Improving survival in recurrent ovarian cancer, miles to go before we sleep
Editorial Commentary

Improving survival in recurrent ovarian cancer, miles to go before we sleep

Peter G. Rose ORCID logo

Section Gynecologic Oncology, Cleveland Clinic, Case Western Reserve University, Cleveland, OH, USA

Correspondence to: Peter G. Rose, MD. Tenured Professor Reproductive Biology and Oncology, Section Gynecologic Oncology, Cleveland Clinic, Case Western Reserve University, A-81, 9500 Euclid Ave., Cleveland, OH 44195, USA. Email: rosep@ccf.org.

Comment on: Gonzalez Martin A, Rubio Perez MJ, Heitz F, et al. Atezolizumab (atezo) combined with platinum-based chemotherapy (CT) and maintenance niraparib for recurrent ovarian cancer (rOC) with a platinum-free interval (TFIp) >6 months: Primary analysis of the double-blind placebo (pbo)-controlled ENGOT-Ov41/GEICO 69-O/ANITA phase III trial. Ann Oncol 2023;34:S1278-9.

Keywords: Ovarian cancer; checkpoint inhibition; atezolizumab

Received: 08 January 2024; Accepted: 21 June 2024; Published online: 30 August 2024.

doi: 10.21037/gpm-24-3

The authors report the phase III ENGOT-Ov41/GEICO 69-O/ANITA trial which tested whether the addition of an immune checkpoint inhibitor (atezolizumab) to standard platinum-based regimens and niraparib maintenance improves the progression-free survival (PFS) for platinum sensitive recurrent ovarian cancer (1). Patients were stratified by carboplatin doublet [paclitaxel, gemcitabine or pegylated liposomal doxorubicin (PLD)], TFIp (6–12 vs. >12 months), BRCA status (mutated vs. nonmutated) and programmed death-ligand 1 (PD-L1) status (PD-L1-expressing immune cells on <1% vs. ≥1% vs. noninformative. Four hundred and seventeen patients were randomized 1:1 to atezolizumab vs. placebo. Patient characteristics were similar to other trials in platinum sensitive ovarian cancer (14% BRCA mutated, 66% TFIp >12 months). The response rate to chemotherapy/niraparib/atezolizumab was 45% vs. chemotherapy/niraparib which was 43%. The median PFS for all patients were 11.2 vs. 10.1 months, P=0.28 for the atezolizumab and placebo patients, respectively. Among the PD-L1 positive patients, median PFS was 12.8 vs. 11.1 months for the atezolizumab and placebo patients, respectively. The authors concluded that the addition of atezolizumab to platinum-based chemotherapy and niraparib for late relapsing ovarian cancer did not improve response rates or PFS.

The development and Food and Drug Administration (FDA) approval of the checkpoint inhibitors has greatly expanded immuno-oncology therapies. These agents that interrupt the cancer cells suppression of T-cells restoring innate immunity. There are currently 8 checkpoint inhibitors approved for various cancers (Table 1).

Table 1

FDA approved checkpoint inhibitor

Check point inhibitor Immune target Year FDA approval Indication
Ipilimumab Anti CTLA-4 3/2011 Melanoma
Nivolumab Anti PD-1 12/2014 Melanoma
Pembrolizumab Anti PD-1 10/2015 NSCLC
Durvalumab Anti PD-L1 3/2020 SCLC
Atezolizumab Anti PD-L1 5/2020 NSCLC
Avelumab Anti PD-L1 6/2020 Urothelial carcinoma
Cemiplimab Anti PD-1 2/2021 Basel cell carcinoma
Dostarlimab Anti PD-1 4/2021 Endometrial cancer

FDA, Food and Drug Administration; CTLA-4, cytotoxic T-lymphocyte associated protein 4; PD-1, programmed cell death 1; NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1; SCLC, small cell lung cancer.

Although immune checkpoint inhibitors have significant activity in MMR deficient endometrial cancer and PD-L1 positive cervical cancer the response rates in ovarian cancer have been disappointingly low. While the different histologies of ovarian cancer; high grade serous, endometrioid, clear cell and mucinous tumors are almost equally distributed in early stage, high grade serous is the predominant histology in advanced stage ovarian cancer (2). In platinum resistant ovarian cancer patients 90–95% have high grade serous histology (3). In a systematic review by Mitric et al. the prevalence of MMRd, MSI-high, and LS in EOC was 6%, 13%, and 2%, respectively (4). Hypermethylation was present in 76% of patients with MLH1 deficiency. The MMRd prevalence was highest in endometrioid (12%) followed by non-serous non-mucinous (9%) and lowest in serous (1%) histological subtypes. MSI-high prevalence was highest in endometrioid (12%) and non-serous non-mucinous (12%) and lowest in serous (9%) histological subtypes. Haminishi first reported the use of immune checkpoint inhibitor nivolumab in two 10 patient cohorts of 1 and 3 mg/kg (5). There was one partial response at 1 mg/kg and two complete responses at 3 mg/kg. Varga et al. first reported pembrolizumab in ovarian cancer in KEYNOTE 28 (6). Among 26 evaluable ovarian cancer patients treated with pembrolizumab, at 10 mg/kg every 2 weeks, 3 responses were observed (11.1%). Matulonis et al. reported the results of KEYNOTE 100, a study of single agent pembrolizumab 200 mg every 3 weeks in patients with ovarian cancer (7). Cohort A enrolled 285 patients with 1–3 prior lines of treatment with a platinum-free interval (PFI) or treatment-free interval (TFI) between 3 and 12 months with an objective response rate (ORR) of 7.4%. Cohort B enrolled 91 patients who received 4–6 prior lines with a PFI/TFI of ≥3 months with an ORR of 9.9%. The expression of PD-L1 was evaluated using combined positive score (CPS) score defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells × 100. In patients with CPS <1, the response rate was 5.0% while for patients with CPS ≥1 and ≥10, it was 10.2% and 17.1%, respectively. The fact that PD-L1 scores of <1 respond to immunotherapy suggests that this is an imperfect biomarker. Perhaps we should only be looking at the PD-L1 staining of the tumor cells, or other cell populations. Other factors in the tumor microenvironment or immune resistant stem cells may also explain the failure of immunotherapy in high grade serous ovarian cancer (8,9).

Numerous studies have attempted to increase exposure of tumor associated antigens converting “cold ovarian cancer cells” to “hot ovarian cancer cells” now sensitive to immune checkpoint inhibitors. One such example is supported by data that suggests that immunomodulation induced by DNA hypomethylating agents such as guadecitabine can sensitize tumors to immune checkpoint inhibitors (10). Utilizing this strategy in platinum resistant ovarian cancer, guadecitabine priming was used before prembrolizumab with a 9.9% response rate (11).

The combination of a PARP inhibitor and immune checkpoint inhibitor has been studied in numerous phase I/II trials. The TOPACIO/KEYNOTE-162 trial enrolled patients with niraparib in combination with pembrolizumab in patients with triple-negative breast cancer or ovarian cancer (12). Nine patients in the phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients. The overall response rate was 18% [90% confidence interval (CI): 11–29%], including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, with a disease control rate of 65% (90% CI: 54–75%). Lampert et al. studied the combination of olaparib in combination with durvalumab in 35 ovarian cancer patients with a median of 4 prior lines of therapy (86% platinum resistant and 77% BRCA wild type) with a 14% response rate (13). A treatment enhanced immune response was associated with improved PFS [hazard ratio (HR) 0.37, 95% CI: 0.16–0.87, P=0.023], while elevated VEGFR3 levels were associated with worse PFS (HR 3.22, 95% CI: 1.23–8.40, P=0.017) suggesting VEGF/VEGFR pathway blockade would be necessary for improved efficacy of the combination. Liu et al. reported the combination of nivolumab 240-mg and bevacizumab 10 mg/kg every 14 days in patients with recurrent ovarian cancer (14). Of the 38 women enrolled, 18 had platinum-resistant and 20 had platinum-sensitive disease. The ORR was 40.0% (95% CI: 19.1–64.0%) in platinum-sensitive and 16.7% (95% CI: 3.6–41.4%) in platinum-resistant participants. Zsiros et al. reported the combination of pembrolizumab, bevacizumab, and metronomic cyclophosphamide in patients with recurrent ovarian cancer (15). Among 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer. Six of the 10 platinum sensitive and 13 of the 30 platinum resistant patients responded.

More recently, Harter et al. (16) reported the DUO-O/ENGOT-ov46/AGO-OVAR 23/GOG3025 trial comparing:

  • Arm 1: standard treatment with upfront paclitaxel/carboplatin plus bevacizumab, followed by maintenance bevacizumab for 15 months.
  • Arm 2: standard treatment as above, plus durvalumab upfront and durvalumab added to maintenance bevacizumab for 24 months.
  • Arm 3: standard treatment as above, plus durvalumab upfront and durvalumab and olaparib added to maintenance bevacizumab for 24 months.

This demonstrated an increase in PFS for patients in arm 3 compared to arm 1 (median 24.2 vs. 19.3 months). Longest median PFS in homologous recombination deficiency (HRD)-positive patients: median of 37.3 months with durvalumab/olaparib. Benefit for durvalumab/olaparib in HRD-negative patients: median PFS 20.9 months. No significant difference between arm 3 vs. arm 2; both contain durvalumab, but arm 3 also contained olaparib for maintenance. This again demonstrates the importance of VEGF/VEGFR pathway blockade with immune checkpoint inhibitors in ovarian cancer. Maybe the negative results of the ENGOT-Ov41/GEICO 69-O/ANITA phase III trial is the failure to block the VEGF/VEGFR pathway.

We have been conducting clinical trials under the mantra that a checkpoint inhibitor is a checkpoint inhibitor, is a checkpoint inhibitor, is a checkpoint inhibitor. While all the currently approved immune checkpoint inhibitors have demonstrated efficacy in randomized clinical trials, disparate results in randomized trial in gynecologic cancer have been reported (Table 2). Let’s try to compare the most similar of these studies. The CALLA trial and KEYNOTE A18 both accrued locally advanced cervical cancer patients receiving primary chemoradiation (17,18). The CALLA study showed the addition of durvalumab did not statistically significant outcome but the KEYNOTE A18 trial showed the addition of pembrolizumab resulted in improvement in PFS at 24 months. The patients in the study differed in their risk category. In the CALLA trial, 12% of the the patients in the durvalumab arm had radiologic evidence of paraaortic nodal metastasis while in the KEYNOTE A18 trial, 22.4% in the pembrolizumab arm had radiologic evidence of paraaortic nodal metastasis. In the CALLA trial the greatest benefit of durvalumab as in the patients with paraaortic nodal metastasis but this was not statistically significant. NRG-018, Ruby and MITO END-3 are very similar with respect to patient population (22-24). While there are very similar results for MMR deficient endometrial cancer patients treated with pembrolizumab or dostarlimab there are discrepancies in the response of MMR proficient patients (22,23). Most striking is that the use of avelumab in the same patient population shows no significant activity (24). In ovarian cancer with the results of ENGOT-Ov41/GEICO 69-O/ANITA there are now three studies, two of which included bevacizumab, failing to show improvement with atezolizumab (1,26,28). But atezolizumab is active with bevacizumab in cervical cancer (20).

Table 2

Randomized trials of checkpoint inhibitors in gynecologic cancer

Primary site Treatment setting I-O agent HR/P value
Cervix
   CALLA (17) LACC/cisplatin chemoradiation Durvalumab (anti PD-L1) during radiation and maintenance for 2 years NS
   ENGOT-cx11/GOG-3047/Keynote-A18 (18) LACC/cisplatin chemoradiation Pembrolizumab (anti PD-1) during radiation and maintenance for 2 years PFS at 24 months 67.8% vs. 57.3%; P=0.002
   Keynote 826 (19) 1st line metastatic with cisplatin, paclitaxel +/− bevacizumab Pembrolizumab (anti PD-1) PFS HR 0.62, P<0.0001
   BEATcc study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030) (20) 1st line metastatic with cisplatin, paclitaxel + bevacizumab +/− atezolizumab (anti PD-L1) PFS HR 0.62, P<0.0001
OS HR 0.68, P=0.0046
   GOG Protocol 3016/ENGOT Protocol En-Cx9 (21) 2nd line metastatic Cemiplimab (anti PD-1) vs. physician choice single agent chemotherapy PFS HR 0.75; P<0.001
OS HR 0.69; P<0.001
Endometrium
   NRG 018 (22) 1st line metastatic with carboplatin and paclitaxel Pembrolizumab (anti PD-1) during chemotherapy and for 15 cycles dMMR (PFS HR 0.30, P<0.05, OS = NR)
pMMR (PFS HR 0.54, P<0.05, OS = NR)
   Ruby (23) 1st line metastatic with carboplatin and paclitaxel Dostarlimab (anti PD-1) during chemotherapy and for 26 cycles dMMR (PFS HR 0.28, P<0.001; OS HR 0.30, P<0.05)
pMMR (PFS HR 0.76, P<0.05; OS HR 0.73, P>0.05)
   MITO END-3 (24) 1st line metastatic with carboplatin and paclitaxel Avelumab (anti PD-L1) during chemotherapy and as maintenance PFS HR 0.78, P=0.085 (one-tailed)
OS HR 1.13, P=0.91 (two-tailed)
   KEYNOTE 775 (25) 2nd line metastatic Pembrolizumab (anti PD-1) vs. physician choice doxorubicin or weekly taxol PFS HR 0.60, P<0.001
OS HR 0.68, P<0.001
Ovary
   IMagyn050/GOG 3015/ENGOT-OV39 (26) 1st line metastatic with carboplatin, paclitaxel + bevacizumab Atezolizumab (anti PD-L1) PFS HR 0.92, P=0.28, OS = NR
   Javelin 100 (27) 1st line metastatic with carboplatin, paclitaxel Avelumab (anti PD-L1) maintenance vs. combination (during chemotherapy and maintenance) vs. control (chemotherapy alone) PFS HR 1.43, P=0.99
Avelumab maintenance PFS HR 1.14, P=0.79; avelumab combination vs. control
   ATALANTE/ENGOT-ov29 (28) Recurrent platinum sensitive Platinum doublet/bevacizumab +/− atezolizumab (anti PD-L1) PFS HR 0.83, P>0.05
OS HR 0.81, P>0.05
   ENGOT-Ov41/GEICO 69-O/ANITA (1) Recurrent platinum sensitive Platinum doublet/niraparib +/− atezolizumab (anti PD-L1) PFS HR 0.89, P=0.28
   Javelin 200 (29) Recurrent platinum resistant Avelumab (anti PD-L1) alone or avelumab plus PLD vs. PLD alone PFS
- Combination vs. PLD: HR 0.78, P>0.05
- Avelumab vs. PLD HR 1.68, P>0.99

I-O, immunotherapy; HR, hazard ratio; LACC, locally advanced cervical cancer; PD-L1, programmed death-ligand 1; NS, not significant; PD-1, programmed cell death 1; PFS, progression-free survival; OS, overall survival; dMMR, deficient mismatch repair; NR, not reported; pMMR, proficient mismatch repair; PLD, pegylated liposomal doxorubicin.

How can we better select an immune checkpoint inhibitor for trial. It seems we are in a situation described in Siddhartha Mukherjee book Song of the Cell “We can name cells, and even systems of cells, but we are yet to learn the songs of cell biology” (30). In the KEYNOTE 100 an exploratory analysis failed to identify gene expression signatures and outcomes with pembrolizumab (31). However, higher densities of myeloid cell phenotypes CD11c+ and CD11c+/MHCII−/CD163−/CD68− trended toward improved efficacy. In the TOPACIO trial, biomarkers include tumor BRCA mutation status, HRD status (assessed by the Myriad HRD test), and PD-L1 status were not associated with response to the niraparib/pembrolizumab combination (32). However, mutational signature 3 and interferon signaling in the CD8+ T-cell compartment of the tumor microenvironment correlated with more frequent disease control. These findings will need to be confirmed in future studies. Identification and confirmation of predictive biomarkers to guide individualized patient therapy and future trial design in ovarian cancer are desperately needed (33).

Unfortunately, the addition of atezolizumab to a platinum doublet and niraparib maintenance failed to improve outcome in the ENGOT-Ov41/GEICO 69-O/ANITA study for platinum sensitive recurrent ovarian cancer. This does not exclude possible benefit with a different anti PD-L1 or programmed cell death 1 (PD-1) agent. We obviously need greater understanding of how the immune cells, cancer cells and immune checkpoint inhibitors are singing to each other. Paraphrasing Robert Frost “we have promises to keep and miles to go before we sleep”.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-3/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-3/coif). The author reported consulting fees from Eisai. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Gonzalez Martin A, Rubio Perez MJ, Heitz F, et al. Atezolizumab (atezo) combined with platinum-based chemotherapy (CT) and maintenance niraparib for recurrent ovarian cancer (rOC) with a platinum-free interval (TFIp) >6 months: Primary analysis of the double-blind placebo (pbo)-controlled ENGOT-Ov41/GEICO 69-O/ANITA phase III trial. Ann Oncol 2023;34:S1278-9. [Crossref]
  2. Peres LC, Cushing-Haugen KL, Köbel M, et al. Invasive Epithelial Ovarian Cancer Survival by Histotype and Disease Stage. J Natl Cancer Inst 2019;111:60-8. [Crossref] [PubMed]
  3. Morton M, Yao M, Chalif J, et al. Association of Clinical Trial Participation With Improved Overall Survival for Recurrent, Platinum-Resistant Ovarian Cancer. Obstet Gynecol 2023;142:459-66. [Crossref] [PubMed]
  4. Mitric C, Salman L, Abrahamyan L, et al. Mismatch-repair deficiency, microsatellite instability, and lynch syndrome in ovarian cancer: A systematic review and meta-analysis. Gynecol Oncol 2023;170:133-42. [Crossref] [PubMed]
  5. 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. J Clin Oncol 2015;33:4015-22. [Crossref] [PubMed]
  6. Varga A, Piha-Paul SA, Ott PA, et al. Pembrolizumab in patients (pts) with PD-L1–positive (PD-L1+) advanced ovarian cancer: Updated analysis of KEYNOTE-028. J Clin Oncol 2017;35:5513. [Crossref]
  7. 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. Ann Oncol 2019;30:1080-7. [Crossref] [PubMed]
  8. Lv B, Wang Y, Ma D, et al. Immunotherapy: Reshape the Tumor Immune Microenvironment. Front Immunol 2022;13:844142. [Crossref] [PubMed]
  9. Ahmed N, Escalona R, Leung D, et al. Tumour microenvironment and metabolic plasticity in cancer and cancer stem cells: Perspectives on metabolic and immune regulatory signatures in chemoresistant ovarian cancer stem cells. Semin Cancer Biol 2018;53:265-81. [Crossref] [PubMed]
  10. Papadatos-Pastos D, Yuan W, Pal A, et al. Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors. J Immunother Cancer 2022;10:e004495. [Crossref] [PubMed]
  11. Chen S, Xie P, Cowan M, et al. Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer. J Clin Invest 2022;132:e158800. [Crossref] [PubMed]
  12. 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;5:1141-9. [Crossref] [PubMed]
  13. Lampert EJ, Zimmer A, Padget M, et al. Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study. Clin Cancer Res 2020;26:4268-79. [Crossref] [PubMed]
  14. Liu JF, Herold C, Gray KP, et al. Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial. JAMA Oncol 2019;5:1731-8. [Crossref] [PubMed]
  15. 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. JAMA Oncol 2021;7:78-85. [Crossref] [PubMed]
  16. Harter P, Trillsch F, Okamoto A, et al: Durvalumab with paclitaxel/carboplatin and bevacizumab followed by maintenance durvalumab, bevacizumab and olaparib in patients with newly diagnosed advanced ovarian cancer without a tumor BRCA1/BRCA2 mutation: Results from the randomized, placebo-controlled phase III DUO-O/ENGOT-ov46/AGO-OVAR 23/GOG-3025 trial. 2023 ASCO Annual Meeting. Abstract LBA5506. Presented June 3, 2023.
  17. Monk BJ, Toita T, Wu X, et al. Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial. Lancet Oncol 2023;24:1334-48. [Crossref] [PubMed]
  18. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: A randomized, doubleblind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. Ann Oncol 2023;34:S1279-80. [Crossref]
  19. Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med 2021;385:1856-67. [Crossref] [PubMed]
  20. Oaknin A, Gladieff L, Martinez-Garcia J, et al. Primary results from BEATcc (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030), a randomised phase III trial of first-line atezolizumab (atezo) combined with a platinum doublet and bevacizumab (bev) for metastatic (stage IVB), persistent or recurrent cervical cancer (R/M CC). Ann Oncol 2024;34:1198-2000. [Crossref]
  21. Tewari KS, Monk BJ, Vergote I, et al. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med 2022;386:544-55. [Crossref] [PubMed]
  22. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer. N Engl J Med 2023;388:2159-70. [Crossref] [PubMed]
  23. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med 2023;388:2145-58. [Crossref] [PubMed]
  24. Pignata S, Scambia G, Schettino C, et al. Carboplatin and paclitaxel plus avelumab compared with carboplatin and paclitaxel in advanced or recurrent endometrial cancer (MITO END-3): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol 2023;24:286-96. [Crossref] [PubMed]
  25. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775. J Clin Oncol 2023;41:2904-10. [Crossref] [PubMed]
  26. Moore KN, Bookman M, Sehouli J, et al. Atezolizumab, Bevacizumab, and Chemotherapy for Newly Diagnosed Stage III or IV Ovarian Cancer: Placebo-Controlled Randomized Phase III Trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol 2021;39:1842-55. [Crossref] [PubMed]
  27. Monk BJ, Colombo N, Oza AM, et al. Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:1275-89. [Crossref] [PubMed]
  28. Kurtz JE, Pujade-Lauraine E, Oaknin A, et al. Atezolizumab Combined With Bevacizumab and Platinum-Based Therapy for Platinum-Sensitive Ovarian Cancer: Placebo-Controlled Randomized Phase III ATALANTE/ENGOT-ov29 Trial. J Clin Oncol 2023;41:4768-78. [Crossref] [PubMed]
  29. Pujade-Lauraine E, Fujiwara K, Ledermann JA, et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol 2021;22:1034-46. [Crossref] [PubMed]
  30. Mukherjee S. The Song of the Cell: An Exploration of Medicine and the New Human. First edition. Scribner; 2022.
  31. Ledermann JA, Shapira-Frommer R, Santin AD, et al. Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100. Gynecol Oncol 2023;178:119-29. [Crossref] [PubMed]
  32. Färkkilä A, Gulhan DC, Casado J, et al. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nat Commun 2020;11:1459. [Crossref] [PubMed]
  33. Ethier JL, Fuh KC, Arend R, et al. State of the Biomarker Science in Ovarian Cancer: A National Cancer Institute Clinical Trials Planning Meeting Report. JCO Precis Oncol 2022;6:e2200355. [Crossref] [PubMed]
doi: 10.21037/gpm-24-3
Cite this article as: Rose PG. Improving survival in recurrent ovarian cancer, miles to go before we sleep. Gynecol Pelvic Med 2025;8:27.

Article Options

Download Citation

Share