Table Info

Table 1.

Comparison of pembrolizumab/chemotherapy versus olaparib from a practical standpoint

Comparative aspect	Olaparib	Pembrolizumab/Chemotherapy
Clinical trial	OlympiAD	Keynote 355
Eligibility in mTNBC	gBRCA, sBRCA, gPALB2^*	CPS ≥ 10
Response rate reported	60%	41%
Median duration of response	6.4 Months (IQR, 2.8 to 9.7) in the olaparib group compared to 7.1 months (IQR, 3.2 to 12.2) in the standard chemotherapy group	12.8 Months (95% CI 9.9–25.9) in pembrolizumab/chemotherapy group compared to 7.3 months (95% CI 5.5–15.4) in the chemotherapy group
Median time to onset of response	47 Days	Not reported
Median PFS	7.0 Months versus 4.2 months in the olaparib group compared to the standard-therapy group respectively (HR 0.58; 95% Cl 0.43–0.80; P < 0.001).	9.7 Months with pembrolizumab-chemotherapy compared to 5.6 months with placebo-chemotherapy respectively; HR 0.65, 95% CI 0.49–0.86; one-sided P = 0.0012 (co-primary objective met)
OS	No OS benefit in the ITT. OS of 22.6 months compared to 14.7 months if used in the 1st line setting (HR 0.55; 95% CI 0.33–0.95, P = 0.02)^**	OS of 23.0 months compared to 16.1 months in the placebo-chemotherapy group (HR 0.73; 95% CI 0.55–0.95; P = 0.0093)
Contraindications	MDS/AML Pneumonitis	Active severe autoimmune disease
Possible adverse effects	Myelosuppression, nausea, vomiting, risk of MDS/AML, pneumonitis	Any autoimmune adverse events including but not limited to irreversible hypophysitis, adrenal insufficiency, thyroiditis, fatal cardiomyositis
Convenience	Oral therapy requiring monthly follow up to monitor	IV therapy every 3 weeks

^* Patients with HER2 negative MBC with gPALB2 or sBRCA1/2 mutations were found to benefit from treatment with olaparib according to TBCRC 048, a phase II trial of olaparib for MBC and homologous recombination-related gene mutations; ^** post hoc analysis. IQR: interquartile range; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia; IV: intravenous

Declarations

Author contributions

SA and SG: Writing—original draft. AMR and LNC: Writing—review & editing. AMR: Data curation. All authors reviewed the manuscript.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Turner NC, Ashworth A. Biomarkers of PARP inhibitor sensitivity. Breast Cancer Res Treat. 2011;127:283–6. [DOI] [PubMed]

Huszno J, Kołosza Z, Grzybowska E. BRCA1 mutation in breast cancer patients: analysis of prognostic factors and survival. Oncol Lett. 2019;17:1986–95. [DOI] [PubMed] [PMC]

Robson ME, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. OlympiAD extended follow-up for overall survival and safety: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Eur J Cancer. 2023;184:39–47. [DOI] [PubMed] [PMC]

Zhang M, Sun H, Zhao S, Wang Y, Pu H, Wang Y, et al. Expression of PD-L1 and prognosis in breast cancer: a meta-analysis. Oncotarget. 2017;8:31347–54. [DOI] [PubMed] [PMC]

Bianchini G, Huang CS, Egle D, Bermejo B, Zamagni C, Thill M, et al. LBA13 Tumour infiltrating lymphocytes (TILs), PD-L1 expression and their dynamics in the NeoTRIPaPDL1 trial. Ann Oncol. 2020;31:S1145–6. [DOI]

Rozenblit M, Huang R, Danziger N, Hegde P, Alexander B, Ramkissoon S, et al. Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers. J Immunother Cancer. 2020;8:e001558. [DOI] [PubMed] [PMC]

Cortes J, Rugo HS, Cescon DW, Im SA, Yusof MM, Gallardo C, et al.; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387:217–26. [DOI] [PubMed]

Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al.; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21. [DOI] [PubMed]

Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al.; IMpassion130 Investigators. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:44–59. [DOI] [PubMed]

10.

Miles D, Gligorov J, André F, Cameron D, Schneeweiss A, Barrios C, et al.; IMpassion131 investigators. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32:994–1004. [DOI] [PubMed]

11.

Roche provides update on Tecentriq US indication for PD-L1-positive, metastatic triple-negative breast cancer [Internet]. F. Hoffmann-La Roche Ltd; c2023 [cited 2023 Mar 10]. Available from: https://bit.ly/3ypzC6K

12.

Cortés J, Lipatov O, Im SA, Gonçalves A, Lee KS, Schmid P, et al. LBA21 - KEYNOTE-119: phase III study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple negative breast cancer (mTNBC). Ann Oncol. 2019;30:v859–60. [DOI]

13.

Winer EP, Lipatov O, Im SA, Goncalves A, Muñoz-Couselo E, Lee KS, et al.; KEYNOTE-119 investigators. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:499–511. [DOI] [PubMed]

14.

Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30:397–404. [DOI] [PubMed]

15.

Adams S, Loi S, Toppmeyer D, Cescon DW, De Laurentiis M, Nanda R, et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30:405–11. [DOI] [PubMed]

16.

Tolaney SM, Kalinsky K, Kaklamani VG, D’Adamo DR, Aktan G, Tsai ML, et al. Eribulin plus pembrolizumab in patients with metastatic triple-negative breast cancer (ENHANCE 1): a phase Ib/II study. Clin Cancer Res. 2021;27:3061–8. [DOI] [PubMed]

17.

Schmid P, Wysocki P, Park YH, Jassem J, Jung KH, Lord SR, et al. Abstract PD11-08: PD11-08 Trastuzumab deruxtecan (T-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic hormone receptor-negative (HR−), HER2-low breast cancer: updated results from BEGONIA, a phase 1b/2 study. Cancer Res. 2023;83:PD11-08-PD11-08. [DOI]

18.

Schmid P, Wysocki P, Ma C, Park YH, Fernandes R, Lord SR, et al. Abstract PD11-09: PD11-09 Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase 1b/2 study. Cancer Res. 2023;83:PD11-09-PD11-09. [DOI]

19.

Hahnen E, Hauke J, Engel C, Neidhardt G, Rhiem K, Schmutzler RK. Germline mutations in triple-negative breast cancer. Breast Care (Basel). 2017;12:15–9. [DOI] [PubMed] [PMC]

20.

Powell SN, Kachnic LA. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene. 2003;22:5784–91. [DOI] [PubMed]

21.

Snouwaert JN, Gowen LC, Latour AM, Mohn AR, Xiao A, DiBiase L, et al. BRCA1 deficient embryonic stem cells display a decreased homologous recombination frequency and an increased frequency of non-homologous recombination that is corrected by expression of a Brca1 transgene. Oncogene. 1999;18:7900–7. [DOI] [PubMed]

22.

Cousineau I, Belmaaza A. BRCA1 haploinsufficiency, but not heterozygosity for a BRCA1-truncating mutation, deregulates homologous recombination. Cell Cycle. 2007;6:962–71. [DOI] [PubMed]

23.

Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001;7:263–72. [DOI] [PubMed]

24.

Tentori L, Graziani G. Chemopotentiation by PARP inhibitors in cancer therapy. Pharmacol Res. 2005;52:25–33. [DOI] [PubMed]

25.

Tentori L, Portarena I, Graziani G. Potential clinical applications of poly(ADP-ribose) polymerase (PARP) inhibitors. Pharmacol Res. 2002;45:73–85. [DOI] [PubMed]

26.

Zhang J, Powell SN. The role of the BRCA1 tumor suppressor in DNA double-strand break repair. Mol Cancer Res. 2005;3:531–9. [DOI] [PubMed]

27.

Mateos R, Pérez-Correa JR, Domínguez H. Bioactive properties of marine phenolics. Mar Drugs. 2020;18:501. [DOI] [PubMed] [PMC]

28.

FDA approves olaparib for germline BRCA-mutated metastatic breast cancer [Internet]. [Cited 2023 May 1]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-germline-brca-mutated-metastatic-breast-cancer

29.

FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer [Internet]. [Cited 2023 May 1]. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-gbrcam-her2-negative-locally-advanced-or-metastatic-breast-cancer

30.

Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379:753–63. [DOI] [PubMed] [PMC]

31.

Litton JK, Hurvitz SA, Mina LA, Rugo HS, Lee KH, Gonçalves A, et al. Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann Oncol. 2020;31:1526–35. [DOI] [PubMed] [PMC]

32.

Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523–33. Erratum in: N Engl J Med. 2017;377:1700. [DOI] [PubMed]

33.

Robson ME, Tung N, Conte P, Im SA, Senkus E, Xu B, et al. OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 2019;30:558–66. [DOI] [PubMed] [PMC]

34.

Garutti M, Pelizzari G, Bartoletti M, Malfatti MC, Gerratana L, Tell G, et al. Platinum salts in patients with breast cancer: a focus on predictive factors. Int J Mol Sci. 2019;20:3390. [DOI] [PubMed] [PMC]

35.

Gerratana L, Fanotto V, Pelizzari G, Agostinetto E, Puglisi F. Do platinum salts fit all triple negative breast cancers? Cancer Treat Rev. 2016;48:34–41. [DOI] [PubMed]

36.

Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial. Nat Med. 2018;24:628–37. [DOI] [PubMed] [PMC]

37.

Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, et al. TBCRC009: A multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol. 2015;33:1902–9. [DOI] [PubMed] [PMC]

38.

Diéras V, Han HS, Kaufman B, Wildiers H, Friedlander M, Ayoub JP, et al. Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:1269–82. [DOI] [PubMed]

39.

Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al.; KEYNOTE-522 Investigators. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810–21. [DOI] [PubMed]

40.

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. N Engl J Med. 2021;384:2394–405. [DOI] [PubMed] [PMC]

41.

Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34:2460–7. [DOI] [PubMed] [PMC]

42.

Miglietta F, Fabi A, Generali D, Dieci MV, Arpino G, Bianchini G, et al. Optimizing choices and sequences in the diagnostic-therapeutic landscape of advanced triple-negative breast cancer: an Italian consensus paper and critical review. Cancer Treat Rev. 2023;114:102511. Erratum in: Cancer Treat Rev. 2023;117:102570. Erratum in: Cancer Treat Rev. 2023;119:102594. [DOI] [PubMed]