Epithelial ovarian cancer (EOC) is most frequently diagnosed at
an advanced stage and, despite high response rates to initial
taxane-platinum-based chemotherapy, more than 70% of
patients will develop recurrent disease and will receive several
chemotherapy treatments. At present, the 5-year overall survival
(OS) for women diagnosed with stage III–IV disease is 46% and
patients with genetic impairments of DNA repair pathways
[BRCA mutations and in general homologous recombination deficiency (HRD)] live longer and possibly will receive even more
lines of chemotherapy

González-Martín, A. (Antonio)

Lorusso, D. (D.)

Pignata, S. (S.)

English

Dadun, University of Navarra

EditorialsChemotherapy-free treatments: are weready for prime time?Epithelial ovarian cancer (EOC) is most frequently diagnosed atan advanced stage and, despite high response rates to initialtaxane-platinum-based chemotherapy, more than 70% ofpatients will develop recurrent disease and will receive severalchemotherapy treatments. At present, the 5-year overall survival(OS) for women diagnosed with stage III–IV disease is46% andpatients with genetic impairments of DNA repair pathways[BRCA mutations and in general homologous recombination de-ficiency (HRD)] live longer and possibly will receive even morelines of chemotherapy [1].The cumulative toxicity of chemotherapy, particularly ifplatinum-based, in terms of neurotoxicity, nephrotoxicity andmyelotoxicity, is a limiting factor in patients scheduled to receivemultiple lines of treatment. Moreover, allergic reactions to plati-num, whose frequency increases with multiple treatment lines, isa great challenge, particularly in long-surviving patients. Finally,the risk of secondary tumors, particularly in HRD patients, seemsto be related to the number of previous chemotherapy lines—andplatinum in particular—thus introducing important concerns onthe long-term safety of patients [2].Based on these issues, the development of active and well-tolerated chemotherapy-free regimens may provide an attractivealternative for patients who will receive multiple lines of therapy.The initial discovery that poly-adenosine diphosphate [ADP]-ribose polymerase (PARP) inhibitor enhance anticancer activityin vitro in BRCA mutated (BRCAmut) cancers led to the initialtesting of PARP inhibitors as single agents and as maintenancetreatment in BRCAmut cancers, platinum-sensitive andplatinum-responsive, and their subsequent regulatory approvalin these settings [3]. More recently, this strategy has been broad-ened to also include all patients in the platinum-sensitive settingregardless of the HRD signature.PARP inhibitors work based on the concept of synthetic lethal-ity, which refers to the presence in the cell of an inherent vulnera-bility (HRD) that is by itself not lethal, but when combined withanother genetic event may become lethal. Some conditions, such ashypoxia, may artificially create or enhance a condition of genomicinstability. Tumor cells exposed to chronic hypoxia following anti-angiogenic treatment [4] have been shown to acquire defects in ho-mologous recombination (HR) DNA repair, throughdownregulation of HR repair proteins such as BRCA1 and RAD51,resulting in an increased sensitivity to PARP inhibition [5].Cediranib, a potent antiangiogenic tyrosine kinase inhibitor ofVEGFR-1/2/3 has demonstrated significant antitumor activity anddelayed tumor progression when given as maintenance therapy inwomen with recurrent ovarian cancer [6]. The primary analysis ofa randomized phase II trial in 90 recurrent platinum-sensitiveovarian cancer patients suggested that the combination of cedira-nib and olaparib, a PARP inhibitor [1], was synergistic with a6-month increase in progression-free survival (PFS) comparedwith olaparib alone [7].In a retrospective analysis of the BRCAmut and BRCAwt sub-groups, the difference in PFS was greatest in BRCAwt women(HR 0.32 compared with HR 0.55 in BRCAmut). Grade 3 orhigher adverse events were observed in 70% of patients treatedwith the initial dose of cediranib 30 mg in the combination, themost frequent being diarrhea, fatigue and hypertension.However, compliance with treatment was very high (97%) due todose reduction of cediranib in 77% of patients [7].In the update analysis at a median follow-up of 46 months pub-lished in this issue, Liu et al. [8] confirmed a significantly longermedian PFS with cediranib/olaparib compared with olaparibalone of 16.5 versus 8.2 months (HR 0.50; P¼ 0.007). Subsetanalyses in BRCAwt/unknown patients demonstrated a statisti-cally significant improvement in PFS (23.7 versus 5.7 months,P¼ 0.002) and OS (37.8 versus 23.0 months, P¼ 0.047), withoutOS differences in the overall study population (44.2 versus33.3 months, HR 0.64; P¼ 0.11).This study reported that a chemotherapy-free treatment in apopulation of platinum-sensitive recurrent EOC can produce thesame oncologic outcomes interms of PFS and OS of the mostcommonly used chemotherapy treatments [9], thus representinga potentially new strategy. Based on the same assumptions ofother chemotherapy-free combinations, the ENGOT-OV24/AVANOVA study is testing the combination of bevacizumab andniraparib in the platinum-sensitive setting (NCT02354131).Immune checkpoint inhibitors have led to important clinicaladvances in the treatment of some solid tumors, butunfortunately have reported limited single-agent activity in ovar-ian cancer leading to the opportunity to test combination strate-gies [10]. The possibility of combining PARP inhibitors andanticheckpoint blockade appears very promising; preclinicalstudies showed DNA damage promotes neoantigen expression[11] and it is possible that increased DNA damage byPARPi would yield greater mutational burden and expand neo-antigen expression, leading to greater immune recognition of thetumor.The TOPACIO trial [12] has tested the combination ofniraparib and pembrolizumab in a population of triple-negative breast cancer and recurrent platinum-resistant EOC(NCT02657889). Among the 60 evaluable EOC patients, an over-all response rate (ORR) of 25% and a disease control rate of 68%were reported. Moreover, responses were not dependent on bio-marker status; ORR was 26% in BRCAwt patients and 29% inpatients with HRD-positive tumors. The combination was well-tolerated with an incidence of grade 3/4 thrombocytopenia (9%),anemia (19%) and neutropenia (6%).VC The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oup.com.With the same strategy, the combination of durvalumab andolaparib registered a disappointing 15% ORR in a population of34 recurrent, mainly platinum-resistant, heavily pretreated EOCpatients [13] while an outstanding 71% RR was reported with thesame combination in a population of recurrent, platinum-sensitive BRCAmt EOC patients. This suggests that appropriateselection of the setting of disease and patient population is im-portant [14].At present, chemotherapy-free treatments are a clinical reality:olaparib has been approved by FDA as a single agent for the treat-ment of BRCAmut-EOC treated with at least three previous che-motherapy lines. Rucaparib, another PARP inhibitor, has beenapproved by FDA and EMA in the same setting in a less pre-treated BRCAmut population (at least two previous chemother-apy lines) based on the results of two phase II studies reportingORR in line with that achieved with standard chemotherapy anda completely different toxicity profile [15].Nevertheless, what clinicians and patients should be con-scious of is that chemotherapy-free treatments still presentsome tricky and sometimes life-threatening toxicities thatmay significantly impact patients quality of life, which couldgreatly reduce their compliance to treatment (particularly inthe case of orally administered drugs) with potential conse-quences on efficacy.Toxicity still remains a concern with respect to these new onco-logic treatments: after definitively abandoning the initial ideathey lacked toxicity; the scientific community has learned in thelast years to manage different, but not less impactful, toxicities ofPARP inhibitors, antiangiogenic agents and immunocheckpointinhibitors. There is sometimes the clear sense that phase I trialsfail to identify the appropriate dosage, and that often these drugshave been developed according to the old criterium of the maxi-mum tolerated dosage, rather than minimum effective dose,which avoids any further consideration of flat dose immunother-apy, which appear sometimes senseless in addition to beinghighly costly [16].Finally, the appropriate setting of disease and patients se-lection remains mandatory even for chemotherapy-free strat-egies: it is very difficult to imagine in the future thatcarboplatin-paclitaxel will be deleted from first-line treatmentof ovarian cancer, while it appears much more convincingthat the combination of a checkpoint inhibitor and a PARPinhibitor or an anti-VEGF and a PARP inhibitors may besubstitutes for chemotherapy in the treatment of recurrentdisease, especially in later lines.D. Lorusso1*, S. Pignata2 & A. Gonzalez-Martin31Fondazione Policlinico Universitario A Gemelli IRCCS, Rome;2Istituto Nazionale Tumori di Napoli Fondazione Pascale, Naples, Italy;3Medical Oncology Department, Clinica Universidad de Navarra,Madrid, Spain(*E-mail: Domenica.lorusso@policlinicogemelli.it)FundingNone declared.DisclosureThe authors have declared no conflicts of interest.References1. Xu K, Yang S, Zhao Y. Prognostic significance of BRCA mutations inovariancancer: an updated systematic review with meta-analysis.Oncotarget 2017; 8(1): 285–302.2. Fotopoulou C. Limitations to the use of carboplatin-based therapy in ad-vanced ovarian cancer. EJC Suppl 2014; 12(2): 13–16.3. Franzese E, Centonze S, Diana A et al. PARP inhibitors in ovarian cancer.Cancer Treat Rev 2019; 73: 1–9.4. Chan N, Bristow RG. “Contextual” synthetic lethality and/or loss of het-erozygosity: tumor hypoxia and modification of DNA repair. ClinCancer Res 2010; 16(18): 4553–4560.5. Hegan DC, Lu Y, Stachelek GC et al. Inhibition of poly(ADP-ribose) po-lymerase down-regulates BRCA1 and RAD51 in a pathway mediated byE2F4 and p130. Proc Natl Acad Sci USA 2010; 107(5): 2201–2206.6. Matulonis UA, Berlin S, Ivy P et al. Cediranib, an oral inhibitor of vascu-lar endothelial growth factor receptor kinases, is an active drug in recur-rent epithelial ovarian, fallopian tube, and peritoneal cancer. JCO 2009;27(33): 5601–5606.7. Liu JF, Barry WT, Birrer M et al. Combination cediranib and olaparibversus olaparib alone for women with recurrent platinum-sensitive ovar-ian cancer: a randomised phase 2 study. Lancet Oncol 2014; 15(11):1207–1214.8. Liu JF, Barry W, Birrer M et al. Overall survival and updatedprogression-free survival outcomes in a randomized phase 2 study ofcombination cediranib and olaparib versus olaparib in relapsed plati-numsensitive ovarian cancer. Ann Oncol 2019; 30, doi.org/10.1093/annonc/mdz018.9. Wilson MK, Pujade-Lauraine E. Aoki D and participants of the fifthovarian cancer consensus conference. Fifth Ovarian Cancer ConsensusConference of the Gynecologic Cancer InterGroup: recurrent disease.Ann Oncol 2017; 28(4): 727–732.10. Hamanishi J, Mandai M, Konishi I. Immune checkpoint inhibition inovarian cancer. Int Immunol 2016; 28(7): 339–348.11. Mouw KW, Goldberg MS, Konstantinopoulos PA, D’Andrea AD. DNAdamage and repair biomarkers of immunotherapy response. CancerDiscov 2017; 7(7): 675–693.12. Konstantinopoulos P, Munster P, Forero-Torres A et al. TOPACIO: pre-liminary activity and safety in patients (pts) with platinum-resistantovarian cancer in a phase 1/2 study of niraparib in combination withpembrolizumab. SGO Annual Meeting, 24–27 March 2018; NewOrleans, LA. Early insights into potential combinatorial or synergistic ef-ficacy of PARP inhibitors when used in combination with PD-1blockade.13. Lee J-M, Annunziata, CM Houston, N. A phase II study of durvalumab,a PD-L1 inhibitor and olaparib in recurrent ovarian cancer (OvCa). AnnOncol 2018; 29(Suppl 8): mdy285.145.14. Drew Y, DeJonge M, Hong S-H et al. An open-label, phase II basketstudy of olaparib and durvalumab (MEDIOLA): results in germlineBRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovariancancer (OC). SGO Annual Meeting, 24–27 March 2018, New Orleans,LA.15. Kurnit KC, Coleman RL, Westin SN. Using PARP inhibitors in the treat-ment of patients with ovarian cancer. Curr Treat Options Oncol 2018;19(12): 1.16. Ochoa de Olza M, Oliva M, Hierro C et al. Early-drug development inthe era of immuno-oncology: are we ready to face the challenges? AnnOncol 2018; 29(8): 1727–1740.doi:10.1093/annonc/mdz079Published online 5 March 2019Editorials Annals of Oncology498 | Lorusso et al. Volume 30 | Issue 4 | 2019

Chemotherapy-free treatments: are we ready for prime time?

Universidad de Navarra

https://dadun.unav.edu/bitstream/10171/62599/1/PIIS0923753419311354.pdf

Chemotherapy-free treatments: are we ready for prime time?

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