Ovary Part 4

Ovarian Cancer
Written By Sydney Oesch

Episode Notes

  1. Recurrence Definitions (Review)

    1. Defined by platinum-free interval (PFI): time from completion of platinum therapy to the detection of recurrence

      1. “Platinum sensitive” if PFI > 6 months

      2. “Platinum resistant” if PFI < 6 months

      3. “Platinum refractory” if progression of disease while on first-line platinum treatment

  2. Prognosis

    1. Median PFS unfortunately low: typically quoted 5-6 months with response rates (usually partial response or clinically stable disease) between 10-30%

  3. Management Options

    1. Do not differ based on histology

    2. Most are phase II trials: thus, majority of recommendations are category 2A or 2B

    3. If patients progress on 2 consecutive chemotherapy regimens w/o clinical benefit, NCCN states these patients may not benefit from additional therapy

    4. Combination therapy does not give additional benefit over single-agent treatment in platinum-resistant setting

  4. Systemic Therapy

    1. Single agent options: docetaxel, etoposide, weekly paclitaxel, liposomal doxorubicin, topotecan

    2. Gordon Trial, 2001

      1. Single-agent Doxil vs single-agent topotecan

      2. No difference in plat-resistant group

      3. No difference when stratified by bulky disease

    3. Other options: altretamine, capecitabine, pazopanib, cyclophosphamide, doxorubicin, ifosfamide, irinotecan, melphalan, oxaliplatin, pemetrexed, vinorelbine

    4. Hormonal options: tamoxifen, aromatase inhibitors, leuprolide acetate, megestrol

    5. Special side effect considerations?

      1. Neuropathy -> topotecan, gemcitabine

      2. Distance, breaks from infusion, low symptoms, low-level disease -> etoposide (has an oral option)

  5. Bevacizumab

    1. 2A for single-agent use

    2. Overall response rate about 20%

    3. GOG170D, 2007

      1. evaluated the use of single-agent bevacizumab in patients with both platinum-sensitive and platinum-resistant disease

      2. ORR 21% and PFS 39% at 6 months

      3. Bevacizumab alone carries a category 2A recommendation for those with plat-sensitive or plat-resistant disease

      4. Platinum sensitivity, age, number of prior lines of therapy not associated with response

    4. Cannistra, 2007

      1. Phase II

      2. Single-agent bevacizumab in PROC

      3. N = 44 who had progressed within 3 months of discontinuing their prior therapy

      4. Median PFS 4.4 mo, median OS 10.7 mo

      5. 11.4% of enrolled patients had a GI perforation!

        1. Rate increased to 24% in pts w/ 3 prior lines of therapy, compared to 0% in 2 prior lines

      6. GOG170D + Cannistra suggest that the risk of GI perforation may be higher in patients who are heavily pretreated

    5. AURELIA, 2015

      1. Investigated bevacizumab in combo w/ investigator’s choice chemo (paclitaxel, doxil, or topoitecan)

      2. PFS improved from 3.4 to 6.7 mo

      3. RR improved from 11.8 to 27.3%

      4. OS not statistically different

      5. Majority of patients on trial had not been treated w/ bevacizumab before

      6. Paclitaxel + bevacizumab group derived the most benefit from addition of bev

    6. AURELIA exploratory analysis, 2017

      1. Of 182 patients randomized to chemo-alone group, 78 were given bev after progression on single-agent chemo

      2. Compared with the patients who never received bevacizumab, patients with up-front chemo + bevacizumab and those who received bevacizumab after progression had a reduced risk of death with a HR 0.68 and 0.6, respectively

  6. PARP Inhibitors

    1. At this time, PARP inhibitors are neither approved for use nor shown to be effective with platinum-resistant ovarian cancer

      1. Kaufman 2015

        1. Olaparib monotherapy in PROC w/ germline BRCA 1 or 2 mutation

        2. ORR 31%

      2. Domcheck 2016

        1. Olaparib monotherapy in heavily-pretreated germline BRCA 1 or 2 mutation

        2. ORR 30%, PFS 8 mo

      3. Takeaway: response to PARP inhibitors in platinum-resistant disease, regardless of BRCA status, is very low

    2. ARIEL 4, 2022

      1. Rucaparib monotherapy vs SOC chemo in recurrent, BRCA mutated epithelial cancer

      2. Both PROC and PSOC

      3. In PROC group, survival detriment seen w/ OS of 14.2 mo vs 22.2 mo in rucaparib monotherapy vs SOC chemo group

  7. Targeted Therapies

    1. Immunotherapy

      1. NINJA, 2021

        1. Phase III RCT in pts w/ PROC

        2. Received <=1 regimen after being diagnosed w/ PROC

        3. Randomized to nivolumab vs SOC chemo (gemcitabine or Doxil)

        4. OS 10 mo vs 12.1 mo w/ nivolumab vs SOC chemo

        5. PFS 2 vs 3.8 mo

        6. No difference in ORR

        7. Takeaway: nivolumab did not improve OS, had worse PFS, and had equivalent ORR compared to the SOC group

      2. Keynote 100, 2020

        1. Phase II study in 2 Cohorts

          1. Cohort A: 1-3 prior lines of treatment with a platinum free interval between 3-12 months

          2. Cohort B: heavily pretreated with 4-6 prior lines and a progression free interval of >= 3 months

        2. Primary endpoint ORR

          1. Cohort A: 7.4%, DOR 8.2 mo

          2. Cohort B: 9.9%, DOR NR

        3. PD-L1 influence

          1. ORR increased to 18% in Cohort B if PD-L1 CPS >= 10

            1. OS 21.9 mo and 24 mo in Cohort A and B, respectively

          2. If CPS >=1 -> ORR 7% and 10% in cohort A/B

      3. TOPACIO/KEYNOTE 162, 2019

        1. Phase II, n = 62

        2. Combination of pembrolizumab + niraparib in PROC

        3. Duration of response not reached

        4. In exploratory analysis, ORR 21% in PD-L1 pos and 10% in PD-L1 neg

        5. HRD status, BRCA mutation, prior bev exposure did not predict response

      4. NRG-GY003, 2020

        1. Phase II, n = 100, all recurrent, 63% PROC

        2. Evaluated combination of nivolumab + ipilimumab vs nivolumab alone

        3. ORR higher in combo group, PFS improved but only by 1.9 mo, OS not different

        4. Combo regimen more toxic w/ higher rates of discontinuation

        5. In exploratory analysis, pts w/ poor prognostic markers (i.e. performance status, PROC, older age, more prior regimens, clear cell histology), responded more robustly to combo regimen

      5. Takeaway: checkpoint inhibitors don’t sound like a “home run” but probably could be considered for some of our patients with disease that is harder to treat.

    2. Mirvetuximab

      1. Folate receptor alpha antibody + microtubule inhibitor antibody drug conjugate

      2. FORWARD 1, 2018

        1. Phase III

        2. Mirvetuximab vs investigator’s choice chemo in PROC

        3. PFS not different

        4. ORR 24% in mirv vs 10% in chemo

        5. Pts w/ higher folate receptor alpha expression had best response

        6. Less dose reductions or discontinuations in mirv group

      3. MIRASOL, 2023

        1. Phase III, n = 453

        2. Mirv vs SOC chemo (paclitaxel, Doxil, topotecan) in FRalpha high expression

        3. 62% prior bev, 55% prior PARP inhibitor

        4. PFS improved from 3.9 mo in chemo group to 5.6 mo in mirv group

        5. ORR 15.9% in chemo arm to 42.3% in mirv arm

        6. 5.3% of pts in mirv group had CR vs 0% in chemo arm

        7. OS improved from 12.8 mo in chemo group to 16.5 mo in mirv group

        8. Led to full FDA approval of mirvetuximab-soravtansine for folate-receptor positive, platinum-resistant ovarian cancer for patients treated with up to three prior therapies.

      4. Gilbert, 2023

        1. Phase II, n=94

        2. Evaluated combination of mirv + bev in PROC

        3. All had FRa saturation > 25%

        4. 52% heavily pretreated with >=3 prior lines of therapy

        5. 59% with prior bev

        6. ORR 44%; 5 pts w/ complete response

          1. DOR 9.7 mo

          2. PFS 8.2 mo

      5. GLORIOSA

        1. Ongoing phase III trial

        2. Evaluating mirv + bev vs bev alone

      6. ELUCIDA

        1. Ongoing phase II trial evaluating a different folate receptor therapy in PROC

    3. Endocrine Therapy

      1. Consider in pts w/ limited or no symptoms w/ evidence of progression

      2. Tamoxifen ~10% ORR

      3. Letrozole ~10% ORR

    4. Clinical Trials

      1. Don’t forget about these!

      2. Get tumor molecular profiling on your patients!

    5. Lesser Known Therapies

      1. Fu, 2022

        1. WEE1 inhibitor adavosertib in refractory solid tumors w/ a CCNE1 mutation

        2. Ovarian cancer ORR 36%, PFS 6.3 mo, OS 14.9 mo

    6. Palliative Care

      1. majority of patients who develop a malignant bowel obstruction will have a life expectancy of less than 6 months

      2. Consider palliative chemo, G-tube placement, or TPN on individualized basis

      3. Hospice care w/ goal of patient-centered end of life care

Reference List

1. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II Trial of Bevacizumab in Persistent or Recurrent Epithelial Ovarian Cancer or Primary Peritoneal Cancer: A Gynecologic Oncology Group Study. Published online 2007. doi:10.1200/JCO.2007.11.5345

2. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II Study of Bevacizumab in Patients With Platinum-Resistant Ovarian Cancer or Peritoneal Serous Cancer. J Clin Oncol. 2007;25:5180-5186. doi:10.1200/JCO.2007.12.0782

3. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. Journal of Clinical Oncology. 2014;32(13):1302-1308. doi:10.1200/JCO.2013.51.4489

4. Bamias A, Gibbs E, Lee CK, et al. Bevacizumab with or after chemotherapy for platinum-resistant recurrent ovarian cancer: exploratory analyses of the AURELIA trial. doi:10.1093/annonc/mdx228

5. Konstantinopoulos PA, Waggoner S, Vidal GA, et al. Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. JAMA Oncol. 2019;5(8):1141-1149. doi:10.1001/jamaoncol.2019.1048

6. Wolf JK, Bodurka DC, Verschraegen C, et al. A Phase II trial of oral capecitabine in patients with platinum-and taxane-refractory ovarian, fallopian tube, or peritoneal cancer ☆. Published online 2006. doi:10.1016/j.ygyno.2005.12.040

7. Friedlander M, Hancock KC, Rischin D, et al. A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer ☆. Published online 2010. doi:10.1016/j.ygyno.2010.05.033

8. Hamanishi J, Mandai M, Ikeda T, et al. Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. Published online 2015. doi:10.1200/JCO.2015.62.3397

9. Hamanishi J, Takeshima N, Katsumata N, et al. Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA). J Clin Oncol. 2021;39:3671-3681. doi:10.1200/JCO.21

10. Matulonis U, Herrstedt J, Oza A, et al. Final overall survival and long-term safety in the ENGOT-OV16/ NOVA phase III trial of niraparib in patients with recurrent ovarian cancer (LBA 6). doi:10.1016/j.ygyno.2023.06.507

11. Matulonis UA, Shapira R, Santin A, et al. Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer. https://doi.org/101200/JCO20203815_suppl6005. 2020;38(15_suppl):6005-6005. doi:10.1200/JCO.2020.38.15_SUPPL.6005

12. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. Journal of Clinical Oncology. 2015;33(3):244-250. doi:10.1200/JCO.2014.56.2728

13. Pignata S, Lorusso D, Scambia G, et al. Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label, phase 2 trial. Lancet Oncol. 2015;16:561-568. doi:10.1016/S1470-2045(15)70115-4

14. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AL. Recurrent Epithelial Ovarian Carcinoma: a randomized phase iii study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19:3312-3322.

15. Kristeleit R, Lisyanskaya A, Fedenko A, et al. Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(4):465-478. doi:10.1016/S1470-2045(22)00122-X

16. Oza AM, Lisyanskaya AS, Fedenko AA, et al. 518O Overall survival results from ARIEL4: A phase III study assessing rucaparib vs chemotherapy in patients with advanced, relapsed ovarian carcinoma and a deleterious BRCA1/2 mutation. Ann Onc. 2023;33(S7):S780. doi:10.1016/j.annonc.2022.07.646

17. Zamarin D, Burger RA, Sill MW, et al. Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: An NRG Oncology Study. Vol 38.; 2020. https://doi.org/10.

18. Moore KN, Oza AM, Colombo N, et al. Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary&nbsp;analysis of FORWARD I. Annals of Oncology. 2021;32:757-765. doi:10.1016/j.annonc.2021.02.017

19. Moore KN, Angelergues A, Konecny GE, et al. Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. https://doi.org/101200/JCO20234117_supplLBA5507. 2023;41(17_suppl):LBA5507-LBA5507. doi:10.1200/JCO.2023.41.17_SUPPL.LBA5507

20. Gilbert L, Oaknin A, Matulonis UA, et al. Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2023;170:241-247. doi:10.1016/j.ygyno.2023.01.020

21.Fu S, Yao S, Yuan Y, et al. Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification. Journal of Clinical Oncology. 2023;41(9):1725-1734. doi:10.1200/JCO.22.00830/ASSET/IMAGES/LARGE/JCO.22.00830TA2.JPEG

Sydney Oesch
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