Ovary Part 4

Ovarian Cancer

Jul 23

Episode Notes

Recurrence Definitions
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
Prognosis
1. Median PFS unfortunately low: typically quoted 5-6 months w/ response rates (usually partial response or clinically stable disease) between 10-30%
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
Treatment Pathway Framework (A Suggestion)
1. 1. Understand patient’s goals of care, performance status, ability to tolerate chemo (best supportive care may be the best option
2. 2. Screen for clinical trials
3. 3. Review somatic and germline data to assess for targeted therapies
4. 4. Consider chemo choices (typically single agent +/- targeted therapy)
Targeted Therapy
1. 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. In high FRa group (>75% with >=2+ staining): 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, final OS in 2025
    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
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. Platinum sensitivity, age, number of prior lines of therapy not associated w/ response
4. Cannistra, 2007
  1. Phase II
  2. Single-agent bev in PROC
  3. N = 44 who had progressed w/i 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 topotecan)
  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 in subanalyses
  7. NCCN recs taxol, doxil, topotecan in combo w/ bev due to this trial
6. AURELIA exploratory analysis, 2017
  1. Published to evaluate the effect of high crossover rate to bev from single-agent chemo
  2. Of 182 patients randomized to chemo-alone group, 78 were given bev after progression on single-agent chemo
  3. 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
Immunochemotherapy
1. KEYNOTE B96, 2026
  1. Phase III double-blinded RCT
  2. Weekly taxol + pembrolizumab vs placebo every 6 weeks
  3. Bev allowed at physician discretion
  4. N = 643
  5. OS benefit of 3.7 mo in ITT population!
    1. ITT HR 0.82
  6. In CPS 1+, HR 0.76
  7. Bev did not modify effect of pembro added to taxol
  8. NCCN rec for this combo in PD-L1 tumors; however final OS reports had OS benefit in all-comers so we expect this may change
2. Zsiros et al, 2020
  1. Phase II
  2. Oral cyclophosphamide + pembro + bev
  3. 75% of included patients with PROC
  4. ORR 47%
    1. 35% in PD-L1 neg, 53% in PD-L1 pos
  5. Median PFS 10 months
  6. Listed in NCCN under other recommended therapies
3. 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
4. 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
5. 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
6. 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
Pazopanib
1. Multitargeted tyrosine kinase inhibitor
2. Best for patients with low volume recurrent ovarian cancer
3. Friedlander et al, 2010
  1. Phase II study
  2. 18% RR in patients w/ measurable disease
Cytotoxic Therapy
1. Combination therapy does not give additional benefit over single-agent treatment in the platinum-resistant, recurrent setting
2. Single agent options: docetaxel, etoposide, weekly paclitaxel, liposomal doxorubicin, topotecan
3. Other options: altretamine, capecitabine, pazopanib, cyclophosphamide, doxorubicin, ifosfamide, irinotecan, melphalan, oxaliplatin, pemetrexed, vinorelbine
4. Special side effect considerations?
  1. Neuropathy -> topotecan, gemcitabine
  2. Distance, breaks from infusion, low symptoms, low-level disease -> etoposide (has an oral option)
5. 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
6. ROSELLA, 2026
  1. Phase III RCT, n = 381
  2. Randomized to weekly nab-paclitaxel with or without relicorilant
  3. Relacorilant: glucocorticoid-receptor antagonist found to be synergistic with paclitaxel in preclinical and earlier phase clinical trials
  4. All patients had received prior bev
  5. Excluded platinum refractory patients, those who had requirement for high dose steroids (adrenal insufficiency, etc)
  6. Median OS: 16 m vs 11.5 m; HR 0.69
  7. Adverse events similar
  8. New option with an OS benefit for an unselected population, not requiring a specific biomarker!
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
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. Moore KN, Angelergues A, Konecny GE, et al. Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer. New England Journal of Medicine. 2023;389(23):2162-2174. doi:10.1056/nejmoa2309169

2. 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

3. 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 analysis of FORWARD I. Annals of Oncology. 2021;32:757-765. doi:10.1016/j.annonc.2021.02.017

4. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. Journal of Clinical Oncology. 2024;42(1):47-58. doi:10.1200/JCO.23.02005

5. 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

6. 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

7. 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

8. 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

9. Colombo N, Zsiros E, Parma G, et al. Pembrolizumab plus weekly paclitaxel in platinum-resistant recurrent ovarian cancer (ENGOT-ov65/KEYNOTE-B96): a multicentre, randomised, double-blind, phase 3 study. Lancet. 2026;407(10538):1525-1537. doi:10.1016/S0140-6736(26)00602-1

10. Zsiros E, Lynam S, Attwood KM, et al. Efficacy and Safety of Pembrolizumab in Combination with Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer: A Phase 2 Nonrandomized Clinical Trial. In: JAMA Oncology. Vol 7. American Medical Association; 2021:78-85. doi:10.1001/jamaoncol.2020.5945

11. 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

12. 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

13. 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

14. 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

15. 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.

16. 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

17. 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.

18. Olawaiye AB, Gladieff L, O’Malley DM, et al. Relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): an open-label, randomised, controlled, phase 3 trial. The Lancet. 2025;405(10496):2205-2216. doi:10.1016/S0140-6736(25)01040-2

19. 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

20. Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140(2):199-203. doi:10.1016/J.YGYNO.2015.12.020

21. 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

22. 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

23. 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

24. 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

Updated July 2026

Ovarian CancerJuly 2024part 4Updated 2026

Sydney Oesch

Ovary Part 4

Episode Notes

Reference List

Ovary Part 5

Ovary Part 3