Ovary Part 3

Ovarian Cancer
Written By Sydney Oesch

Episode Notes

  1. 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

  2. How to detect

    1. General consensus is to define recurrence based on imaging

    2. MRC OV05/EORTC 55955

      1. RCT evaluating potential benefit for treating patients for recurrence based on rising CA-125 alone vs imaging

      2. If CA-125 is two times greater than upper limit of normal (2x ULN) -> randomized to immediate treatment vs delayed treatment at the time when disease was visualized on imaging

      3. No difference in OS

  3. Treatment options

    1. Secondary cytoreduction - further discussed in surgical considerations for ovarian cancer episode

  4. Systemic chemotherapy

    1. First-line chemotherapy for recurrence

      1. Platinum-based chemo for 6 cycles

        1. Category 2A recommendations:

          1. carboplatin + paclitaxel ± bevacizumab

          2. carboplatin + liposomal doxorubicin ± bevacizumab

          3. carboplatin + gemcitabine ± bevacizumab

          4. cisplatin + gemcitabine

        2. Gordon Trial, 2001

          1. Single-agent Doxil vs single-agent topotecan

          2. PFS improved by 5 weeks and OS improved by 37 weeks in plat-sensitive group who received Doxil

          3. No difference in plat-resistant group

        3. ICON4, 2003

          1. Phase 3 RCT

          2. Conventional platinum chemo (carbo, CAP, cis-doxo, cis) vs carbo/taxol

          3. PFS improved 3 months and OS improved 5 months w/ carbo/taxol

          4. No difference in QOL or completion of regimen

        4. Pfisterer, 2006

          1. Carboplatin vs carboplatin + gemcitabine

          2. PFS improved 3 months, no difference in OS

          3. No difference in QOL

          4. Increase in grade 3-4 toxicity, primarily hematologic, in combo group

        5. Calypso 2010, long-term data 2012

          1. Phase 3 non-inferiority RCT

          2. Carbo/Doxil vs Carbo/Taxol

          3. PFS 11.3 mo in carbo/doxil vs 9.4 in carbo/taxol

          4. OS not different

          5. Carbo/doxil is noninferior to carbo/taxol, is better tolerated with less treatment discontinuation, and may have less long-term side effects from neuropathy.  It also had significantly less carboplatin hypersensitivity reactions, which can prove to be a challenging clinical situation if carboplatin desensitization is needed

    2. Bevacizumab

      1. OCEANS 2012, long term f/u 2015

        1. Phase 3 RCT

        2. Carbo + gemcitabine +/- bevacizumab

        3. PFS 12.4 vs 8.4 mo favoring bevacizumab arm

        4. OS not different

        5. Increased grade 3-4 HTN and proteinuria in bevacizumab arm

        6. 2 GI perforations in the ~240 study participants

        7. This study showed that the addition of bevacizumab to carboplatin + gemcitabine followed by bevacizumab maintenance can improve progression free survival, but does not affect overall survival.  It also carries several unique toxicities

      2. GOG213, 2017

        1. Bifactorial phase 3 trial

        2. Two objectives:

          1. to evaluate secondary cytoreduction in platinum-sensitive disease

          2. to evaluate the addition of bevacizumab to chemotherapy in platinum-sensitive disease

        3.  randomized to investigator choice chemo (being either carboplatin + paclitaxel or carboplatin + gemcitabine) with or without bevacizumab + bevacizumab maintenance

        4. PFS was 13.8 vs 10.4 months, favoring the bevacizumab arm, which was a statistically significant improvement

          1. results were consistent regardless of participation in the surgical cytoreduction objective, platinum-free interval, or prior treatment of bevacizumab

        5. OS not different in ITT population

      3. GOG170D

        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. MITO16b/MANGO-OV2/ENGOT-ov17, 2012

        1. Phase 3 RCT

        2. patients with recurrent platinum-sensitive epithelial ovarian cancer who had received bevacizumab during their first-line treatment

        3. randomized to standard platinum doublet therapy (carbo/taxol, carbo/gem, carbo/doxil) vs platinum doublet + bevacizumab

        4. PFS improved by 3 months with the addition of bevacizumab with no new unexpected toxicities

      5. Takeaway:  in the recurrent setting, bevacizumab tends to grant about 4 month benefit in progression free survival, but overall survival is not consistently improved.  With bevacizumab, there are additional toxicities to consider, and no study has demonstrated its cost-effectiveness.

  5. PARP Inhibitors

    1. Olaparib

      1. Study 19, 2012

        1. Phase II

        2. Evaluated maintenance olaparib in plat-sensitive EOC

        3. In the ITT population, 22% were BRCA mutated, 15% were BRCA wild type, and 63% were status unknown

        4. PFS benefit was 8.4 vs 4.8 months

      2. SOLO2/ENGOT-OV21, 2021

        1. evaluated olaparib maintenance after chemotherapy in patients with platinum sensitive high grade serous ovarian cancer or high-grade endometrioid ovarian cancer with BRCA mutations who had received 2 or more prior lines of chemotherapy

        2. PFS improved from 5.5 months to 19.1 months with olaparib maintenance

        3. OS not different

      3. SOLO3, 2020; f/u OS data as abstract in Gyn Oncol 2022

        1. olaparib mono-therapy versus non-platinum chemotherapy in patients with heavily pretreated (meaning ≥ 2 prior lines of platinum chemotherapy) platinum-sensitive, BRCA1/2 epithelial ovarian cancer

        2. In patients with measurable disease, ORR was 72.2% vs 51.4% with olaparib vs chemotherapy

        3. In the subgroup with > 2 prior lines of treatment, ORR favored olaparib with 84.6% vs 61.5%

        4. PFS improved with olaparib vs chemotherapy with 13.4 vs 9.2 months.  

        5. In the follow-up analysis, OS not different

        6. As a result of these studies, the FDA indication was withdrawn for PARP monotherapy for patients with 3 or more lines of prior therapy, even if they are BRCA mutated!

    2. Rucaparib

      1. ARIEL 2, 2017

        1. Phase II study

        2. evaluate the utility of LOH to predict response to rucaparib in recurrent, platinum-sensitive, high grade serous and endometrioid ovarian cancer with at least 1 prior platinum chemotherapy

        3. Classified into predefined homologous recombination deficiency (HRD) subgroups:

          1. somatic or germline BRCA mutation

          2. genome-wide loss of heterozygosity in the tumor (“LOH high”)

          3. LOH low

        4. PFS was best in the BRCA mutated group (12.8m), followed by the LOH high group and LOH low group ( 5.7 and 5.2 months, respectively)

      2. ARIEL 3, 2017

        1. Phase 3, double blinded, RCT

        2. Evaluating rucaparib maintenance in patients with: (1) genetic or somatic BRCA mutation (2) BRCA wild-type HRD positive (i.e. LOH high) and (3) BRCA wild-type and LOH low or indeterminate

        3. PFS improved in  BRCA mutated and HRD+/LOH-high populations compared to LOH-low: 16.6 vs 13.6 vs 5.4 months

        4. In ITT, PFS was 10.8 months vs 5.4 months placebo

        5. No OS benefit in in the ITT or any subgroup

        6. Takeaway: This study found that across all primary analysis groups, PFS was significantly improved, giving further evidence for PARP inhibitor maintenance

      3. ARIEL 4, 2022

        1. Phase 3 RCT

          1. Different than other studies for two reasons: 

            1. recurrent, BRCAmutated epithelial ovarian cancer with platinum-sensitive OR platinum-resistant disease

            2. evaluated rucparib monotherapy (and not maintenance) vs. SOC chemotherapy

          2. ITT population: PFS improved 7.4 mo vs 5.7 mo

          3. OS not different in ITT population or platinum-sensitive group

          4. 70% of patients who progressed on chemotherapy crossed over to PARPi (meaning 90% of people in this trial eventually got PARPi)

            1. when excluding these crossover patients, there was a survival benefit observed of 19.4 vs 8.1 months

            2. patients with platinum-resistant disease treated with PARP monotherapy had an overall survival detriment, with a median OS of 14.2m vs. 22.2m, HR 1.5!

    3. Niraparib

      1. NOVA, 2016

        1. evaluated niraparib maintenance in recurrent, platinum sensitive ovarian cancer with >= 2 prior chemotherapies stratified by the presence or absence of germline BRCA mutation

        2. In pts w/o a germline BRCA mutation, defined by MyChoice HRD test as (a) HRD-positve/somatic BRCA mutation, (b) HRD-positive/BRCA wildtype (with other mutations in the HRD pathway, and (c) HRD-negative

        3. PFS: gBRCA 21 mo, HRD+ groups 12.9mo, overall non-germline BRCA cohort (including those with and without HRD mutations) had a PFS advantage of 9.3 vs 3.9 months

        4. OS data was not significant for any subpopulation, even the germline BRCA mutation.  

        5. Subsequently, FDA approval has been withdrawn for all maintenance therapy for patients without germline or somatic BRCA mutations for recurrent, platinum-sensitive disease

    4. FDA PARP inhibitor approval statuses as ove 2023

      1. no indication for PARP monotherapy at this time in recurrent, either platinum-sensitive or platinum-resistant, ovarian cancer

      2. can be used for 2nd or greater line maintenance therapy following response to platinum-based chemotherapy for patients with recurrent platinum-sensitive ovarian cancer in the following situations:

        1. for olaparib and rucaparib, any patient with germline or somatic BRCA deleterious mutation

        2. for niraparib, germline or suspected germline BRCA deleterious mutation.  

      3. FDA approval has been removed for BRCA wild-type patients given the lack of overall survival benefit. As we’ll discuss in the following episode, for platinum resistant patients, PARPi are not recommended.

    5. PARP after PARP

      1. OREO/ENGOT-ov38, 2023

        1.  patients, with or without BRCA mutations, with heavily pre-treated (>=3 prior lines of chemo) platinum-sensitive disease who had previously received one prior PARP treatment

          1. re-challenged with olaparib and were in response to platinum when the treatment was started

        2. BRCA mutated cohort, PFSwas 4.3 mo vs 2.8 mo favoring olaparib. 

          1. In fact, 1 year PFS was 19% in that group vs 0% without olaparib

        3. BRCA non-mutated group, PFS was 5.3 months with olaparib re-challenge vs 2.8 months with placebo.  

        4. Takeaway: this is early data with limited studies and time will tell how we use this data to inform treatment decisions

  6. Targeted Therapies

    1. Keynote 100, 2019

      1. studied single-agent pembrolizumab in patients with recurrent EOC until progression of disease, intolerable toxicity, or maximum duration of treatment 2 years

      2. Two study groups:

        1. Cohort A: patients who had received 1-3 prior lines of treatment and had a platinum free interval between 3-12 months

        2. Cohort B: heavily pretreated patients with 4-6 prior lines of treatment with a progression free interval of ≥ 3 months

      3. stratified by the combined positive score (CPS): the number of PD-L1 staining cells (including tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells x 100

      4. ORR in Cohort B increased to 18% from 9.9% if the PD-L1 CPS was ≥ 10%

      5. Median OS was 18.7 mo and 17.6 mo in cohort A and B

        1. OS increased to 21.9 mo and 24 mo in cohorts A and B if the CPS score was ≥ 10%

      6. 75% of patients had treatment related adverse events, with 20% being grade 3-4.  There were 2 treatment-related deaths, related to Stevens Johnson Syndrome and hypoaldosteronism

    2. NTRK

      1. Entrectinib/larotrectinib can be considered for NTRK gene fusion positive tumors

      2. Very limited data for use of these agents in ovarian cancer

      3. Mutation occurs in <1% of ovarian cancers

    3. Subbiah, 2022 (pralsetinib)

      1. RET fusion positive solid tumors

      2. 1 patient w/ ovarian cancer w/ partial response, w/ duration of response 14.5 mo

    4. Pazopanib

      1. Phase II trial of 36 patients

      2. ORR 18% in pts w/ CR to initial therapy

      3. 75% of total patients were platinum sensitive

    5. Mirvetuximab ± bevacizumab

      1. Can be considered; however, trials were performed in pts w/ platinum-resistant ovarian cancer

        Reference List

1. 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. Articles Lancet Oncol. 2017;18:779-791. doi:10.1016/S1470-2045(17)30279-6

2. Coleman RL, Spirtos NM, Enserro D, et al. Secondary Surgical Cytoreduction for Recurrent Ovarian Cancer. New England Journal of Medicine. 2019;381(20):1929-1939. doi:10.1056/nejmoa1902626

3. S Rustin GJ, L van der Burg ME, Griffi CL, et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. www.thelancet.com. 376:1155-1163. doi:10.1016/S0140-6736(10)61268-8

4. GERSHENSON DM, KAVANAGH JJ, COPELAND LJ, STRINGER CA, MORRIS M, WHARTON JT. Re-Treatment of Patients With Recurrent Epithelial Ovarian Cancer With Cisplatin-Based Chemotherapy. Obstetrics & Gynecology. 1989;73(5). https://journals.lww.com/greenjournal/fulltext/1989/05000/re_treatment_of_patients_with_recurrent_epithelial.24.aspx

5. 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.

6. Pignata S, Lorusso D, Joly F, et al. Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial. Articles Lancet Oncol. 2021;22:267-276. Accessed March 25, 2024. www.thelancet.com/oncology

7. The ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: The ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361(9375):2099-2106. doi:10.1016/S0140-6736(03)13718-X

8. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine Plus Carboplatin Compared With Carboplatin in Patients With Platinum-Sensitive Recurrent Ovarian Cancer: An Intergroup Trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006;24:4699-4707. doi:10.1200/JCO.2006.06.0913

9. 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. Journal of Clinical Oncology. 2010;28(20):3323-3329. doi:10.1200/JCO.2009.25.7519

10. Wagner U, Marth C, Largillier R, et al. Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br J Cancer. 2012;107:588-591. doi:10.1038/bjc.2012.307

11. Aghajanian C, Blank S V, Goff BA, et al. OCEANS: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Chemotherapy With or Without Bevacizumab in Patients With Platinum-Sensitive Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer. J Clin Oncol. 2012;30:2039-2045. doi:10.1200/JCO.2012.42.0505

12. Aghajanian C, Goff B, Nycum LR, Wang Y V, Husain A, Blank S V. 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. Published online 2015. doi:10.1016/j.ygyno.2015.08.004

13. Matulonis UA, Shapira-Frommer R, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Annals of Oncology. 2019;30:1080-1087. doi:10.1093/annonc/mdz135

14. 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

15. 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

16. O’Malley DM, Myers TKN, Zamagni C, Diver E, Lorusso D. GLORIOSA: A randomized, open-label, phase 3 study of mirvetuximab soravtansine with bevacizumab vs. bevacizumab as maintenance in platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. https://doi.org/101200/JCO20234116_supplTPS5622. 2023;41(16_suppl):TPS5622-TPS5622. doi:10.1200/JCO.2023.41.16_SUPPL.TPS5622

17. 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

18. Poveda A, Floquet A, Ledermann JA, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial. Articles Lancet Oncol. 2021;22:620-651. doi:10.1016/S1470-2045(21)00073-5

19. Penson R, Valencia RV, Colombo N, et al. Final overall survival results from SOLO3: Phase III trial assessing olaparib monotherapy versus non-platinum chemotherapy in heavily pretreated patients with germline BRCA1 - and/or BRCA2-mutated platinum-sensitive relapsed ovarian cancer (026). Gynecol Oncol. 2022;166:S19-S20. doi:10.1016/S0090-8258(22)01244-6

20. Ledermann J, Harter P, Gourley C, et al. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. New England Journal of Medicine. 2012;366(15):1382-1392. doi:10.1056/nejmoa1105535

21. Swisher EM, Lin KK, Oza AM, et al. Articles Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. www.thelancet.com/oncology. 2017;18:75. doi:10.1016/S1470-2045(16)30559-9

22. 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. The Lancet. Published online 2017. doi:10.1016/S0140-6736(17)32440-6

23. Coleman RL, Oza AM, Lorusso D, et al. 2022-RA-249-ESGO OVERALL SURVIVAL RESULTS FROM ARIEL3: A PHASE 3 RANDOMISED, DOUBLE-BLIND STUDY OF RUCAPARIB VS PLACEBO FOLLOWING RESPONSE TO PLATINUM-BASED CHEMOTHERAPY FOR RECURRENT OVARIAN CARCINOMA 1,2. doi:10.1136/ijgc-2022-ESGO.488

24. 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

25. 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

26. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. New England Journal of Medicine. 2016;375(22):2154-2164. doi:10.1056/NEJMOA1611310/SUPPL_FILE/NEJMOA1611310_DISCLOSURES.PDF

27. 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

28. Pujade-Lauraine E, Selle F, Scambia G, et al. Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial. Annals of Oncology. 2023;34(12):1152-1164. doi:10.1016/j.annonc.2023.09.3110

29. 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

30.Subbiah V, Wolf J, Konda B, Kang H, Spira A, Weiss J. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Articles Lancet Oncol. 2022;23:1261-1273. doi:10.1016/S1470-2045(22)00541-1

Sydney Oesch
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