1 of 3 treatments. All 3 arms included chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg/m², plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment for cycles 2 through 22. Each cycle lasted for 3 weeks.

Patients in the control arm received chemotherapy with placebo added in cycles 2 through 22. Those in the bevacizumab-initiated arm received chemotherapy with bevacizumab (15 mg per kilogram of body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22. Patients in the bevacizumab-throughout treatment arm received chemotherapy with bevacizumab added in cycles 2 through 22. The primary endpoint was PFS.

In this phase III trial, Burger et al reported that the median PFS was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group. Relative to the control treatment, the hazard ratio for progression or death was 0.908 with bevacizumab initiation (95% CI, 0.795-1.040; P = .16) and 0.717 with bevacizumab throughout (95% CI, 0.625-0.824; P <.001).

Table. PARP Inhibitor Summary in Ovarian Cancer

The FDA has approved 3 PARP inhibitors for use in ovatian cancer settings: olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula). Among the clinical trials in which the role of these agents has been explored are SOLO-2, ARIEL3, and NOVA (Table).

SOLO-2 (NCT01874353) enrolled 295 eligible patients who were randomly assigned to receive olaparib (n = 196) or placebo (n = 99). Investigator-assessed median PFS was significantly longer with olaparib (19.1 months; 95% CI, 16.3-25.7) than with placebo (5.5 months; 95% CI, 5.2-5.8).

Investigators noted no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Apart from anemia, toxicities with olaparib were low grade and manageable. Serious adverse events (AEs) were experienced by 35 (18%) patients in the olaparib group and 8 (8%) patients in the placebo group. The most common AEs in the olaparib group were anemia (7 [4%] patients), abdominal pain (3 [2%] patients), and intestinal obstruction (3 [2%] patients). The most common AEs in the placebo group were constipation (2 [2%] patients) and intestinal obstruction (2 [2%] patients). One (1%) patient in the olaparib group had a treatment- related AE (acute myeloid leukaemia) with an outcome of death.⁵

In a previous study, SOLO-1⁶, 391 patients were randomized to receive 300 mg of olaparib twice daily (n = 260) or placebo (n = 131). After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (HR, 0.30; 95% CI, 0.23-0.41; P <.001).

ARIEL3⁷ defined a molecular signature of homologous recombination deficiency (HRD) in ovarian cancer that correlates with response to rucaparib and enables selection of appropriate ovarian cancer patients for treatment with rucaparib. The HRD signature will be based on an association between the extent of genomic scarring (a downstream consequence of HRD) in a patient’s tumor and observed clinical benefit from rucaparib treatment.

In NOVA, Mirza and colleagues⁸ enrolled 2 independent cohorts on the basis of the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort), as determined by BRCA analysis testing. The duration of PFS in the niraparib group was significantly longer than that in the placebo group in all 3 primary efficacy populations (P <.001). In the gBRCA cohort, the median duration of PFS was 21.0 months in the niraparib group and 5.5 months in the placebo group (HR, 0.27; 95% CI, 0.17-0.4).

Looking to the future, Birrer pointed toward cell surface proteins, which are selectively expressed on ovarian cancer cells and are therapeutic targets. The FORWARD I study is an open-label, randomized phase III trial that evaluates the safety and efficacy of mirvetuximab soravtansine versus investigator’s choice chemotherapy in women with folate receptor α—positive (FRα-positive), platinum-resistant epithelial ovarian cancer. The trial did not improve PFS compared with chemotherapy and there was no significant difference in PFS in the overall study population. Although the PFS was longer with mirvetuximab soravtansine in the prespecified high FRα-positive subgroup, it did not reach statistical significance as per a prespecified statistical analysis plan.

Nonetheless, mirvetuximab soravtansine had a favorable safety profile and increased response and survival rates among patients with high FRα levels. ImmunoGen, the manufacturer of the agent, will continue studying the treatment in combination approaches.

References

1. Birrer MJ. Biomarkers in ovarian cancer: to be or not to be. Keynote address presented at: European Society for Medical Oncology’s 12th International Symposium on Advanced Ovarian Cancer; February 22, 2019;Valencia, Spain.
2. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20(5):1248-1259. doi: 10.1200/JCO.2002.20.5.1248
3. Riester M, Wei W, Waldron L, et al. Risk prediction for late-stage ovarian cancer by meta-analysis of 1525 patient samples. J Natl Cancer Inst. 2014;106(5):dju048. doi: 10.1093/jnci/dju048.
4. Burger BA, Brady MF, Bookman MA, et al; Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483. doi: 10.1056/NEJMoa1104390.
5. Pujade-Lauraine E, Ledermann JA, Selle F, et al; SOLO2/ENGOT-Ov21 Investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2.
6. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2496-2505. doi: 10.1056/NEJMoa1810858.
7. Konecny, GE, Ozo, AM, Tinker, AV. Rucaparib in patients with relapsed, primary platinum-sensitive high-grade ovarian carcinoma with germline or somatic BRCA mutations: integrated summary of efficacy and safety from the phase 2 study ARIEL2. Gynecol Oncol. 2017;145(suppl 1):2. doi: 10.1016/j.ygyno.2017.03.028.
8. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-V16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164. doi: 10.1056/NEJMoa1611310.