131-I-MIBG therapy in combination with PARP inhibitors for young adult patient with relapsed neuroblastoma and DNA repair pathway alterations

To the editor, Neuroblastoma is the most common extracranial solid tumor of childhood and encompasses a wide range of clinical presentations and related prognoses. Patients with high-risk neuroblastoma have the poorest prognosis, with 5-year survival rates of approximately 50% [[1]Irwin M.S. Naranjo A. Zhang F.F. Cohn S.L. London W.B. Gastier-Foster J.M. et al.Revised Neuroblastoma Risk Classification System: A Report From the Children’s Oncology Group.J Clin Oncol. 2021; 39: 3229-3241https://doi.org/10.1200/JCO.21.00278Crossref PubMed Scopus (152) Google Scholar]. 131I-metaiodobenzylguanidine (131I-MIBG) is an active radiotherapeutic for neuroblastoma, including in the context of refractory or relapsed disease, with recent reports showing increased response rates in combination with vorinostat [[2]DuBois S.G. Granger M.M. Groshen S. Tsao-Wei D. Ji L. Shamirian A. et al.Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium.J Clin Oncol. 2021; 39: 3506-3514https://doi.org/10.1200/JCO.21.00703Crossref PubMed Scopus (28) Google Scholar]. Pediatric patients with hard-to-cure cancers now have access to comprehensive precision oncology programs and the genetic landscape of high-risk neuroblastoma is well described [[3]Pugh T.J. Morozova O. Attiyeh E.F. Asgharzadeh S. Wei J.S. Auclair D. et al.The genetic landscape of high-risk neuroblastoma.Nat Genet. 2013; 45: 279-284https://doi.org/10.1038/ng.2529Crossref PubMed Scopus (838) Google Scholar]. An 18-year-old patient had been diagnosed with metastatic high-risk neuroblastoma - left retroperitoneal mass, bone and bone marrow involvement - at age 5. Biology studies had then identfied no MYCN amplification and loss of heterozygosity of chromosome 11q. She had experienced multiple metastatic relapses and therapeutic approaches over 13 years including 131I-MIBG therapy twice. 131I-MIBG therapy had been given as single agent, at the dose of 18 mCi/kg, at ages 11 and 12 in the context of metastatic bony relapse (reponse data available as part of Fig. 1C). Later on their journey and as part of clinical trials, the patient had received temozolomide and irinotecan followed by consolidation with lenalidomide and dinutuximab, topotecan and pazopanib, and nivolumab. At the time of latest relapse, the patient’s bone metastasis was subjected to molecular profiling as part of a local pediatric precision oncology program [[4]Villani A. Davidson S. Kanwar N. Lo W.W. Li Y. Cohen-Gogo S. et al.The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.Nat Cancer. 2023; 4: 203-221https://doi.org/10.1038/s43018-022-00474-yCrossref PubMed Scopus (16) Google Scholar]. This analysis demonstrated a pathogenic germline heterozygous variant in PALB2 (p.Lys346Thrfs*13). The somatic tumor analysis showed heterozygous loss of ATM and CHEK1, as well as the presence of Single Base Substitution Signature (SBS) 3 in the tumor, which is thought to be a surrogate for defective homologous recombination-based DNA damage repair (HRR) [[5]Alexandrov L.B. Kim J. Haradhvala N.J. Huang M.N. Tian Ng A.W. Wu Y. et al.The repertoire of mutational signatures in human cancer.Nature. 2020; 578: 94-101https://doi.org/10.1038/s41586-020-1943-3Crossref PubMed Scopus (1572) Google Scholar]. PALB2 encodes a tumor suppressor and component of the Fanconi anaemia complementation group involved in DNA double-strand break repair. Well-known partners of the PALB2 protein are the BRCA1 and BRCA2 proteins. Germline mutations in PALB2 have been reported in adult patients with breast, ovarian, prostate and pancreatic cancer and rarely in pediatric patients with cancer, such as neuroblastoma [6Yang X. Leslie G. Doroszuk A. Schneider S. Allen J. Decker B. et al.Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families.J Clin Oncol. 2020; 38: 674-685https://doi.org/10.1200/JCO.19.01907Crossref PubMed Scopus (234) Google Scholar, 7Reid S. Schindler D. Hanenberg H. Barker K. Hanks S. Kalb R. et al.Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.Nat Genet. 2007; 39: 162-164https://doi.org/10.1038/ng1947Crossref PubMed Scopus (512) Google Scholar]. Mutations in PALB2 have also been shown to predict response to PARP inhibition in prostate cancer [[8]Castro E. Mateo J. Olmos D. de Bono J.S. Targeting DNA Repair: The Role of PARP Inhibition in the Treatment of Castration-Resistant Prostate Cancer.Cancer J. 2016; 22: 353-356https://doi.org/10.1097/PPO.0000000000000219Crossref PubMed Scopus (22) Google Scholar]. In the absence of HRR, cells with utilize alternate DNA repair pathways that are dependent on PARP; inhibiting PARP has then the potential to limit the viability of HRR deficient cells. Interestingly, in vitro testing of talazoparib in a pediatric cancer cell line panel showed high level of drug activity against a Wilm’s tumor cell line harboring a truncating mutation in PALB2, analogous to PALB2 mutations associated with hereditary breast and ovarian cancer [[9]Smith M.A. Hampton O.A. Reynolds C.P. Kang M.H. Maris J.M. Gorlick R. et al.Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673.Pediatr Blood Cancer. 2015; 62: 91-98https://doi.org/10.1002/pbc.25201Crossref PubMed Scopus (66) Google Scholar]. While this context supported the conclusion that defective HRR was likely one of the tumor drivers for neuroblastoma in this patient, there was no available clinical trial through which they could access a PARP inhibitor (PARPi) at that time in Canada. Given the extensive prior history and multiple lines of therapy, there were limited therapeutic options. Although the combination of 131I-MIBG and PARPi has not been previously reported in patients, there is preclinical evidence that PARPi may act as radiosensitizers and thereby enhance the efficacy of 131I-MIBG [[10]Nile D.L. Rae C. Hyndman I.J. Gaze M.N. Mairs R.J. An evaluation in vitro of PARP-1 inhibitors, rucaparib and olaparib, as radiosensitisers for the treatment of neuroblastoma.BMC Cancer. 2016; 16: 621https://doi.org/10.1186/s12885-016-2656-8Crossref PubMed Scopus (44) Google Scholar]. Based on the presence of HRR pathway pathogenic mutations and SBS3 - two biomarkers for PARPi sensitivity in breast and ovarian cancers - we hypothesized the patients tumor might be sensitive to combination 131I-MIBG and PARPi. Here we report on feasibility, safety, tolerability, and outcome of 131I-MIBG in combination with PARPi in a single patient with homologous recombination repair pathway alterations. Baseline disease staging involved cross-sectional and MIBG imaging and revealed bony lesions to the cranium, thorax, sternum, ribs, pelvis and femurs. No intra-abdominal recurrence was noted. 131I-MIBG (18 mCi/kg) was administered in combination with olaparib (90 mg/m2 b.i.d. for 10 days) [[11]Gatz S.A. Rubino J. Rossoni C. Andre N. Aerts I. Thebaud E. et al.AcSé-ESMART: European Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors in Children and Adolescents–Arm D: Olaparib and irinotecan.JCO. 2019; 37 (10047–10047)https://doi.org/10.1200/JCO.2019.37.15_suppl.10047Crossref Google Scholar] (Fig. 1A). Olaparib was accessed through commercial supply. Patient experienced transient grade 3 nausea, grade 3 fatigue, grade 4 low platelet, white cell and neutrophil counts and grade 3 anemia. No unexpected adverse events from the combination were noted. Disease reassessment 43 days post MIBG showed an improvement in metastatic burden as measured by the Curie score. Although there was a reduction in Curie score, this did not meet the definition for a partial response as per INRC criteria (> 50% reduction in MIBG bone score) (Fig. 1B). Patient recovered from expected myelotoxicity following peripheral blood stem cell administration and started maintenance talazoparib therapy on day 78. Talazoparib was administered at starting dose 600 μg/m2 once daily continuously in 28-day cycles [[12]Schafer E.S. Rau R.E. Berg S.L. Liu X. Minard C.G. Bishop A.J.R. et al.Phase 1/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory/recurrent solid tumors including Ewing sarcoma: A Children’s Oncology Group Phase 1 Consortium study (ADVL1411).Pediatr Blood Cancer. 2020; 67e28073https://doi.org/10.1002/pbc.28073Crossref Scopus (44) Google Scholar]. Access to talazoparib occurred through a single patient study, approved by Health Canada and the Hospital’s Research Ethics Board, with written consent for reporting of results [[13]Revon-Riviere G. Young L.C. Stephenson E.A. Brodeur-Robb K. Cohen-Gogo S. Deyell R. et al.Ensuring access to innovative therapies for children, adolescents, and young adults across Canada: The single patient study experience.Paediatrics & Child Health. 2023; : pxac122https://doi.org/10.1093/pch/pxac122Crossref Scopus (0) Google Scholar]. Talazoparib dose was reduced during cycle 1 and then further during cycles 2 and 3 due to grade 4 thrombocytopenia, and eventually resumed at a dose of 250 µg/m2 every other day, with no other significant adverse events to report. Patient experienced prolonged stable disease until progressive disease was detected after 18 cycles (16 months) of maintenance therapy with talazoparib. In contrast, the patient had previously experienced periods of disease response of 9 and 8 months respectively following two prior courses of single agent 131I-MIBG (Fig. 1C). Administration of 131I-MIBG in combination with a PARPi, followed by maintenance therapy with single agent PARPi was safe and feasible. This novel treatment approach, in the context of a single patient study, was associated with prolonged stable disease in a patient with multiply relapsed disease and evidence of HRR pathway aberrations. This case report, together with previous pre-clinical studies, provides rationale for future early phase trials utilizing molecular selection of patients with hard-to-treat neuroblastoma, based on HRR pathway alterations, for delivery of 131I-MIBG along with inhibition of the DNA damage response pathway. This work was supported by the following grants: our local precision oncology program, KiCS (SickKids Cancer Sequencing), is supported by the Garron Family Cancer Centre at The Hospital for Sick Children through funding from the SickKids Foundation.

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