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Treatment of recurrent ovarian cancer
Annals of Oncology 28 (Supplement 8): viii51–viii56, 2017 doi:10.1093/annonc/mdx441
SYMPOSIUM ARTICLE
Treatment of recurrent ovarian cancer S. Pignata1*, S. C. Cecere1, A. Du Bois2, P. Harter2 & F. Heitz2 1 Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale,” Naples, Italy; 2Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany
*Correspondence to: Dr Sandro Pignata, Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale,” Via Mariano Semmola, 80131 Naples, Italy. Tel: þ39-0815903637; Fax: þ39-0815903861; E-mail: [email protected]
Despite optimal surgery and appropriate first-line chemotherapy, 70%–80% of patients with epithelial ovarian cancer will develop disease relapse. The same modalities as used primarily are available for treatment of recurrent ovarian cancer (ROC). The rationale for repetitive surgery in ROC was based on a stable body of retrospective data; however, prospective data were missing. Now, preliminary data from the prospective AGO-DESKTOP III give evidence that surgery for ROC seems to be of benefit for selected patients with platinum-sensitive relapse undergoing complete resection. With respect to systemic therapy, tumor histology, BRCA status, the platinum-free interval (PFI) and previous treatment with bevacizumab (anti-VEGF monoclonal antibody) are considered the most important features that influence treatment choice in ROC. In patients with resistant or refractory relapse (PFI < 6 months), monotherapy with a non-platinum drug or participation in clinical trials is indicated. The association of non-platinum monotherapy with bevacizumab, followed by maintenance has been approved in this setting in some European countries due to PFS benefit. In patients with partially sensitive relapse (PFI between 6 and 12 months), two options are available: platinum doublets or non-platinum therapy (single agent or combination). The pegylated liposomal doxorubicin/trabectedin combination represents a viable alternative in patients that cannot receive platinum. In platinumsensitive patients, treatment with platinum-based combinations is associated with PFS advantage compared with single agents or non-platinum combinations. The presence of germline or somatic BRCA mutations allows platinum-responsive patients to optimize chemotherapy efficacy and prolonging PFS by the use of olaparib (PARP inhibitor) given as maintenance therapy until progression. In patients not pretreated with bevacizumab in first line, the carboplatin/gemcitabine/bevacizumab combination, followed by maintenance is a viable alternative in platinum-sensitive patients (PFI> 6 months). The integration of surgery, with a ‘personalized’ approach by the use of antiangiogenic agent and of PARP inhibitors is affecting survival of patients with recurrent disease and will help epithelial ovarian cancer to become a chronic disease. Key words: ovarian cancer, recurrent, chemotherapy
Introduction Epithelial ovarian cancer (EOC) is an aggressive malignancy and it is most frequently diagnosed in an advanced disease stage [1]. The mainstay of primary treatment is surgery with the goal of complete resection [2]. Even if no complete resection is feasible to obtain, patients still have some benefit of surgery, if tumor reduction to residual disease <1 cm is achieved [3]. The introduction of bevacizumab to the standard chemotherapy with platinum/taxane and maintenance therapy up to 15 months have improved PFS [4, 5]. Despite that, 23% of patients relapse during or within 6 months after end of primary chemotherapy and 60% relapse after 6 months [3]. The standard approach for treating recurrent ovarian cancer (ROC) is chemotherapy and surgery
remains—so far—an option for individual patients who should be carefully selected.
Surgery for relapsed ovarian cancer Most recently, one of the two prospective randomized trials designed to evaluate the impact of surgery for recurrent OC has reported first results of an interim analysis. In this trial (DESKTOP III), patients were recruited who had a so-called platinum-sensitive ROC and a positive AGO (Arbeitsgemeinschaft Gyna¨kologische Onkologie) Score; 408 patients with platinum-sensitive ROC and a positive AGO score (see below) were randomized to surgery followed by chemotherapy, or chemotherapy alone. Patients
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Table 1. Overview of published series evaluating the Arbeitsgemeinschaft Gyna¨kologische Onkologie (AGO)-DESKTOP Score AGO score positive
Harter et al. DESKTOP II [18] Harter et al. [19] Janco et al. [21] van de Laar et al. [22] Laas et al. [23] Muallem et al. [20]
AGO score negative
Pts.
Complete resection (%)
Median OS (months)
Pts.
Complete resection (%)
Median OS (months)
129 112 102 111 33 139
76.0 89.3 84.3 82.0 81.8 67.0
n.a. 57.3 n.a. n.a. n.a. 54.0
63 105 90 162 32 70
63.5 66.7 64.4 68.5 65.6 48.5
n.a. 33.5 n.a. n.a. n.a. 21.7
n.a., not reported.
undergoing surgery showed a prolonged PFS compared with patients undergoing chemotherapy alone [19.6 versus 14.0 months, hazard ratio (HR) 0.66 with 95% CI 0.52–0.83; P < 0.001]. Subgroup analysis demonstrated that only patients with complete resection had a benefit of surgery. Surgery was safe as 30-, 60- and 90-day mortality was not increased in patients undergoing surgery [6]. The rationale for conducting AGO-OVAR DESKTOP III was based on a broad body of retrospective data. A comprehensive review of all published retrospective series to this topic was published in 2005 [7]. This review was limited to series with >100 patients and cytoreductive surgery for platinum-sensitive ROC, as most of the identified series were rather small or had mixed patient cohorts. Eight series could be identified which reported prognostic factors for survival after cytoreductive surgery in ROC [8–15]. Primary FIGO-stage, localization and outcome of primary surgery were never reported to be of prognostic significance in the recurrent disease setting. Two series identified preoperative chemotherapy as a negative prognostic factor. All series reported surgical outcome as independent prognostic factor for survival. The multicenter Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer I (DESKTOP I OVAR) by the AGO Study Group reported only complete resection as beneficial with an OS of 45.2 months. There were no differences between minimal residuals of 1–10 or >10 mm (19.7 versus 19.6 months). There were two series describing a benefit of cytoreduction to 1–20 mm compared with >20 mm [13] and 0.1–10 mm compared with >10 mm [14]. However, very heterogeneous patients’ cohorts and missing additional chemotherapy after surgery in a substantial frequency of patients, limited the value of these analyses. In contrast, the largest single center series published by Sehouli et al. [15] confirmed the findings that only complete resection is beneficial. Moreover, a large international collaborative multicenter analysis including 1100 patients showed that complete resection was strongly associated with the improvement of survival, with a median survival of 57.7 months, compared with 27.0 months in those patients with residual disease of 0.1–1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P < 0.0001) [16]. In addition to complete resection, which was the strongest prognostic factor for further survival (HR: 2.94), the DESKTOP I series
identified absence of ascites (HR: 2.30) and postoperative platinum-based chemotherapy (HR: 1.82) as further prognostic factors. In the past, it was difficult to identify suitable patients in whom complete resection was feasible. Therefore, the reported rates of complete resection varied between 20% and 80% [17]. The AGO DESKTOP I study evaluated three predictive factors for complete resection: Good performance status (ECOG 0), complete resection at first surgery (alternatively, FIGO I/II in patients with unknown residual disease after primary surgery), and absence of ascites. Patients, in whom all these factors were present, a complete resection was feasible in 79% (AGO-score positive). In the subsequent AGO DESKTOP II study, this score was validated prospectively. The study was planned to show that a positive AGO score reaches a positive predictive value for complete resection of > 66% (2 of 3 pts) with 95% probability at a significance level of P< 0.05. Five hundred sixteen patients with platinum-sensitive relapse were screened within 19 months. About 32% of the patients with first relapse were operated on. One hundred twenty-nine patients had a positive score. In patients with a positive score, a complete resection could be achieved in 76%, resulting in a positive validation of the AGO score [18]. Since the publication of the DEKTOP II study, the AGO score has been validated by several other groups [19–20] (Table 1). Complete resection rates in patients with positive AGO score ranged between 67.0% and 89.3%, indicating that the AGO score is able to predict operability with complete resection with high reliability. On the other hand, the AGO score was not intended to give any information about inoperability. DESKTOP II already reported complete resection rates of 63.5% in AGOscore negative patients and in the consecutive analyses by other groups revealed complete resection rates ranging between 48.5% and 68.5%. Primary surgery for advanced EOC bears a curative opportunity for affected patients. Therefore, it seems to be appropriate to accept an increased morbidity and even low rates of mortality. Due to the fact, that the impact of surgery on survival of r ROC is still not validated prospectively, and that the current understanding of treatment of ROC is merely prolongation of survival and not cure, morbidity and mortality are of highest importance. Perioperative complications have been prospectively documented in DESKTOP
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Annals of Oncology II. About 44% of patients had to receive packed blood cells, and 33% of patients had at least one perioperative complication. About 24% of patients received antibiotic treatment and 11% did undergo relaparotomy. In a meta-analysis, the weighted mean morbidity rate was 19.2% [24]. The 30-day mortality in DESKTOP II was reported to be 0.8% [18], in meta-analysis 1.2% [24] and up to 7.8% in single institutions [15]. As described earlier, the AGO DESKTOP III trial (NCT01166737) has only presented PFS, but data on OS are still premature. Another ongoing study investigating the role of cytoreductive surgery for platinum-sensitive ROC is carried out by the Gynecologic Oncology Group (GOG) (GOG 213; NCT00565851).
Medical treatment of relapsed ovarian cancer Waiting for clarifications about the role of surgery in the relapsed disease setting, actually the standard treatment is still represented by systemic therapy. Despite optimal surgery and appropriate first-line chemotherapy, 80% of patients with EOC will develop a recurrence at different time points. The likelihood of relapse depends on many factors, including distribution of disease at initial presentation, success of initial surgical cytoreduction (i.e. the presence of any residual disease), rapidity of CA125 resolution, and treatment response after primary therapy. ROC can be detected biochemically (rising of CA125), clinically or radiologically. Subsequent sequential treatment strategies maximize quality and length of life but are not curative. Retreatment with chemotherapy should not be routinely started in asymptomatic patients with CA125 progression alone. Literature data have demonstrated that early initiation of chemotherapy is not associated to any survival advantage and in fact will have a negative effect on quality of life (QoL). Prognosis at relapse is mainly dominated by chemosensitivity of the tumor. The choice of second-line chemotherapy depends on several factors such as platinum-free interval (PFI), persistent side-effects after prior treatments, schedules and toxicity profiles of next therapies and patient preferences. Until now, the PFI has been considered as the main prognostic factor that guides the treatment choice at time of the recurrence. The fourth International Ovarian Cancer Consensus Meeting held in Vancouver in June 2010 on behalf of Gynecologic Cancer InterGroup (GCIG) established definition of PFI as the interval from the last date of platinum dose until progressive disease is documented [25]. According to this definition, ROC has been characterized into four different categories known as platinumrefractory, resistant, partially sensitive, and fully sensitive depending on when the relapse occurs after the last platinum treatment (during treatment or within 4 weeks; between 6 and 12 months; or beyond 12 months, respectively). Although these definitions have been used to identify different populations, the resistance to platinum-based treatment is not a categorical variable. Furthermore, considering the recent introduction of maintenance therapies, the concept of PFI has been recently challenged. In the last consensus (5th Ovarian Carcinoma Consensus Conference) conference of Tokyo [26], the PFI paradigm has been partially revisited and the concept of treatment-free interval
introduced, considering PFI, previous bevacizumab, BRCA status and different histological subtypes.
Treatment of early relapse Patients relapsing during first-line treatment (refractory) or in the few following months thereafter (resistant) represent a very heterogeneous group with various biological tumor behaviors. This condition is linked to unfavorable prognosis, so the main objective of treatment is to palliate symptoms and preserve QoL. Monotherapy with non-platinum compounds has showed to be equally effective and less toxic compared with combinations. A Cochrane systematic review of trials in platinum-resistant EOC found that paclitaxel, pegylated liposomal doxorubicin (PLD) and topotecan offer similar objective response rates (10%–20%), median PFS (3–4 months), and overall survival (12 months) with different toxicity profiles [27]. Regarding molecular targeted therapy, interesting data have been obtained in this setting with antiangiogenic compounds. In the randomized phase III AURELIA trial [28], bevacizumab in combination with standard chemotherapy (PLD, weekly paclitaxel, or topotecan) and as single agent maintenance until progression demonstrated to prolong PFS (6.7 versus 3.4 months HR 0.48; 95% CI 0.38–0.60; P < 0.001). However, overall survival was not found prolonged, most probably partially due to the fact patients in the standard chemotherapy alone arm could receive bevacizumab at time of progression [HR 0.85 (95% CI 0.85–1.08); P ¼ 0.174; median 16.6 months with bevacizumab plus chemotherapy versus 13.3 months with chemotherapy alone]. However, in a sub-group analysis, a significant OS benefit was shown for bevacizumab in the weekly paclitaxel group (median 22 versus 13 months). According to those results, bevacizumab was licensed in this setting.
Treatment of relapse after 6 months This subgroup refers to a wide heterogeneous group that include platinum-sensitive (PFI 12 months) and partially sensitive (PFI 6 <12 months) patients. Chemosensitivity to platinum compounds is supposed to increase with longer interval from the initial therapy. For patients with PFI >12 months, the use of platinum-based combinations (carboplatin/PLD; carboplatin/ paclitaxel and carboplatin/gemcitabine) is associated to a better outcome (PFS, OS, ORR) compared with non-platinum or platinum single agent treatments [29, 30]. In patients with a PFI between 6 and 12 months (partially platinum-sensitive), two options are available: platinum doublets or non-platinum therapy (single agent or combination). The hypothesis that a benefit could be derived from the artificial extension of PFI by introducing a non-platinum therapy in partially sensitive disease to make the following platinum more effective has been proposed many years ago, without any prospective confirmation of its validity. Some studies have been designed to test this hypothesis (MITO8, INOVATYON). The MITO 8 study a phase III trial comparing the experimental sequence of a non-platinum single agent chemo (NPBC) followed by a platinum based chemotherapy (PBC) versus the reversed sequence, recently demonstrated that the use of
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Symposium article NPBC to artificially prolong the PFI is not effective in partially sensitive d ROC patients [median OS was 21.8 versus 24.5 months (HR 1.38, 95% CI: 0.99–1.94, P ¼ 0.06)] [31]. This evidence confirms that platinum-based treatment should be the first choice in this population. A non-platinum containing doublet (trabectedin plus PLD) has been recently introduced in the treatment of patients with platinum-sensitive ROC that are not candidate for platinum. This approach is based on the PFS advantage observed with the combination versus PLD alone in the OVA-301 randomized trial (median PFS of 7.4 months in the trabectedin/PLD arm versus 5.5 months in the PLD arm) [32]. A subgroup analysis of this trial has suggested an OS prolongation in the same population of the MITO 8 trial, with a significant 41% decrease in the risk of death compared with PLD alone (HR ¼ 0.59; 95% CI, 0.43–0.82; P ¼ 0.0015). Median OS was 23.0 months in the trabectedin/PLD arm versus 17.1 months in the PLD arm. Interestingly, it has been suggested that the combination of trabectedin/PLD is able to prolong OS affecting the efficacy of platinum received later after progression. This hypothesis is under evaluation in the prospective phase III trial comparing trabectedin/PLD, followed by platinum versus platinum-based chemotherapy (INOVATYON trial) (ClinicalTrials.gov identifier: NCT01379989). For women who are unable to tolerate platinum chemotherapy because of hypersensitivity, comorbidity, or other previous toxicity, single-agent chemotherapy may be used. Treatment of platinum sensitive relapsed OC has changed in the last years also due to the introduction of two biological agents: bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, and olaparib, an inhibitor of poly [adenosine diphosphate (ADP)-ribose] polymerase (PARPi). Bevacizumab in combination with chemotherapy for platinum-sensitive ROC has been approved on the basis of results from two randomized, controlled phase III studies, GOG-0213 and OCEANS. The GOG-0213 study demonstrated that adding bevacizumab to platinum based chemotherapy showed a nonstatistically significant OS difference of 5 months compared with chemotherapy alone (median OS: 42.6 versus 37.3 months; HR ¼ 0.84, 95% CI: 0.69–1.01) and a statistically significant advantage of 3.4 months in median PFS (13.8 versus 10.4 months; HR ¼ 0.61, 95% CI: 0.51–0.72) [33]. In the OCEANS trial, 484 women with platinum-sensitive t ROC were randomized to carboplatin and gemcitabine plus either bevacizumab or placebo. The bevacizumab-containing combination was associated with a better objective response rate (ORR, 78.5% versus 57.4% with the non-bevacizumab containing combination), and a longer PFS (12.4 versus 8.4 months; HR¼ 0.484; 95% CI, 0.388–0.605; logrank P < 0.0001). No difference in OS has been observed, probably due to crossover (HR ¼ 0.95, 95% CI: 0.77–1.17) [34]. Olaparib is the first-in-class PARP inhibitors to be licensed for the treatment of ROC harboring deleterious BRCA mutations. The activity of olaparib as maintenance after response to a platinum-based chemotherapy in the platinum-sensitive highgrade serous ROC has firstly been shown in the ‘study 19’ trial and then confirmed in the SOLO-2 phase III trial. Maintenance therapy with olaparib showed a 70% reduction in the risk of progression or death compared with placebo assessed both by investigator (median 19.1 versus 5.5 months; HR¼ 0.30, 95% CI 0.22–0.41; P < 0.0001) and by blinded independent central review (BICR) (median 30.2 versus 5.5 months; HR 0.25,
Annals of Oncology 0.18–0.35; P < 0.0001), and significantly longer time to second progression (PFS2) (HR 0.50, 0.34–0.72; P ¼ 0.0002) [35, 36]. Olaparib is actually approved as maintenance after platinum response in ROC patients with a somatic or germline BRCA mutation. Two other PARP inhibitors have been recently been approved by the FDA for the treatment of recurrent disease, not only in BRCA mutated or in platinum sensitive relapsed cases. Niraparib, an oral highly selective, potent PARP-1 and PARP-2 inhibitor, is approved in USA for the maintenance treatment of adult women with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer responding to last platinum-based chemotherapy. It is also under regulatory review in the EU for use as maintenance treatment in patients with platinum-sensitive ROC who are in response to platinum-based chemotherapy based on the results of the phase III trial, the ENGOT-OV16/ NOVA study. This is an international phase III, double-blind, placebo-controlled study that enrolled 553 patients with ROC who had achieved either a partial or complete response (PR or CR) to their most recent platinum-based chemotherapy. Patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the homologous recombination deficiency (HRD) status and were randomly assigned in a 2 : 1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was PFS. Patients in the niraparib group had a significantly longer median PFS than those in the placebo group, i.e. 21.0 versus 5.5 months in the gBRCA cohort (HR¼ 0.27; 95% CI, 0.17–0.41), 12.9 versus 3.8 months in the non-gBRCA cohort for patients who had tumors with HRD (HR ¼0.38; 95% CI, 0.24–0.59) and 9.3 versus 3.9 months in the overall non-gBRCA cohort (HR¼ 0.45; 95% CI, 0.34–0.61; P < 0.001 for all three comparisons). The results of several secondary end points from this trial, including chemotherapy-free interval, time to second subsequent therapy (TSST), and PFS-2, demonstrate the positive and durable treatment effect of niraparib in a broad population of patients with ROC, regardless of the presence or absence of germline BRCA mutations and HRD status [37]. Another PARP inhibitor, rucaparib an oral, small molecule that targets the PARP enzyme, will probably enrich the therapeutic armamentarium of BRCA-mutated EOC patients. Rucaparib has been recently approved by the FDA as monotherapy for the treatment of ROC patients who are carriers of deleterious (germline and/or somatic) BRCA mutations [38]. The approval of rucaparib is based on results from two single-arm clinical trials involving 106 women with ROC who had been treated with two or more chemotherapy regimens and had their BRCA-mutations confirmed by the companion diagnostic test. In the trials, known as Study 10 and ARIEL2 (Assessment of Rucaparib In Ovarian CancEr TriaL2) Parts 1, the drug obtained an overall response rate of 54% (complete, 9%; partial, 45%) and a median duration of response of 9.2 months. In the ARIEL2 Part 1, patients with platinum-sensitive, high-grade ROC were classified into one of three predefined HRD subgroups on the basis of tumor mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and loss of heterozygosis high (LOH high group), or BRCA wild-type and LOH low group and treated with oral rucaparib at 600 mg twice daily for continuous 28-day cycles until disease progression or any other reason for discontinuation.
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Annals of Oncology The primary end point was PFSl. Median PFS after rucaparib treatment was 12.8 months (95% CI 9.0–14.7) in the BRCA mutant subgroup, 5.7 months (5.3–7.6) in the LOH high subgroup, and 5.2 months (3.6–5.5) in the LOH low subgroup. PFS was significantly longer in the BRCA mutant (HR¼ 0.27, 95% CI 0.16–0.44, P < 0.0001) and LOH high (HR ¼ 0.62, 95% CI 0.42– 0.90, P ¼ 0.011) subgroups compared with the LOH low subgroup. These results confirm the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutation [39]. More data on rucaparib will eventually come from other trials (ARIEL 3; ARIEL 4) exploring the role of the drug as maintenance after chemotherapy or as single agent (https://clinicaltrials.gov/ ct2/show/NCT01968213, https://clinicaltrials.gov/ct2/show/NC T02855944).
Chemotherapy according to tumor biology and BRCA status: treatment in the following lines It is well recognized that there are five different histological types of OC with a different genomic landscape, natural histories and patterns of response to therapy. The existing treatment strategies based on PFI in ROC has been largely driven by the activity of chemotherapy found in high-grade serous (HGSOC) and endometrioid (HGSEC) histology. In rare subtypes, where chemotherapy is less effective, the option of a clinical trial with targeted therapy may be appropriate. Several studies have been conducted to test the activity of MEK inhibitors in low grade serous ovarian cancer (LGSOC) [40]. The results of such studies are waited in the near future; these drugs are associated with 15%–20% response rate compared with 5% of chemotherapy [40]. Interesting data of hormonotherapy have also been reported in LGSOC, during the 2016 ASCO Annual Meeting. A long-term retrospective study of 204 patients with FIGO stage II–IV lowgrade serous carcinoma demonstrated that hormonal therapy given as maintenance following primary treatment reduced the risk of disease progression by 77%, compared with surveillance (P < 0.001). Hormonal maintenance therapy was associated with a statistically significant increase of the median PFS (64.9 versus 27.3 months; HR ¼ 0.23; P < 0.001) compared with the surveillance; this benefit seems to be greater in patients without evidence of disease after chemotherapy (median PFS 81.1 versus 29.9 months P < 0.001) and gained also a prolongation of median overall survival (191.3 versus 106.8 months; P ¼ 0.04) [41]. In the 5th Ovarian Carcinoma Consensus Conference, the need of trials in rare histologic subtypes, that have different prognosis and biological behavior, has been underlined and includes, among others, clear cell cancer and mucinous tumors, that are less responsive to standard chemotherapy options [42]. The tailored therapy approach based on the different subtypes and tumor biology is still far away from utilization in clinical practice. However, there are some examples of a biology driven approaches that can be proposed. As an example, chemotherapy choice can be adapted according to BRCA mutation. Three studies (of which two retrospective) have shown a higher efficacy of PLD in BRCA-mutated tumors compared with unselected cases (RR of 7%–25%, probably due to the mechanism of action of this
drug (DNA adducts, topoisomerse II inhibition in HRD cells, immunomodulatory effects). In addition, trabectedin (a minor groove DNA binder derived from marine organisms) has been associated with high response rates and prolonged PFS when used both as a single agent and in combination with PLD [32, 43, 44] in BRCA-mutated patients. There is no conclusive evidence about an impact of BRCA mutations on response to taxanes (e.g. paclitaxel). Despite the absence of prospective clinical trials, platinum, PLD and trabectedin, can be considered the chemotherapy agents of choice in the BRCA-mutated patients. In conclusion, the treatment approach to patients with ROC has evolved dramatically in recent years. The integration of surgery, with a ‘personalized’ approach in using antiangiogenic agents and PARP inhibitors has increased the survival of such patients and will help EOC to become a chronic disease.
Funding SP is recipient of a grant from AIRC (Associazione Italiana Ricerca sul Cancro) (no grant number applies). The publication of this supplement and the symposium on which it is based have been supported through partnership between the Spanish Ovarian Cancer Research Group (GEICO) and the European Society for Medical Oncology (ESMO).
Disclosure FH received honoraria from Roche, AstraZeneca and PharmaMar and he received travel support from PharmaMar and Roche. SP received honoraria from Roche, AstraZeneca, MSD, Pfizer and PharmaMar. ADB received honoraria from Roche, Astra Zeneca, PharmaMar, Tesaro, Pfizer, and Advaxis. PH has received honoraria from Astra Zeneca, Roche, Tessaro, Clovis, PharmaMar. SCC has received honoraria from Roche, AZ, PharmaMar.
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Symposium article 7. Harter P, du Bois A. The role of surgery in ovarian cancer with special emphasis on cytoreductive surgery for recurrence. Curr Opin Oncol 2005; 17: 505–514. 8. Eisenkop SM, Friedman RL, Spirtos NM. The role of secondary cytoreductive surgery in the treatment of patients with recurrent epithelial ovarian carcinoma. Cancer 2000; 188(1): 144–153. 9. Scarabelli C, Gallo A, Carbone A. Secondary cytoreductive surgery for patients with recurrent epithelial ovarian carcinoma. Gynecol Oncol 2001; 83: 504–512. 10. Zang RY, Li ZT, Tang J et al. Secondary cytoreductive surgery for patients with relapsed epithelial ovarian carcinoma: who benefits? Cancer 2004; 100: 1152–1161. 11. Harter P, du Bois A, Hahmann M et al. Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR trial. Ann Surg Oncol 2006; 13: 1702–1710. 12. Chi DS, McCaughty K, Diaz JP et al. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinumsensitive epithelial ovarian carcinoma. Cancer 2006; 106: 1933–1939. 13. Oksefjell H, Sandstad B, Trope C. The role of secondary cytoreduction in the management of the first relapse in epithelial ovarian cancer. Ann Oncol 2009; 20: 286–293. 14. Tian WJ, Jiang R, Cheng X et al. Surgery in recurrent epithelial ovarian cancer: benefits on Survival for patients with residual disease of 0.1-1 cm after secondary cytoreduction. J Surg Oncol 2010; 101: 244–250. 15. Sehouli J, Richter R, Braicu EI et al. Role of secondary cytoreductive surgery in ovarian cancer relapse: who will benefit? A systematic analysis of 240 consecutive patients. J Surg Oncol 2010; 102: 656–662. 16. Zang RY, Harter P, Chi DS et al. Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort. Br J Cancer 2011; 105: 890–896. 17. Harter P, Hilpert F, Mahner S et al. Prognostic factors for complete debulking in first- and second-line ovarian cancer. Int J Gynecol Cancer 2009; 19(Suppl 2): S14–S17. 18. Harter P, Sehouli J, Reuss A et al. Prospective validation study of a predictive score for operability of recurrent ovarian cancer: the Multicenter Intergroup Study DESKTOP II. A project of the AGO Kommission OVAR, AGO Study Group, NOGGO, AGO-Austria, and MITO. Int J Gynecol Cancer 2011; 21: 289–295. 19. Harter P, Beutel B, Alesina PF et al. Prognostic and predictive value of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) score in surgery for recurrent ovarian cancer. Gynecol Oncol 2014; 132: 537–541. 20. Muallem MZ, Gasimli K, Richter R et al. AGO score as a predictor of surgical outcome at secondary cytoreduction in patients with ovarian cancer. Anticancer Res 2015; 35: 3423–3429. 21. Janco JM, Kumar A, Weaver AL et al. Performance of AGO score for secondary cytoreduction in a high-volume U.S. center. Gynecol Oncol 2016; 141: 140–147. 22. van de Laar R, Massuger LF, Van Gorp T et al. External validation of two prediction models of complete secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer. Gynecol Oncol 2015; 137: 210–215. 23. Laas E, Luyckx M, De Cuypere M et al. Secondary complete cytoreduction in recurrent ovarian cancer: benefit of optimal patient selection using scoring system. Int J Gynecol Cancer 2014; 24: 238–246. 24. Bristow RE, Puri I, Chi DS. Cytoreductive surgery for recurrent ovarian cancer: a meta-analysis. Gynecol Oncol 2009; 112: 265–274. 25. Friedlander M, Trimble E, Tinker A et al. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer 2011; 21: 771–775. 26. McGee J, Bookman M, Harter P et al. 5th Ovarian Cancer Consensus Conference: individualized therapy and patient factors. Ann Oncol 2017; 28: 702–710. 27. Lihua P, Chen XY, Wu T. Topotecan for ovarian cancer. Cochrane Database Syst Rev 2008; 2: CD005589. 28. Poveda AM, Selle F, Hilpert F et al. Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-
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resistant recurrent ovarian cancer: analysis by Chemotherapy Cohort of the Randomized Phase III AURELIA Trial. J Clin Oncol 2015; 33: 3836–3838. Parmar MK, Ledermann JA, Colombo N et al. 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: 2099–2106. 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. Pignata S, Scambia G, Raspagliesi F et al. The MITO8 phase III international multicenter randomized study testing the effect on survival of prolonging platinum-free interval (PFI) in patients with ovarian cancer (OC) recurring between 6 and 12 months after previous platinum-based chemotherapy: a collaboration of MITO, MANGO, AGO, BGOG, ENGOT, and GCIG. J Clin Oncol 2016; 34(Suppl): abstr #5505. Poveda A, Vergote I, Tjulandin S et al. Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol 2011; 22: 39–48. 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. Lancet Oncol 2017; 18: 779–791. Aghajanian C, Goff B, Nycum LR et al. 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. Gynecol Oncol 2015; 139: 10–16. Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15: 852–861. Pujade-Lauraine E, Ledermann JA, Penson RT et al. Treatment with olaparib monotherapy in the maintenance setting significantly improves progression-free survival in patients with platinum-sensitive relapsed ovarian cancer: Results from the phase III SOLO2 study. 2017 Society of Gynecologic Oncologists Annual Meeting. Abstract LBA2. Presented March 14, 2017. Mirza MR, Monk BJ, Herrstedt J et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; 1375: 2154–2164. Syed YY1. Rucaparib: first global approval. Drugs 2017; 77: 585–592. Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinumsensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017; 18: 75–87. Farley J, Brady WE, Vathipadiekal V et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol 2013; 14: 134–140. Gershenson DM, Bodurka DC, Coleman RL et al. Hormonal maintenance therapy for women with low grade serous carcinoma of the ovary or peritoneum. J Clin Oncol 2017; 35: 1103–1111. Leary AF, Quinn M, Fujiwara K et al. 5th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG): clinical trial design for rare ovarian tumours. Ann Oncol 2017; 28: 718–726. Mantia-Smaldone G, Ronner L, Blair A et al. The immunomodulatory effects of pegylated liposomal doxorubicin are amplified in BRCA1– deficient ovarian tumors and can be exploited to improve treatment response in a mouse model. Gynecol Oncol 2014; 133: 584–590. Lorusso D, Scambia G, Pignata S et al. Prospective phase II trial of trabectedin in BRCA-mutated and/or BRCAness phenotype recurrent ovarian cancer patients: the MITO 15 trial. Ann Oncol 2016; 27: 487–493.
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SYMPOSIUM ARTICLE
Treatment of recurrent ovarian cancer S. Pignata1*, S. C. Cecere1, A. Du Bois2, P. Harter2 & F. Heitz2 1 Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale,” Naples, Italy; 2Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany
*Correspondence to: Dr Sandro Pignata, Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale,” Via Mariano Semmola, 80131 Naples, Italy. Tel: þ39-0815903637; Fax: þ39-0815903861; E-mail: [email protected]
Despite optimal surgery and appropriate first-line chemotherapy, 70%–80% of patients with epithelial ovarian cancer will develop disease relapse. The same modalities as used primarily are available for treatment of recurrent ovarian cancer (ROC). The rationale for repetitive surgery in ROC was based on a stable body of retrospective data; however, prospective data were missing. Now, preliminary data from the prospective AGO-DESKTOP III give evidence that surgery for ROC seems to be of benefit for selected patients with platinum-sensitive relapse undergoing complete resection. With respect to systemic therapy, tumor histology, BRCA status, the platinum-free interval (PFI) and previous treatment with bevacizumab (anti-VEGF monoclonal antibody) are considered the most important features that influence treatment choice in ROC. In patients with resistant or refractory relapse (PFI < 6 months), monotherapy with a non-platinum drug or participation in clinical trials is indicated. The association of non-platinum monotherapy with bevacizumab, followed by maintenance has been approved in this setting in some European countries due to PFS benefit. In patients with partially sensitive relapse (PFI between 6 and 12 months), two options are available: platinum doublets or non-platinum therapy (single agent or combination). The pegylated liposomal doxorubicin/trabectedin combination represents a viable alternative in patients that cannot receive platinum. In platinumsensitive patients, treatment with platinum-based combinations is associated with PFS advantage compared with single agents or non-platinum combinations. The presence of germline or somatic BRCA mutations allows platinum-responsive patients to optimize chemotherapy efficacy and prolonging PFS by the use of olaparib (PARP inhibitor) given as maintenance therapy until progression. In patients not pretreated with bevacizumab in first line, the carboplatin/gemcitabine/bevacizumab combination, followed by maintenance is a viable alternative in platinum-sensitive patients (PFI> 6 months). The integration of surgery, with a ‘personalized’ approach by the use of antiangiogenic agent and of PARP inhibitors is affecting survival of patients with recurrent disease and will help epithelial ovarian cancer to become a chronic disease. Key words: ovarian cancer, recurrent, chemotherapy
Introduction Epithelial ovarian cancer (EOC) is an aggressive malignancy and it is most frequently diagnosed in an advanced disease stage [1]. The mainstay of primary treatment is surgery with the goal of complete resection [2]. Even if no complete resection is feasible to obtain, patients still have some benefit of surgery, if tumor reduction to residual disease <1 cm is achieved [3]. The introduction of bevacizumab to the standard chemotherapy with platinum/taxane and maintenance therapy up to 15 months have improved PFS [4, 5]. Despite that, 23% of patients relapse during or within 6 months after end of primary chemotherapy and 60% relapse after 6 months [3]. The standard approach for treating recurrent ovarian cancer (ROC) is chemotherapy and surgery
remains—so far—an option for individual patients who should be carefully selected.
Surgery for relapsed ovarian cancer Most recently, one of the two prospective randomized trials designed to evaluate the impact of surgery for recurrent OC has reported first results of an interim analysis. In this trial (DESKTOP III), patients were recruited who had a so-called platinum-sensitive ROC and a positive AGO (Arbeitsgemeinschaft Gyna¨kologische Onkologie) Score; 408 patients with platinum-sensitive ROC and a positive AGO score (see below) were randomized to surgery followed by chemotherapy, or chemotherapy alone. Patients
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Annals of Oncology
Table 1. Overview of published series evaluating the Arbeitsgemeinschaft Gyna¨kologische Onkologie (AGO)-DESKTOP Score AGO score positive
Harter et al. DESKTOP II [18] Harter et al. [19] Janco et al. [21] van de Laar et al. [22] Laas et al. [23] Muallem et al. [20]
AGO score negative
Pts.
Complete resection (%)
Median OS (months)
Pts.
Complete resection (%)
Median OS (months)
129 112 102 111 33 139
76.0 89.3 84.3 82.0 81.8 67.0
n.a. 57.3 n.a. n.a. n.a. 54.0
63 105 90 162 32 70
63.5 66.7 64.4 68.5 65.6 48.5
n.a. 33.5 n.a. n.a. n.a. 21.7
n.a., not reported.
undergoing surgery showed a prolonged PFS compared with patients undergoing chemotherapy alone [19.6 versus 14.0 months, hazard ratio (HR) 0.66 with 95% CI 0.52–0.83; P < 0.001]. Subgroup analysis demonstrated that only patients with complete resection had a benefit of surgery. Surgery was safe as 30-, 60- and 90-day mortality was not increased in patients undergoing surgery [6]. The rationale for conducting AGO-OVAR DESKTOP III was based on a broad body of retrospective data. A comprehensive review of all published retrospective series to this topic was published in 2005 [7]. This review was limited to series with >100 patients and cytoreductive surgery for platinum-sensitive ROC, as most of the identified series were rather small or had mixed patient cohorts. Eight series could be identified which reported prognostic factors for survival after cytoreductive surgery in ROC [8–15]. Primary FIGO-stage, localization and outcome of primary surgery were never reported to be of prognostic significance in the recurrent disease setting. Two series identified preoperative chemotherapy as a negative prognostic factor. All series reported surgical outcome as independent prognostic factor for survival. The multicenter Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer I (DESKTOP I OVAR) by the AGO Study Group reported only complete resection as beneficial with an OS of 45.2 months. There were no differences between minimal residuals of 1–10 or >10 mm (19.7 versus 19.6 months). There were two series describing a benefit of cytoreduction to 1–20 mm compared with >20 mm [13] and 0.1–10 mm compared with >10 mm [14]. However, very heterogeneous patients’ cohorts and missing additional chemotherapy after surgery in a substantial frequency of patients, limited the value of these analyses. In contrast, the largest single center series published by Sehouli et al. [15] confirmed the findings that only complete resection is beneficial. Moreover, a large international collaborative multicenter analysis including 1100 patients showed that complete resection was strongly associated with the improvement of survival, with a median survival of 57.7 months, compared with 27.0 months in those patients with residual disease of 0.1–1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P < 0.0001) [16]. In addition to complete resection, which was the strongest prognostic factor for further survival (HR: 2.94), the DESKTOP I series
identified absence of ascites (HR: 2.30) and postoperative platinum-based chemotherapy (HR: 1.82) as further prognostic factors. In the past, it was difficult to identify suitable patients in whom complete resection was feasible. Therefore, the reported rates of complete resection varied between 20% and 80% [17]. The AGO DESKTOP I study evaluated three predictive factors for complete resection: Good performance status (ECOG 0), complete resection at first surgery (alternatively, FIGO I/II in patients with unknown residual disease after primary surgery), and absence of ascites. Patients, in whom all these factors were present, a complete resection was feasible in 79% (AGO-score positive). In the subsequent AGO DESKTOP II study, this score was validated prospectively. The study was planned to show that a positive AGO score reaches a positive predictive value for complete resection of > 66% (2 of 3 pts) with 95% probability at a significance level of P< 0.05. Five hundred sixteen patients with platinum-sensitive relapse were screened within 19 months. About 32% of the patients with first relapse were operated on. One hundred twenty-nine patients had a positive score. In patients with a positive score, a complete resection could be achieved in 76%, resulting in a positive validation of the AGO score [18]. Since the publication of the DEKTOP II study, the AGO score has been validated by several other groups [19–20] (Table 1). Complete resection rates in patients with positive AGO score ranged between 67.0% and 89.3%, indicating that the AGO score is able to predict operability with complete resection with high reliability. On the other hand, the AGO score was not intended to give any information about inoperability. DESKTOP II already reported complete resection rates of 63.5% in AGOscore negative patients and in the consecutive analyses by other groups revealed complete resection rates ranging between 48.5% and 68.5%. Primary surgery for advanced EOC bears a curative opportunity for affected patients. Therefore, it seems to be appropriate to accept an increased morbidity and even low rates of mortality. Due to the fact, that the impact of surgery on survival of r ROC is still not validated prospectively, and that the current understanding of treatment of ROC is merely prolongation of survival and not cure, morbidity and mortality are of highest importance. Perioperative complications have been prospectively documented in DESKTOP
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Annals of Oncology II. About 44% of patients had to receive packed blood cells, and 33% of patients had at least one perioperative complication. About 24% of patients received antibiotic treatment and 11% did undergo relaparotomy. In a meta-analysis, the weighted mean morbidity rate was 19.2% [24]. The 30-day mortality in DESKTOP II was reported to be 0.8% [18], in meta-analysis 1.2% [24] and up to 7.8% in single institutions [15]. As described earlier, the AGO DESKTOP III trial (NCT01166737) has only presented PFS, but data on OS are still premature. Another ongoing study investigating the role of cytoreductive surgery for platinum-sensitive ROC is carried out by the Gynecologic Oncology Group (GOG) (GOG 213; NCT00565851).
Medical treatment of relapsed ovarian cancer Waiting for clarifications about the role of surgery in the relapsed disease setting, actually the standard treatment is still represented by systemic therapy. Despite optimal surgery and appropriate first-line chemotherapy, 80% of patients with EOC will develop a recurrence at different time points. The likelihood of relapse depends on many factors, including distribution of disease at initial presentation, success of initial surgical cytoreduction (i.e. the presence of any residual disease), rapidity of CA125 resolution, and treatment response after primary therapy. ROC can be detected biochemically (rising of CA125), clinically or radiologically. Subsequent sequential treatment strategies maximize quality and length of life but are not curative. Retreatment with chemotherapy should not be routinely started in asymptomatic patients with CA125 progression alone. Literature data have demonstrated that early initiation of chemotherapy is not associated to any survival advantage and in fact will have a negative effect on quality of life (QoL). Prognosis at relapse is mainly dominated by chemosensitivity of the tumor. The choice of second-line chemotherapy depends on several factors such as platinum-free interval (PFI), persistent side-effects after prior treatments, schedules and toxicity profiles of next therapies and patient preferences. Until now, the PFI has been considered as the main prognostic factor that guides the treatment choice at time of the recurrence. The fourth International Ovarian Cancer Consensus Meeting held in Vancouver in June 2010 on behalf of Gynecologic Cancer InterGroup (GCIG) established definition of PFI as the interval from the last date of platinum dose until progressive disease is documented [25]. According to this definition, ROC has been characterized into four different categories known as platinumrefractory, resistant, partially sensitive, and fully sensitive depending on when the relapse occurs after the last platinum treatment (during treatment or within 4 weeks; between 6 and 12 months; or beyond 12 months, respectively). Although these definitions have been used to identify different populations, the resistance to platinum-based treatment is not a categorical variable. Furthermore, considering the recent introduction of maintenance therapies, the concept of PFI has been recently challenged. In the last consensus (5th Ovarian Carcinoma Consensus Conference) conference of Tokyo [26], the PFI paradigm has been partially revisited and the concept of treatment-free interval
introduced, considering PFI, previous bevacizumab, BRCA status and different histological subtypes.
Treatment of early relapse Patients relapsing during first-line treatment (refractory) or in the few following months thereafter (resistant) represent a very heterogeneous group with various biological tumor behaviors. This condition is linked to unfavorable prognosis, so the main objective of treatment is to palliate symptoms and preserve QoL. Monotherapy with non-platinum compounds has showed to be equally effective and less toxic compared with combinations. A Cochrane systematic review of trials in platinum-resistant EOC found that paclitaxel, pegylated liposomal doxorubicin (PLD) and topotecan offer similar objective response rates (10%–20%), median PFS (3–4 months), and overall survival (12 months) with different toxicity profiles [27]. Regarding molecular targeted therapy, interesting data have been obtained in this setting with antiangiogenic compounds. In the randomized phase III AURELIA trial [28], bevacizumab in combination with standard chemotherapy (PLD, weekly paclitaxel, or topotecan) and as single agent maintenance until progression demonstrated to prolong PFS (6.7 versus 3.4 months HR 0.48; 95% CI 0.38–0.60; P < 0.001). However, overall survival was not found prolonged, most probably partially due to the fact patients in the standard chemotherapy alone arm could receive bevacizumab at time of progression [HR 0.85 (95% CI 0.85–1.08); P ¼ 0.174; median 16.6 months with bevacizumab plus chemotherapy versus 13.3 months with chemotherapy alone]. However, in a sub-group analysis, a significant OS benefit was shown for bevacizumab in the weekly paclitaxel group (median 22 versus 13 months). According to those results, bevacizumab was licensed in this setting.
Treatment of relapse after 6 months This subgroup refers to a wide heterogeneous group that include platinum-sensitive (PFI 12 months) and partially sensitive (PFI 6 <12 months) patients. Chemosensitivity to platinum compounds is supposed to increase with longer interval from the initial therapy. For patients with PFI >12 months, the use of platinum-based combinations (carboplatin/PLD; carboplatin/ paclitaxel and carboplatin/gemcitabine) is associated to a better outcome (PFS, OS, ORR) compared with non-platinum or platinum single agent treatments [29, 30]. In patients with a PFI between 6 and 12 months (partially platinum-sensitive), two options are available: platinum doublets or non-platinum therapy (single agent or combination). The hypothesis that a benefit could be derived from the artificial extension of PFI by introducing a non-platinum therapy in partially sensitive disease to make the following platinum more effective has been proposed many years ago, without any prospective confirmation of its validity. Some studies have been designed to test this hypothesis (MITO8, INOVATYON). The MITO 8 study a phase III trial comparing the experimental sequence of a non-platinum single agent chemo (NPBC) followed by a platinum based chemotherapy (PBC) versus the reversed sequence, recently demonstrated that the use of
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Symposium article NPBC to artificially prolong the PFI is not effective in partially sensitive d ROC patients [median OS was 21.8 versus 24.5 months (HR 1.38, 95% CI: 0.99–1.94, P ¼ 0.06)] [31]. This evidence confirms that platinum-based treatment should be the first choice in this population. A non-platinum containing doublet (trabectedin plus PLD) has been recently introduced in the treatment of patients with platinum-sensitive ROC that are not candidate for platinum. This approach is based on the PFS advantage observed with the combination versus PLD alone in the OVA-301 randomized trial (median PFS of 7.4 months in the trabectedin/PLD arm versus 5.5 months in the PLD arm) [32]. A subgroup analysis of this trial has suggested an OS prolongation in the same population of the MITO 8 trial, with a significant 41% decrease in the risk of death compared with PLD alone (HR ¼ 0.59; 95% CI, 0.43–0.82; P ¼ 0.0015). Median OS was 23.0 months in the trabectedin/PLD arm versus 17.1 months in the PLD arm. Interestingly, it has been suggested that the combination of trabectedin/PLD is able to prolong OS affecting the efficacy of platinum received later after progression. This hypothesis is under evaluation in the prospective phase III trial comparing trabectedin/PLD, followed by platinum versus platinum-based chemotherapy (INOVATYON trial) (ClinicalTrials.gov identifier: NCT01379989). For women who are unable to tolerate platinum chemotherapy because of hypersensitivity, comorbidity, or other previous toxicity, single-agent chemotherapy may be used. Treatment of platinum sensitive relapsed OC has changed in the last years also due to the introduction of two biological agents: bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, and olaparib, an inhibitor of poly [adenosine diphosphate (ADP)-ribose] polymerase (PARPi). Bevacizumab in combination with chemotherapy for platinum-sensitive ROC has been approved on the basis of results from two randomized, controlled phase III studies, GOG-0213 and OCEANS. The GOG-0213 study demonstrated that adding bevacizumab to platinum based chemotherapy showed a nonstatistically significant OS difference of 5 months compared with chemotherapy alone (median OS: 42.6 versus 37.3 months; HR ¼ 0.84, 95% CI: 0.69–1.01) and a statistically significant advantage of 3.4 months in median PFS (13.8 versus 10.4 months; HR ¼ 0.61, 95% CI: 0.51–0.72) [33]. In the OCEANS trial, 484 women with platinum-sensitive t ROC were randomized to carboplatin and gemcitabine plus either bevacizumab or placebo. The bevacizumab-containing combination was associated with a better objective response rate (ORR, 78.5% versus 57.4% with the non-bevacizumab containing combination), and a longer PFS (12.4 versus 8.4 months; HR¼ 0.484; 95% CI, 0.388–0.605; logrank P < 0.0001). No difference in OS has been observed, probably due to crossover (HR ¼ 0.95, 95% CI: 0.77–1.17) [34]. Olaparib is the first-in-class PARP inhibitors to be licensed for the treatment of ROC harboring deleterious BRCA mutations. The activity of olaparib as maintenance after response to a platinum-based chemotherapy in the platinum-sensitive highgrade serous ROC has firstly been shown in the ‘study 19’ trial and then confirmed in the SOLO-2 phase III trial. Maintenance therapy with olaparib showed a 70% reduction in the risk of progression or death compared with placebo assessed both by investigator (median 19.1 versus 5.5 months; HR¼ 0.30, 95% CI 0.22–0.41; P < 0.0001) and by blinded independent central review (BICR) (median 30.2 versus 5.5 months; HR 0.25,
Annals of Oncology 0.18–0.35; P < 0.0001), and significantly longer time to second progression (PFS2) (HR 0.50, 0.34–0.72; P ¼ 0.0002) [35, 36]. Olaparib is actually approved as maintenance after platinum response in ROC patients with a somatic or germline BRCA mutation. Two other PARP inhibitors have been recently been approved by the FDA for the treatment of recurrent disease, not only in BRCA mutated or in platinum sensitive relapsed cases. Niraparib, an oral highly selective, potent PARP-1 and PARP-2 inhibitor, is approved in USA for the maintenance treatment of adult women with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer responding to last platinum-based chemotherapy. It is also under regulatory review in the EU for use as maintenance treatment in patients with platinum-sensitive ROC who are in response to platinum-based chemotherapy based on the results of the phase III trial, the ENGOT-OV16/ NOVA study. This is an international phase III, double-blind, placebo-controlled study that enrolled 553 patients with ROC who had achieved either a partial or complete response (PR or CR) to their most recent platinum-based chemotherapy. Patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the homologous recombination deficiency (HRD) status and were randomly assigned in a 2 : 1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was PFS. Patients in the niraparib group had a significantly longer median PFS than those in the placebo group, i.e. 21.0 versus 5.5 months in the gBRCA cohort (HR¼ 0.27; 95% CI, 0.17–0.41), 12.9 versus 3.8 months in the non-gBRCA cohort for patients who had tumors with HRD (HR ¼0.38; 95% CI, 0.24–0.59) and 9.3 versus 3.9 months in the overall non-gBRCA cohort (HR¼ 0.45; 95% CI, 0.34–0.61; P < 0.001 for all three comparisons). The results of several secondary end points from this trial, including chemotherapy-free interval, time to second subsequent therapy (TSST), and PFS-2, demonstrate the positive and durable treatment effect of niraparib in a broad population of patients with ROC, regardless of the presence or absence of germline BRCA mutations and HRD status [37]. Another PARP inhibitor, rucaparib an oral, small molecule that targets the PARP enzyme, will probably enrich the therapeutic armamentarium of BRCA-mutated EOC patients. Rucaparib has been recently approved by the FDA as monotherapy for the treatment of ROC patients who are carriers of deleterious (germline and/or somatic) BRCA mutations [38]. The approval of rucaparib is based on results from two single-arm clinical trials involving 106 women with ROC who had been treated with two or more chemotherapy regimens and had their BRCA-mutations confirmed by the companion diagnostic test. In the trials, known as Study 10 and ARIEL2 (Assessment of Rucaparib In Ovarian CancEr TriaL2) Parts 1, the drug obtained an overall response rate of 54% (complete, 9%; partial, 45%) and a median duration of response of 9.2 months. In the ARIEL2 Part 1, patients with platinum-sensitive, high-grade ROC were classified into one of three predefined HRD subgroups on the basis of tumor mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and loss of heterozygosis high (LOH high group), or BRCA wild-type and LOH low group and treated with oral rucaparib at 600 mg twice daily for continuous 28-day cycles until disease progression or any other reason for discontinuation.
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Symposium article
Annals of Oncology The primary end point was PFSl. Median PFS after rucaparib treatment was 12.8 months (95% CI 9.0–14.7) in the BRCA mutant subgroup, 5.7 months (5.3–7.6) in the LOH high subgroup, and 5.2 months (3.6–5.5) in the LOH low subgroup. PFS was significantly longer in the BRCA mutant (HR¼ 0.27, 95% CI 0.16–0.44, P < 0.0001) and LOH high (HR ¼ 0.62, 95% CI 0.42– 0.90, P ¼ 0.011) subgroups compared with the LOH low subgroup. These results confirm the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutation [39]. More data on rucaparib will eventually come from other trials (ARIEL 3; ARIEL 4) exploring the role of the drug as maintenance after chemotherapy or as single agent (https://clinicaltrials.gov/ ct2/show/NCT01968213, https://clinicaltrials.gov/ct2/show/NC T02855944).
Chemotherapy according to tumor biology and BRCA status: treatment in the following lines It is well recognized that there are five different histological types of OC with a different genomic landscape, natural histories and patterns of response to therapy. The existing treatment strategies based on PFI in ROC has been largely driven by the activity of chemotherapy found in high-grade serous (HGSOC) and endometrioid (HGSEC) histology. In rare subtypes, where chemotherapy is less effective, the option of a clinical trial with targeted therapy may be appropriate. Several studies have been conducted to test the activity of MEK inhibitors in low grade serous ovarian cancer (LGSOC) [40]. The results of such studies are waited in the near future; these drugs are associated with 15%–20% response rate compared with 5% of chemotherapy [40]. Interesting data of hormonotherapy have also been reported in LGSOC, during the 2016 ASCO Annual Meeting. A long-term retrospective study of 204 patients with FIGO stage II–IV lowgrade serous carcinoma demonstrated that hormonal therapy given as maintenance following primary treatment reduced the risk of disease progression by 77%, compared with surveillance (P < 0.001). Hormonal maintenance therapy was associated with a statistically significant increase of the median PFS (64.9 versus 27.3 months; HR ¼ 0.23; P < 0.001) compared with the surveillance; this benefit seems to be greater in patients without evidence of disease after chemotherapy (median PFS 81.1 versus 29.9 months P < 0.001) and gained also a prolongation of median overall survival (191.3 versus 106.8 months; P ¼ 0.04) [41]. In the 5th Ovarian Carcinoma Consensus Conference, the need of trials in rare histologic subtypes, that have different prognosis and biological behavior, has been underlined and includes, among others, clear cell cancer and mucinous tumors, that are less responsive to standard chemotherapy options [42]. The tailored therapy approach based on the different subtypes and tumor biology is still far away from utilization in clinical practice. However, there are some examples of a biology driven approaches that can be proposed. As an example, chemotherapy choice can be adapted according to BRCA mutation. Three studies (of which two retrospective) have shown a higher efficacy of PLD in BRCA-mutated tumors compared with unselected cases (RR of 7%–25%, probably due to the mechanism of action of this
drug (DNA adducts, topoisomerse II inhibition in HRD cells, immunomodulatory effects). In addition, trabectedin (a minor groove DNA binder derived from marine organisms) has been associated with high response rates and prolonged PFS when used both as a single agent and in combination with PLD [32, 43, 44] in BRCA-mutated patients. There is no conclusive evidence about an impact of BRCA mutations on response to taxanes (e.g. paclitaxel). Despite the absence of prospective clinical trials, platinum, PLD and trabectedin, can be considered the chemotherapy agents of choice in the BRCA-mutated patients. In conclusion, the treatment approach to patients with ROC has evolved dramatically in recent years. The integration of surgery, with a ‘personalized’ approach in using antiangiogenic agents and PARP inhibitors has increased the survival of such patients and will help EOC to become a chronic disease.
Funding SP is recipient of a grant from AIRC (Associazione Italiana Ricerca sul Cancro) (no grant number applies). The publication of this supplement and the symposium on which it is based have been supported through partnership between the Spanish Ovarian Cancer Research Group (GEICO) and the European Society for Medical Oncology (ESMO).
Disclosure FH received honoraria from Roche, AstraZeneca and PharmaMar and he received travel support from PharmaMar and Roche. SP received honoraria from Roche, AstraZeneca, MSD, Pfizer and PharmaMar. ADB received honoraria from Roche, Astra Zeneca, PharmaMar, Tesaro, Pfizer, and Advaxis. PH has received honoraria from Astra Zeneca, Roche, Tessaro, Clovis, PharmaMar. SCC has received honoraria from Roche, AZ, PharmaMar.
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Volume 28 | Supplement 8 | November 2017