PARP inhibition with rucaparib alone followed by combination with atezolizumab: Phase Ib COUPLET clinical study in advanced gynaecological and triple-negative breast cancers.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
06 Jul 2024
06 Jul 2024
Historique:
received:
30
01
2024
accepted:
18
06
2024
revised:
03
06
2024
medline:
7
7
2024
pubmed:
7
7
2024
entrez:
6
7
2024
Statut:
aheadofprint
Résumé
Combining PARP inhibitors (PARPis) with immune checkpoint inhibitors may improve clinical outcomes in selected cancers. We evaluated rucaparib and atezolizumab in advanced gynaecological or triple-negative breast cancer (TNBC). After identifying the recommended dose, patients with PARPi-naive BRCA-mutated or homologous recombination-deficient/loss-of-heterozygosity-high platinum-sensitive ovarian cancer or TNBC received rucaparib plus atezolizumab. Tumour biopsies were collected pre-treatment, during single-agent rucaparib run-in, and after starting combination therapy. The most common adverse events with rucaparib 600 mg twice daily and atezolizumab 1200 mg on Day 1 every 3 weeks were gastrointestinal effects, fatigue, liver enzyme elevations, and anaemia. Responding patients typically had BRCA-mutated tumours and higher pre-treatment tumour levels of PD-L1 and CD8 + T cells. Markers of DNA damage repair decreased during rucaparib run-in and combination treatment in responders, but typically increased in non-responders. Apoptosis signature expression showed the reverse. CD8 + T-cell activity and STING pathway activation increased during rucaparib run-in, increasing further with atezolizumab. In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens. ClinicalTrials.gov (NCT03101280).
Sections du résumé
BACKGROUND
BACKGROUND
Combining PARP inhibitors (PARPis) with immune checkpoint inhibitors may improve clinical outcomes in selected cancers. We evaluated rucaparib and atezolizumab in advanced gynaecological or triple-negative breast cancer (TNBC).
METHODS
METHODS
After identifying the recommended dose, patients with PARPi-naive BRCA-mutated or homologous recombination-deficient/loss-of-heterozygosity-high platinum-sensitive ovarian cancer or TNBC received rucaparib plus atezolizumab. Tumour biopsies were collected pre-treatment, during single-agent rucaparib run-in, and after starting combination therapy.
RESULTS
RESULTS
The most common adverse events with rucaparib 600 mg twice daily and atezolizumab 1200 mg on Day 1 every 3 weeks were gastrointestinal effects, fatigue, liver enzyme elevations, and anaemia. Responding patients typically had BRCA-mutated tumours and higher pre-treatment tumour levels of PD-L1 and CD8 + T cells. Markers of DNA damage repair decreased during rucaparib run-in and combination treatment in responders, but typically increased in non-responders. Apoptosis signature expression showed the reverse. CD8 + T-cell activity and STING pathway activation increased during rucaparib run-in, increasing further with atezolizumab.
CONCLUSIONS
CONCLUSIONS
In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens.
CLINICAL TRIAL REGISTRATION
BACKGROUND
ClinicalTrials.gov (NCT03101280).
Identifiants
pubmed: 38971950
doi: 10.1038/s41416-024-02776-7
pii: 10.1038/s41416-024-02776-7
doi:
Banques de données
ClinicalTrials.gov
['NCT03101280']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Vikas P, Borcherding N, Chennamadhavuni A, Garje R. Therapeutic potential of combining PARP inhibitor and immunotherapy in solid tumors. Front Oncol. 2020;10:570.
pubmed: 32457830
pmcid: 7228136
doi: 10.3389/fonc.2020.00570
Rudolph J, Jung K, Luger K. Inhibitors of PARP: number crunching and structure gazing. Proc Natl Acad Sci USA. 2022;119:e2121979119.
pubmed: 35259019
pmcid: 8931346
doi: 10.1073/pnas.2121979119
Rose M, Burgess JT, O’Byrne K, Richard DJ, Bolderson E. PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance. Front Cell Dev Biol. 2020;8:564601.
pubmed: 33015058
pmcid: 7509090
doi: 10.3389/fcell.2020.564601
Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, 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;18:1274–84.
pubmed: 28754483
doi: 10.1016/S1470-2045(17)30469-2
Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. New Engl J Med. 2016;375:2154–64.
pubmed: 27717299
doi: 10.1056/NEJMoa1611310
Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:1949–61.
pubmed: 28916367
pmcid: 5901715
doi: 10.1016/S0140-6736(17)32440-6
Moore K, Colombo N, Scambia G, Kim B-G, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. New Engl J Med. 2018;379:2495–505.
pubmed: 30345884
doi: 10.1056/NEJMoa1810858
Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. New Engl J Med. 2019;381:2416–28.
pubmed: 31851799
doi: 10.1056/NEJMoa1911361
González-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. New Engl J Med. 2019;381:2391–402.
pubmed: 31562799
doi: 10.1056/NEJMoa1910962
Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. New Engl J Med. 2017;377:523–33.
pubmed: 28578601
doi: 10.1056/NEJMoa1706450
Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee K-H, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. New Engl J Med. 2018;379:753–63.
pubmed: 30110579
doi: 10.1056/NEJMoa1802905
Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, et al. OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. New Engl J Med. 2021;384:2394–405.
pubmed: 34081848
doi: 10.1056/NEJMoa2105215
Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer. 2021;21:345–59.
pubmed: 33837297
pmcid: 8034277
doi: 10.1038/s41568-021-00347-z
Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. New Engl J Med. 2018;379:2108–21.
pubmed: 30345906
doi: 10.1056/NEJMoa1809615
Emens LA, Adams S, Barrios CH, Diéras V, Iwata H, Loi S, et al. First-line atezolizumab plus nab-paclitaxel for unresectable locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol. 2021;32:983–93.
pubmed: 34272041
doi: 10.1016/j.annonc.2021.05.355
Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im S-A, Yusof M, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396:1817–28.
pubmed: 33278935
doi: 10.1016/S0140-6736(20)32531-9
Cortes J, Rugo HS, Cescon DW, Im S-A, Yusof MM, Gallardo C, et al. KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. New Engl J Med. 2022;387:217–26.
pubmed: 35857659
doi: 10.1056/NEJMoa2202809
Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090–100.
pubmed: 32966830
doi: 10.1016/S0140-6736(20)31953-X
Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kümmel S, et al. KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. New Engl J Med. 2022;386:556–67.
pubmed: 35139274
doi: 10.1056/NEJMoa2112651
Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for early triple-negative breast cancer. New Engl J Med. 2020;382:810–21.
pubmed: 32101663
doi: 10.1056/NEJMoa1910549
Moore KN, Bookman M, Sehouli J, Miller A, Anderson C, Scambia G, et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol. 2021;39:1842–55.
pubmed: 33891472
pmcid: 8189598
doi: 10.1200/JCO.21.00306
Monk BJ, Colombo N, Oza AM, Fujiwara K, Birrer MJ, Randall L, et al. Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22:1275–89.
pubmed: 34363762
doi: 10.1016/S1470-2045(21)00342-9
Pujade-Lauraine E, Fujiwara K, Ledermann JA, Oza AM, Kristeleit R, Ray-Coquard I-L, et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol. 2021;22:1034–46.
pubmed: 34143970
doi: 10.1016/S1470-2045(21)00216-3
Kurtz J-E, Pujade-Lauraine E, Oaknin A, Belin L, Leitner K, Cibula D, et al. ATALANTE/ENGOT-ov29 Investigators. Atezolizumab combined with bevacizumab and platinum-based therapy for platinum-sensitive ovarian cancer: placebo-controlled randomized phase III ATALANTE/ENGOT-ov29 trial. J Clin Oncol. 2023;41:4768–78.
pubmed: 37643382
pmcid: 10602539
doi: 10.1200/JCO.23.00529
Hamanishi J, Takeshima N, Katsumata N, Ushijima K, Kimura T, Takeuchi S, et al. Nivolumab versus gemcitabine or pegylated liposomal doxorubicin for patients with platinum-resistant ovarian cancer: open-label, randomized trial in Japan (NINJA). J Clin Oncol. 2021;39:3671–81.
pubmed: 34473544
pmcid: 8601279
doi: 10.1200/JCO.21.00334
Wu Z, Cui P, Tao H, Zhang S, Ma J, Liu Z, et al. The synergistic effect of PARP inhibitors and immune checkpoint inhibitors. Clin Med Insights Oncol. 2021;15:1179554921996288.
pubmed: 33737855
pmcid: 7934064
doi: 10.1177/1179554921996288
Lheureux S, Braunstein M, Oza AM. Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J Clin. 2019;69:280–304.
pubmed: 31099893
doi: 10.3322/caac.21559
Yang C, Xia B-R, Zhang Z-C, Zhang Y-J, Lou G, Jin W-L. Immunotherapy for ovarian cancer: adjuvant, combination, and neoadjuvant. Front Immunol. 2020;11:577869.
pubmed: 33123161
pmcid: 7572849
doi: 10.3389/fimmu.2020.577869
Shen J, Zhao W, Ju Z, Wang L, Peng Y, Labrie M, et al. PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 2019;79:311–9.
pubmed: 30482774
doi: 10.1158/0008-5472.CAN-18-1003
Jiao S, Xia W, Yamaguchi H, Wei Y, Chen M-K, Hsu J-M, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res. 2017;23:3711–20.
pubmed: 28167507
pmcid: 5511572
doi: 10.1158/1078-0432.CCR-16-3215
Mirza MR, Coleman RL, González-Martín A, Moore KN, Colombo N, Ray-Coquard I, et al. The forefront of ovarian cancer therapy: update on PARP inhibitors. Ann Oncol. 2020;31:1148–59.
pubmed: 32569725
doi: 10.1016/j.annonc.2020.06.004
Strickland KC, Howitt BE, Shukla SA, Rodig S, Ritterhouse LL, Liu JF, et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016;7:13587–98.
pubmed: 26871470
pmcid: 4924663
doi: 10.18632/oncotarget.7277
Landen CN, Molinero L, Hamidi H, Sehouli J, Miller A, Moore KN, et al. Influence of genomic landscape on cancer immunotherapy for newly diagnosed ovarian cancer: biomarker analyses from the IMagyn050 randomized clinical trial. Clin Cancer Res. 2023;29:1698–707.
pubmed: 36595569
pmcid: 10150250
doi: 10.1158/1078-0432.CCR-22-2032
Tsao MS, Kerr KM, Kockx M, Beasley M-B, Borczuk AC, Botling J, et al. PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project. J Thorac Oncol. 2018;13:1302–11.
pubmed: 29800747
pmcid: 8386299
doi: 10.1016/j.jtho.2018.05.013
Ung C, Kockx MM. Challenges and perspectives of immunotherapy biomarkers and the HistoOncoImmune™ methodology. Exp Rev Precis Med Drug Dev. 2016;1:9–24.
doi: 10.1080/23808993.2016.1140005
Coleman RL, Swisher EM, Oza AM, Scott CL, Giordano H, Lin KK, et al. Refinement of prespecified cutoff for genomic loss of heterozygosity (LOH) in ARIEL2 part 1: a phase II study of rucaparib in patients (pts) with high grade ovarian carcinoma (HGOC). J Clin Oncol. 2016;34:5540.
doi: 10.1200/JCO.2016.34.15_suppl.5540
FoundationOne
Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:34.
pubmed: 28420421
pmcid: 5395719
doi: 10.1186/s13073-017-0424-2
Swisher EM, Kristeleit RS, Oza AM, Tinker AV, Ray-Coquard I, Oaknin A, et al. Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer. Gynecol Oncol. 2021;163:490–7.
pubmed: 34602290
doi: 10.1016/j.ygyno.2021.08.030
Drew Y, Kaufman B, Banerjee S, Lortholary A, Hong SH, Park YH, et al. Phase II study of olaparib + durvalumab (MEDIOLA): updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC). Ann Oncol 2019;30 (Suppl 5):v485 (Abstract 1190PD).
Penson RT, Valencia RV, Cibula D, Colombo N, Leath CA 3rd, Bidziński M, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J Clin Oncol. 2020;38:1164–74.
pubmed: 32073956
pmcid: 7145583
doi: 10.1200/JCO.19.02745
Emens LA, Molinero L, Loi S, Rugo HS, Schneeweiss A, Diéras V, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer: biomarker evaluation of the IMpassion130 study. J Natl Cancer Inst. 2021;113:1005–16.
pubmed: 33523233
pmcid: 8328980
doi: 10.1093/jnci/djab004
Ovarian Tumor Tissue Analysis (OTTA) Consortium, Goode EL, Block MS, Kalli KR, Vierkant RA, Chen W, Fogarty ZC, et al. Dose-response association of CD8+ tumor-infiltrating lymphocytes and survival time in high-grade serous ovarian cancer. JAMA Oncol. 2017;3:e173290.
doi: 10.1001/jamaoncol.2017.3290
O’Meara TA, Tolaney SM. Tumor mutational burden as a predictor of immunotherapy response in breast cancer. Oncotarget. 2021;12:394–400.
pubmed: 33747355
pmcid: 7939529
doi: 10.18632/oncotarget.27877
Emens LA, Cruz C, Eder JP, Braiteh F, Chung C, Tolaney SM, et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study. JAMA Oncol. 2019;5:74–82.
pubmed: 30242306
doi: 10.1001/jamaoncol.2018.4224
Nasta F, Laudisi F, Sambucci M, Rosado MM, Pioli C. Increased Foxp3+ regulatory T cells in poly(ADP-Ribose) polymerase-1 deficiency. J Immunol. 2010;184:3470–7.
pubmed: 20208002
doi: 10.4049/jimmunol.0901568
Luo X, Nie J, Wang S, Chen Z, Chen WJ, Li D, et al. Poly(ADP-ribosyl)ation of FOXP3 protein mediated by PARP-1 protein regulates the function of regulatory T cells. J Biol Chem. 2015;290:28675–82.
pubmed: 26429911
pmcid: 4661383
doi: 10.1074/jbc.M115.661611
Gu W, Ge R, Zhu F, Li D, Liang R, Ge J, et al. PARP-1 inhibitor-AG14361 suppresses acute allograft rejection via stabilizing CD4+FoxP3+ regulatory T cells. Pathol Res Pr. 2020;216:153021.
doi: 10.1016/j.prp.2020.153021
Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 2019;5:1132–40.
pubmed: 31194225
pmcid: 6567845
doi: 10.1001/jamaoncol.2019.1029
Konstantinopoulos PA, Waggoner S, Vidal GA, Mita M, Moroney JW, Holloway R, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019;5:1141–9.
pubmed: 31194228
pmcid: 6567832
doi: 10.1001/jamaoncol.2019.1048
Yap TA, Bardia A, Dvorkin M, Galsky MD, Beck JT, Wise DR, et al. Avelumab plus talazoparib in patients with advanced solid tumors: the JAVELIN PARP Medley nonrandomized controlled trial. JAMA Oncol. 2023;9:40–50.
pubmed: 36394849
doi: 10.1001/jamaoncol.2022.5228
Schram AM, Colombo N, Arrowsmith E, Narayan V, Yonemori K, Scambia G, et al. Avelumab plus talazoparib in patients with BRCA1/2- or ATM-altered advanced solid tumors: results from JAVELIN BRCA/ATM, an open-label, multicenter, phase 2b, tumor-agnostic trial. JAMA Oncol. 2023;9:29–39.
pubmed: 36394867
doi: 10.1001/jamaoncol.2022.5218
Monk BJ, Coleman RL, Fujiwara K, Wilson MK, Oza AM, Oaknin A, et al. ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA-MONO) and rucaparib in combination with nivolumab (ATHENA-COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer. Int J Gynecol Cancer. 2021;31:1589–94.
pubmed: 34593565
pmcid: 8666815
doi: 10.1136/ijgc-2021-002933
Banerjee S, Imbimbo M, Roxburgh P, Kim J-W, Plummer R, Stemmer S, et al. Phase II study of olaparib plus durvalumab with or without bevacizumab (MEDIOLA): final analysis of overall survival in patients with non-germline BRCA-mutated platinum-sensitive relapsed ovarian cancer. Ann Oncol. 2022;33(S7):S788.