PARPi related toxicities: do we need more appropriate instruments to evaluate it?
Authors: D. Lorusso, S. Pignata
Journal: Annals of Oncology (2018)

The development of poly(ADP-ribose) polymerase inhibitors (PARPi) for therapy is a successful application of bench-to-bedside medicine and at present represents a major breakthrough in ovarian cancer care. Almost half of all ovarian cancers present deficiencies in the homologous recombination (HR) DNA repair pathway and PARP inhibitors are being utilized in the clinic to manage recurrent ovarian cancers that display defects in the HR repair pathway. However, PARP inhibitors have also shown significant clinical benefit in patients without HR deficiencies [1.Norquist B.M. Harrell M.I. Brady M.F. et al.Inherited mutations in women with ovarian carcinoma.JAMA Oncol. 2016; 2: 482-490Crossref PubMed Scopus (454) Google Scholar]. Between December 2014 and July 2017, three PARPi (olaparib, rucaparib, and niraparib) were licensed for the treatment of recurrent ovarian cancer and approvals for additional disease indications are anticipated. Olaparib received FDA approval as monotherapy in BRCA mutated ovarian cancer who had received at least three previous chemotherapy lines [2.Matulonis U.A. Penson R.T. Domchek S.M. et al.Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety.Ann Oncol. 2016; 27: 1013-1019Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar] and as maintenance in platinum sensitive, platinum responsive ovarian cancer patients' regardless BRCA mutation [3.Pujade-Lauraine E. Ledermann J.A. Selle F. et al.Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2017; 18: 1274-1284Abstract Full Text Full Text PDF PubMed Scopus (1103) Google Scholar]. EMA approval of Olaparib is limited to the maintenance treatment of BRCA mutated, platinum sensitive, recurrent ovarian cancer patients who had responded to platinum-based chemotherapy. FDA approval of rucaparib as monotherapy in BRCA mutated patients who had received at least two previous chemotherapy lines was announced on December 2016 [4.Kristeleit R. Shapiro G.I. Burris H.A. et al.A phase I–II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors.Clin Cancer Res. 2017; 23: 4095-4106Crossref PubMed Scopus (176) Google Scholar]. Recently, EMA approved the drug in the same indication. Niraparib has been approved by FDA and EMA for maintenance therapy of recurrent platinum sensitive ovarian, fallopian tube or primary peritoneal cancer, regardless of BRCA status [5.Mirza M.R. Monk B.J. Herrstedt J. et al.Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.N Engl J Med. 2016; 375: 2154-2164Crossref PubMed Scopus (1490) Google Scholar]. Several adverse events (AEs) to PARPi have been observed and although there are a number of overlapping class specific toxicities, there are also some marked differences for each of them. Class specific toxicities are grade 3 and 4 anaemia that was reported in 18%–45% of patients and nausea/vomiting and fatigue which impact in more than 70% of patients but are mainly grades 1 and 2. In contrast, grade 3 and 4 thrombocytopenia were notably higher in the niraparib trial (33.8%) compared with Olaparib (1%), and Rucaparib studies (5%) while grade 3 and 4 transaminates elevation was a typical Rucaparib toxicity (11%) [6.Bitler B.G. Watson Z.L. Wheeler L.J. Behbakht K. PARP inhibitors: clinical utility and possibilities of overcoming resistance.Gynecol Oncol. 2017; 147: 695-704Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar]. Rare (≤1%) but important class-specific AEs also included myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) and pneumonitis. The incidence of MDS/AML was similar across all PARPi and seems non-influenced by duration of treatment [6.Bitler B.G. Watson Z.L. Wheeler L.J. Behbakht K. PARP inhibitors: clinical utility and possibilities of overcoming resistance.Gynecol Oncol. 2017; 147: 695-704Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar]. Notably observed AEs resulted in dose reduction in 25%–66.5% of cases and dose discontinuation in 9%–11% of cases. In particular, in NOVA trial the recommended dose of niraparib (300 mg/die) did cause prominent grade 3 and 4 haematological (thrombocytopenia 34%; anaemia 25%; neutropenia 20%) and non-haematological (hypertension 8%, fatigue 8%, nausea 3%) toxicities leading to dose reductions in 66.5% of patients and to permanent treatment discontinuation in 14.7% of cases. 74.1% of patients randomized to niraparib and 22.9% assuming placebo reported grade 3 and 4 toxicities the vast majority of which were haematological [5.Mirza M.R. Monk B.J. Herrstedt J. et al.Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.N Engl J Med. 2016; 375: 2154-2164Crossref PubMed Scopus (1490) Google Scholar]. Given that lower doses are associated with substantial improvements in the incidence of treatment-emergent AEs while do not appear to compromise efficacy, approaches that would permit the individualization of optimal doses in patients at higher risk of grade 3 or 4 haematological toxicity have been evaluated. In their retrospective RADAR analysis on Nova trial, Bereck et al. [7.Berek J.S. Matulonis U.A. Peen U. et al.Safety and dose modification for patients receiving niraparib.Annal Oncol. 2018; 29: 1784-1792Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar] identified two risk factors able to predict myelosuppression (body weight <77 kg and/or basal platelets count <150 000/μl) suggesting that, when one or both are present, the starting dose of niraparib should be reduced to 200 mg/day. The incidence of grade 3/4 thrombocytopenia was 35% for patients having at least one risk factor compared with 12% in patients without either risk factor and, as a results of dose interruptions and reductions, average daily dose delivered in the first 2 months was 200 mg. Moreover, progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. The author concluded that, in the presence of one or both risk factors the starting dose of niraparib should be 200 mg/die and if no haematological events occur within the first 2–3 months of treatment, consideration for dose escalation may be entertained with close monitoring of blood counts. This analysis is being submitted to regulatory authorities to support consideration for dose modification. It is not the first time that a new drug enters the market with a dose which is not the one that will be usually used in the clinical setting: Pegylated Liposomal Doxorubicin was labelled for the treatment of recurrent ovarian cancer at the dose of 50 mg/mq every 28 days, but the elevated incidence of grade 3 and 4 hand food syndrome prompted the clinician to reduce the dose to 40 mg/mq q 28 days without any impact on efficacy [8.Rose P.G. Pegylated liposomal doxorubicin: optimizing the dosing schedule in ovarian cancer.Oncologist. 2005; 10: 205-214Crossref PubMed Scopus (135) Google Scholar]. Topotecan received the indication for the treatment of recurrent ovarian cancer at the dose of 1.5 mg/mq days 1–5 q 21, but the unmanageable haematological toxicity forced clinicians to reduce the dose to 1.25 mg/mq for 5 days every 3 weeks or to transform the schedule into a less toxic weekly administration [9.Sehouli J. Stengel D. Harter P. et al.Topotecan weekly versus conventional 5-day schedule in patients with platinum-resistant ovarian cancer: a randomized multicenter phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group.J Clin Oncol. 2011; 29: 242-248Crossref PubMed Scopus (86) Google Scholar]. An important point of discussion, particularly in this setting where three drugs appear similar in efficacy but different in safety, is if the data we have from the three registration trials effectively reflect the burden of toxicity during this treatment. The reporting of toxicity as peak toxicity is adequate for a daily chronic therapy that may last months or years? The authors of the present paper should be complimented for going deeply in the NOVA database to better understand the safety issue. More data should be made available from all the studies particularly showing the duration of side-effects. A grade 2 side-effect could be more heavy for a patient than a peak and transient grade 3 AE. How to report this? Area under the curve could be a tool to better report low grade chronic side-effects? Also the point of view of the patients should be more clearly investigated; it may help in our clinical decision among the three different drugs. In fact, accurate monitoring of symptomatic AEs is essential in clinical trials to assess and ensure patient safety, as well as to inform decisions related to treatment and/or continuation of trial participation [10.Basch E. The missing voice of patients in drug-safety reporting.N Engl J Med. 2010; 362: 865-869Crossref PubMed Scopus (428) Google Scholar]. Usually in oncological studies the safety findings are reported using standard investigator-reported CTCAE grades. There is empirical evidence that investigators miss up to half of symptomatic AEs [11.Di Maio M. Basch E. Bryce J. et al.Patient-reported outcomes in the evaluation of toxicity of anticancer treatments.Nat Rev Clin Oncol. 2016; 13: 319-325Crossref PubMed Scopus (138) Google Scholar] and that the collection of this information directly from study participants as patient-reported outcomes (PROs) may improve the reliability and accuracy of symptomatic AEs detection. In fact, regardless of which self-reporting measure was used, the majority of studies that directly compared CTCAE and PRO ratings confirmed a poor to moderate association between clinician and patient-based AEs [12.Fromme E.K. Eilers K.M. Mori M. et al.How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire.J Clin Oncol. 2004; 22: 3485-3490Crossref PubMed Scopus (397) Google Scholar]. In 2005, the Food and Drug Administration published a draft guidance document (finalized in 2009) recommending the use of PROs whenever measuring concepts in clinical trials that are better evaluated from the patient's perspective [13.Tanvetyanon T. Soares H.P. Djulbegovic B. et al.A systematic review of quality of life associated with standard chemotherapy regimens for advanced non-small cell lung cancer.J Thorac Oncol. 2007; 2: 1091-1097Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar] with a similar statement from the European Medicines Agency [14.Belani C.P. Pereira J.R. von Pawel J. et al.Effect of chemotherapy for advanced non-small cell lung cancer on patients' quality of life. A randomized controlled trial.Lung Cancer. 2006; 53: 231-239Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]. At present PROs are used in clinical trials for measurement of health-related quality of life, physical functioning, and disease-related symptoms [15.Basch E. Reeve B.B. Mitchell S.A. et al.Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE).J Natl Cancer Inst. 2014; 106: dju244Crossref PubMed Scopus (524) Google Scholar]. In particular, electronic-based PRO-CTCAE system represents the patient's perception of the treatment related symptoms in terms of frequency, severity, and interference with daily life activities, without any potentially misleading interpretation by the clinician, and may assist in the general understanding of a therapy's safety and tolerability. Multiple studies have demonstrated that PRO-CTCAE data may provide different results than CTCAE for the same symptoms and, as such, the overall evaluation of toxicity needs to be supported by the clinical interpretation [16.Basch E. Iasonos A. McDonough T. et al.Patient versus clinician symptom reporting using the national cancer institute common terminology criteria for adverse events: results of a questionnaire based study.Lancet Oncol. 2006; 7: 903-909Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar, 17.Xiao C. Polomano R. Bruner D.W. Comparison between patient-reported and clinician-observed symptoms in oncology.Cancer Nurs. 2013; 36: E1-E16Crossref PubMed Scopus (86) Google Scholar]. Nevertheless, a patient's perception of symptoms can provide a better understanding of treatment outcomes from the patient's perspective because PRO data are more systematically assessed and often may investigate about different aspects of the toxicity than what CTCAE may capture. Moreover, one additional advantage of the electronic PRO data registration over the traditional paper method is represented by the ability to collect data between clinical visits providing potential immediacy of the information. As such, there is growing interest in using PRO-CTCAE assessments in the care setting [18.Buttner M. Zebralla V. Dietz A. Singer S. Quality of life measurements: any value for clinical practice?.Curr Treat Options Oncol. 2017; 18: 30.Crossref PubMed Scopus (18) Google Scholar] and recently, a systematic review by Gotay et al. [19.Gotay C.C. Kawamoto C.T. Bottomley A. Efficace F. The prognostic significance of patient-reported outcomes in cancer clinical trials.J Clin Oncol. 2008; 26: 1355-1363Crossref PubMed Scopus (423) Google Scholar], demonstrated that PRO-CTCAE measures significantly correlate with patients survival and provide information above and beyond more conventional clinical assessments. The need for such an approach is particularly outstanding in the modern oncology because we are entering into a new therapeutic era in which long-term, orally administered target therapies and immunotherapies may cause elongated-standing, low grade AEs that contribute to treatment non-adherence, discontinuations, dose reductions, and, above all, patient distress [20.Bhattacharya D. Easthall C. Willoughby K.A. et al.Capecitabine non-adherence: exploration of magnitude, nature and contributing factors.J Oncol Pharm Pract. 2012; 18: 333-342Crossref PubMed Scopus (81) Google Scholar]. Nevertheless several challenges and bags need to be addressed: (i) although multiple translations are in progress, translation and linguistic validation of PRO-CTCAE items in other languages are needed; (ii) personnel and infrastructure are required for the collection of data and potential concerns about workload for clinical research staff need to be considered; (iii) there is limited experience with respect to how optimally analysing and interpreting PRO-CTCAE data and is necessary to identify the most informative way to merge symptomatic toxicity scores in combination with CTCAE grades [21.Basch E. Pugh S.L. Dueck A.C. et al.Feasibility of patient reporting of symptomatic adverse events via the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in a chemoradiotherapy cooperative group multicenter clinical trial.Int J Radiat Oncol Biol Phys. 2017; 98: 409-418Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. In conclusion systematic capture of patient perspective can inform the development of new cancer therapies and should be incorporated in clinical trials in order to better capture toxicities and inform the appropriate dosage and schedule of the new drugs before entering into the market. From the informed patient's perspective, the patient voice has been a key missing element in the current system of drug safety assessment and the mistake should not be repeated in the future. Better reporting of safety in the clinical trials with daily oral therapy is mandatory. High grade peak toxicity may not reflect the full toxicity burden of these drugs. Chronic low grade AEs may be even more important for the patients. PARPi are an incredible step forward for our patients. However, we still need to fully learn how to preserve the benefit reducing the impact of toxicities. The RADAR analysis adds an important information, but more data are needed for all PARPi. None declared.