Zie ook hier wat artikelen met olaparib in de titel op onze website: https://kanker-actueel.nl/search.html?search_text=olaparib&search_in=title

Zie ook in gerelateerde artikelen hieronder of hiernaast

2 september 2025: Nature d.d. 13 mei 2025

Uit een deelstudie van de fase II/III Partner studie blijkt dat het geven van de parpremmer olaparib (Lynparza) 48 uur na de chemotherapie met Paclitaxel - Taxol vooraf aan een operatie van borstkanker met aangetoonde BRCA 1 en/of 2 status de 3-jaars overall overleving op 100 procent brengt. In vergelijking met een controlegroep waar de overall overleving 88 procent bedroeg op 3-jaars meting.

Van de 39 patiënten die chemotherapie gevolgd door olaparib (Lynparza) kregen, kreeg slechts één patiënt drie jaar na de operatie een recidief en overleefde 100% van de patiënten.
Ter vergelijking: de overlevingskans in de controlegroep was drie jaar na de operatie 88%. Van de 45 patiënten in de controlegroep die alleen chemotherapie kregen, kregen negen patiënten een recidief voor 3-jaars meting, van wie er zes overleden.

Uit de resultaten blijkt dat het aanhouden van een ‘gat’ van 48 uur tussen chemotherapie en olaparib (Lynparza) tot betere resultaten leidt, mogelijk omdat het beenmerg van de patiënt tijd heeft om te herstellen van de chemotherapie, terwijl de tumorcellen gevoelig blijven voor het beoogde medicijn, aldus prof. dr. Jean Abraham van de afdeling Precision Breast Cancer Medicine at the University of Cambridge and Fellow at St John's College die deze studie uitvoerden. Zie haar toelichting op hun website via deze link: New approach to treating aggressive breast cancers shows significant improvement in survival.

Hier een grafisch schema van de deelstudies uit de fase II/III Partner studie:

A Schematic of single-agent and combination schedules of olaparib and carboplatin in TNBC gBRCAm SUM149PT cells. Squares represent treatment days with purple for olaparib and green, carboplatin treatment.
B Cell cycle distribution analysis of SUM149PT. Day 4 (D4) analysis following olaparib (1 µM) and/or carboplatin (10 µM) treatment (mean values ± SD from three independent biological replicates).
C DNA damage assessment at D4 of SUM149PT cells using γH2AX. Following olaparib (1 μM) and/or carboplatin (10 μM) treatment, γH2AX foci were visualised by immunofluorescence staining (mean values ± SD from three independent biological replicates, a.u. arbitrary units).
D Cell viability of SUM149PT cells at day six after olaparib (0.3 μM) or carboplatin (1 μM) single agent treatments, concurrent combination or carboplatin first or olaparib first combination schedules.
Viability was assessed using a cell titre glow assay (see methods). Shown are the % viability for each treatment (mean values ± SD, from three independent biological replicates). Also provided are the p-values from one-way ANOVA multiple comparisons. Source data is provided as a Source Data file.

Het abstract vertaald in het Nederlands:

SamenvattingPoly (ADP-ribose) polymeraseremmers (PARPi) maken gebruik van DNA-hersteldeficiëntie bij kiembaankankers met BRCA1 en BRCA2 pathogene varianten (gBRCAm). Hematologische toxiciteit beperkt de mogelijkheden voor chemotherapie-PARPi-behandelingscombinaties. In preklinische modellen identificeerden we een schema met een combinatie van olaparib en carboplatine dat verhoogde toxiciteit vermijdt, maar de antitumoractiviteit behoudt.
We onderzochten dit schema in een neoadjuvante, fase II-III, gerandomiseerde gecontroleerde studie voor gBRCAm borstkankers (ClinicalTrials.gov ID:NCT03150576; PARTNER).
De onderzoeksgroep omvatte carboplatine (Area Under the Curve 5, 3-wekelijks); paclitaxel (80 mg/m², wekelijks) op dag 1, plus olaparib (150 mg tweemaal daags) op dag 3-14 (4 cycli), gevolgd door chemotherapie met anthracycline (3 cycli); de controlegroep gaf alleen chemotherapie.
Het primaire eindpunt, pathologisch complete responspercentage, toonde geen statistisch verschil tussen onderzoek 64,1% (25/39); controle 69,8% (30/43) (p = 0,59).
De geschatte overlevingsresultaten na 36 maanden toonden echter een verbeterde recidief vrije overleving: onderzoek 96,4%, controle 80,1% (p = 0,04); totale overleving: onderzoek 100%, controle 88,2% (p = 0,04) en borstkankerspecifieke overleving: onderzoek 100%, controle 88,2% (p = 0,04).
Er waren geen statistische verschillen in recidiefvrije overleving en ziektevrije overleving op afstand, beide waren: onderzoek 96,4%, controle 87,9% (p = 0,20).
De lokale recidiefvrije overleving en de tijd tot tweede kanker waren beide: onderzoek 96,4%, controle 87,8% (p = 0,20).

Conclusie:

De PARTNER-studie identificeerde een veilig, verdraagbaar schema dat neoadjuvante chemotherapie combineert met olaparib. Deze combinatie toonde schema-afhankelijke voordelen voor de algehele overleving bij gBRCAm-borstkanker in een vroeg stadium. Deze resultaten moeten in grotere studies worden bevestigd.

Het volledige studierapport is gratis in te zien op de website van Nature, klik daarvoor op de titel van het abstract:

Article
Open access
Published: 13 May 2025

Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial

Nature Communications volume 16, Article number: 4269 (2025) Cite this article

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m2, weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials.

Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

Article ADS CAS PubMed Google Scholar
Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

Article ADS CAS PubMed Google Scholar
Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).

Article ADS CAS PubMed PubMed Central Google Scholar
Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

Article CAS PubMed Google Scholar
Pilié, P. G., Gay, C. M., Byers, L. A., O’Connor, M. J. & Yap, T. A. PARP inhibitors: extending benefit beyond BRCA-mutant cancers. Clin. Cancer Res. 25, 3759–3771 (2019).

Article PubMed Google Scholar
Tutt, A. N. J. et al. Adjuvant Olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N. Engl. J. Med. 384, 2394–2405 (2021).

Article CAS PubMed PubMed Central Google Scholar
Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).

Article CAS PubMed Google Scholar
Pujade-Lauraine, E. 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. 18, 1274–1284 (2017).

Article CAS PubMed Google Scholar
Moore, K. et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 379, 2495–2505 (2018).

Article CAS PubMed Google Scholar
Copson, E. R. et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 19, 169–180 (2018).

Article CAS PubMed PubMed Central Google Scholar
Armstrong, N., Ryder, S., Forbes, C., Ross, J. & Quek, R. G. A systematic review of the international prevalence of BRCA mutation in breast cancer. Clin. Epidemiol. 11, 543–561 (2019).

Article PubMed PubMed Central Google Scholar
Caramelo, O. et al. Efficacy of different neoadjuvant treatment regimens in BRCA-mutated triple negative breast cancer: a systematic review and meta-analysis. Hered. Cancer Clin. Pract. 20, 34 (2022).

Article CAS PubMed PubMed Central Google Scholar
Abraham, J. E. et al. The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer. Nature 629, 1142–1148 (2024).

Article ADS CAS PubMed PubMed Central Google Scholar
Yau, C. et al. Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients. Lancet Oncol. 23, 149–160 (2022).

Article CAS PubMed Google Scholar
Fasching, P. A. et al. BRCA1/2 mutations and Bevacizumab in the Neoadjuvant treatment of breast cancer: response and prognosis results in patients with triple-negative breast cancer from the GeparQuinto Study. J. Clin. Oncol. 36, 2281–2287 (2018).

Article CAS PubMed PubMed Central Google Scholar
Paluch-Shimon, S. et al. Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers. Breast Cancer Res. Treat. 157, 157–165 (2016).

Article CAS PubMed Google Scholar
Spring, L. M. et al. Neoadjuvant study of niraparib in patients with HER2-negative, BRCA-mutated, resectable breast cancer. Nat. Cancer 3, 927–931 (2022).

Article CAS PubMed PubMed Central Google Scholar
Litton, J. K. et al. Neoadjuvant Talazoparib in patients with germline BRCA1/2 mutation-positive, early-stage triple-negative breast cancer: results of a phase II study. Oncologist 28, 845–855 (2023).

Article PubMed PubMed Central Google Scholar
Pavese, F. et al. BRCA mutation status in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: a pivotal role for treatment decision-making. Cancers (Basel) 14, 4571 (2022).

Article CAS PubMed Google Scholar
O’Connor, M. J. Targeting the DNA damage response in cancer. Mol. Cell 60, 547–560 (2015).

Article PubMed Google Scholar
Hay, T. et al. Poly(ADP-Ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 69, 3850–3855 (2009).

Article CAS PubMed Google Scholar
van der Noll, R. et al. Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1). Invest. N. Drugs 38, 1117–1128 (2020).

Article Google Scholar
Oplustil O’Connor, L. et al. The PARP inhibitor AZD2461 provides insights into the role of PARP3 inhibition for both synthetic lethality and tolerability with chemotherapy in preclinical models. Cancer Res. 76, 6084–6094 (2016).

Article PubMed Google Scholar
O’Connor, M. J. et al. Abstract 4420: generating preclinical models to assess bone marrow toxicity induced by the PARP inhibitor olaparib in combination with chemotherapy. Cancer Res. 73, 4420–4420 (2013).

Article Google Scholar
Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. & Bonner, W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).

Article CAS PubMed Google Scholar
Noor, N. M. et al. Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials. BMJ Open 12, e055615 (2022).

Article PubMed PubMed Central Google Scholar
Pettitt, S. J. et al. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat. Commun. 9, 1849 (2018).

Article ADS PubMed PubMed Central Google Scholar
Geyer, C. E. et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann. Oncol. 33, 1250–1268 (2022).

Article CAS PubMed Google Scholar
Schmid, P. et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N. Engl. J. Med. 386, 556–567 (2022).

Article CAS PubMed Google Scholar
Schmid, P. et al. Pembrolizumab for early triple-negative breast cancer. N. Engl. J. Med. 382, 810–821 (2020).

Article CAS PubMed Google Scholar
Lee, Y. J. et al. Germline BRCA, chemotherapy response scores, and survival in the neoadjuvant treatment of ovarian cancer. BMC Cancer 20, 185 (2020).

Article ADS CAS PubMed PubMed Central Google Scholar
Hahnen, E. et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer. JAMA Oncol. 3, 1378 (2017).

Article PubMed PubMed Central Google Scholar
Geyer, C. E. et al. Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial. Ann. Oncol. 33, 384–394 (2022).

Article CAS PubMed Google Scholar
Yao, D., Dai, C. & Peng, S. Mechanism of the mesenchymal–epithelial transition and its relationship with metastatic tumor formation. Mol. Cancer Res. 9, 1608–1620 (2011).

Article CAS PubMed Google Scholar
Choi, E.-B. et al. PARP1 enhances lung adenocarcinoma metastasis by novel mechanisms independent of DNA repair. Oncogene 35, 4569–4579 (2016).

Article CAS PubMed Google Scholar
Prasad, C. B. et al. Olaparib modulates DNA repair efficiency, sensitizes cervical cancer cells to cisplatin and exhibits anti-metastatic property. Sci. Rep. 7, 12876 (2017).

Article ADS PubMed PubMed Central Google Scholar
Wang, Z., Gao, J., Zhou, J., Liu, H. & Xu, C. Olaparib induced senescence under P16 or P53 dependent manner in ovarian cancer. J. Gynecol. Oncol. 30 (2019).
Hendry, S. et al. Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immunooncology biomarkers working group: part 1: assessing the host immune response, TILs in invasi. Adv. Anat. Pathol. 24, 235–251 (2017).

Article PubMed PubMed Central Google Scholar
Litton, J. K. et al. Standardized definitions for efficacy end points in neoadjuvant breast cancer clinical trials: NeoSTEEP. J. Clin. Oncol. 41, 4433–4442 (2023).

Article PubMed PubMed Central Google Scholar
Tolaney, S. M. et al. Updated standardized definitions for efficacy end points (STEEP) in adjuvant breast cancer clinical trials: STEEP version 2.0. J. Clin. Oncol. 39, 2720–2731 (2021).

Article PubMed PubMed Central Google Scholar
Miettinen, O. & Nurminen, M. Comparative analysis of two rates. Stat. Med. 4, 213–226 (1985).

Article CAS PubMed Google Scholar