Treatment Options Abound in Platinum-Sensitive Ovarian Cancer

Bobbie J. Rimel, MD

In ovarian cancer, disease that returns within 6 months of treatment following platinum-based therapy is defined as platinum-sensitive. A patient’s platinum-sensitivity status can change with minor decisions made in clinical practice; however, oncologists treating these patients have a variety of therapeutics available to choose from, Bobbie J. Rimel, MD, said during a presentation at the 2020 SGO Winter Meeting.

Rimel, an assistant professor of gynecology and obstetrics at Samuel Oschin Comprehensive Cancer Institute, said that early studies by Maurie Markman, MD, helped elucidate platinum-sensitivity in ovarian cancer. Study investigators had looked at how patient response to treatment changes over time, she said. When they went back to perform secondary cytoreduction, a practice which has since fallen out of favor, they found that the vast majority of patients still had tumors.

Therefore, platinum-sensitivity is a function of time. “Time must pass for your patient to have platinum-sensitive disease,” Rimel said. “It doesn't just mean that the patient responded.”

The typical course of therapy means that patient shows a first response to first-line treatment, then the physician follows up with CA-125 or radiographic imaging. Current guidelines do not establish when to perform these tests, and Rimel said that the definition of “platinum sensitive” can change based on how often the physician screens for recurrence.

Approximately 70% to 80% of patients will relapse and receive a second course of treatment that leads to a second response or stability.

Treatment Options

Physicians treating patients with platinum-sensitive ovarian cancer can choose from a range of therapies, including doublet chemotherapy with or without bevacizumab (Avastin) and PARP inhibitors, such as rucaparib (Rubraca), niraparib (Zejula) and olaparib (Lynparza).

Support for platinum doublet chemotherapy goes as far back as 2010 with the CALYPSO trial, which compared carboplatin and pegylated liposomal doxorubicin (CD) versus paclitaxel and carboplatin (CP). The median progression-free survival (PFS) favored the CD arm at 11.3 months versus 9.4 months with CP (HR, 0.821; 95% CI, 0.72-0.94; P = .005).¹

More recently, Jacobus Pfisterer, MD, director of the Gynecologic Oncology Center in Kiel, Germany, reported findings from AGO/OVAR 2.21 at the 2018 ESMO Congress. Investigators determined that CD plus bevacizumab showed a superiority in median PFS compared with carboplatin/gemcitabine/bevacizumab (13.3 vs 11.7 months; HR, 0.807; 95% CI, 0.681-0.956; P = .0128).²

In GOG-0213, the addition of bevacizumab to CP resulted in a median PFS of 13.8 months compared with 10.4 months for CP alone (HR, 0.628; 95% CI, 0.53-0.74).³

In the OCEANS trial, the addition of bevacizumab to carboplatin/gemcitabine resulted in a 4-month improvement in median PFS over carboplatin/gemcitabine alone at 12.4 versus 8.4 months, respectively (HR, 0.484; 95% CI, 0.388-0.605).⁴ Furthermore, the GOG-0213 results showed a 5-month overall survival benefit associated with bevacizumab.

Taken together, findings from these 4 studies show that the addition of bevacizumab to a chemotherapy doublet results in extended PFS.

Options Beyond Antiangiogenic Inhibition

Not all patients are eligible for bevacizumab maintenance. Rimmel said PARP inhibitors are a better choice for those with active fistulas or nonhealing wounds, poorly controlled hypertension, and/or proteinuria. Data from 2 studies, Study 19 and SOLO-2, show that olaparib can improve PFS in this population and especially in patients with BRCA-mutant disease.

In Study 19, patients were assigned to either olaparib at 400 mg twice daily (n = 136) or placebo (n = 129). Eligible patients had platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received ≥2 previous platinum-based regimens and had a partial or complete response to their most recent platinum-based regimen. The median PFS was 8.4 months in the olaparib arm versus 4.8 months for placebo (HR, 0.35; 95% CI, 0.25-0.49; P <.001).⁵

Findings from a prespecified analysis of Study 19 showed that median PFS was significantly longer in the olaparib group among patients with a BRCA mutation than in the placebo group (11.2 vs 4.3 months; HR, 0.18; 95% CI, 0.10-0.31; P <.0001).⁶

The phase III SOLO-2 trial evaluated the benefit of olaparib maintenance therapy in patients with BRCA-mutated ovarian cancer. Patients were assigned to 300 mg of twice-daily olaparib (n = 196) or placebo (n = 99).

Results showed that olaparib was associated with a 70% reduction in the risk for progression or death (HR, 0.30; 95% CI, 0.22-0.41; P <.0001).⁷ Investigator-assessed median PFS was significantly longer with olaparib than with placebo at 19.1 months and 5.5 months, respectively (HR, 0.30; 95% CI, 0.22-0.41; P <.0001).

Moreover, the phase III ARIEL3 study included patients with platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma who had received ≥2 prior platinum-based chemotherapy regimens and had achieved complete or partial response to their last platinum-based regimen. Patients were randomized to receive rucaparib or placebo.

Data demonstrated that, in patients with a BRCA-mutant carcinoma, the median PFS was 16.6 months with rucaparib and 5.4 months with placebo (HR, 0.23; 95% CI, 0.16-0·34]; P <.0001).⁸ In the intent-to-treat population, the median PFS was 10.8 months versus 5.4 months, respectively (HR, 0.36; 95% CI, 0.30-0.45; P <.0001).

For platinum-sensitive PARP inhibitor—naïve patients responding to platinum-based therapy, PARP inhibitor maintenance will prolong PFS, Rimel said. “As in the upfront setting, patients with BRCA mutations of any kind consistently derive the most PFS benefit in these trials.”

References

1. Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol. 2010;28:3323-3329. doi: 10.1200/JCO.2009.25.7519.
2. Pfisterer J, Dean AP, Baumann K, et al: Carboplatin/pegylated liposomal doxorubicin/bevacizumab (CD-BEV) vs. carboplatin/gemcitabine/bevacizumab (CG-BEV) in patients with recurrent ovarian cancer. Ann Oncol. 2018;29(suppl_8):viii332-viii358. doi: 10.1093/annonc/mdy285.
3. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(6):779-791. doi: 10.1016/S1470-2045(17)30279-6.
4. Aghajanian C, Goff B, Nycum LR, Wang YV, Husain A, Blank SV. Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2015;139(1):10-16. doi: 10.1016/j.ygyno.2015.08.004.
5. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392. doi: 10.1056/NEJMoa1105535.
6. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852-861. doi: 10.1016/S1470-2045(14)70228-1.
7. Pujade-Lauraine E, Ledermann JA, Selle F, et al. 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.
8. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949-1961. doi: 10.1016/S0140-6736(17)32440-6.

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