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4 april 2018: lees ook dit artikel: 

https://kanker-actueel.nl/parpremmer-rucaparib-verdubbelt-ziektevrije-overleving-5-vs-11-en-13-maanden-bij-chemo-gevoelige-eierstokkanker-ook-bij-patienten-zonder-brca-mutatie-is-rucaparib-effectief.html

9 november 2015: Bron: N Engl J Med 2015; 373:1697-1708. DOI: 10.1056/NEJMoa1506859

Olaparib - (Lynparza) geeft alsnog een hoge response bij zwaar voorbehandelde mannen met hormoonresistente en uitbehandelde veruitgezaaide prostaatkanker. En bij wie de olaparib aansloeg - gemiddeld 33% (20 tot 48%) reageerde goed op dit medicijn - werd de mediane overlevingstijd zo goed als verdubbeld van 7,5 naar 13,8 maanden.

Opvallend is dat alle responders, dus de mannen waarbij de olaparib aansloeg, een of meerdere specifieke DNA mutaties hadden in de genen verantwoordelijk voor DNA herstel. Waaronder ook BRCA 1 en 2, die veel voorkomen bij eierstokkanker en borstkanker, waar olaparib ook goede resultaten geeft overigens. Dit alles  blijkt uit een gerandomiseerde fase II studie gepubliceerd in The New England Journal of Medicine, Deze deelstudie is onderdeel van de TOTARP-A studie die ook een deel B kent: http://www.icr.ac.uk/our-research/our-research-centres/clinical-trials-and-statistics-unit/clinical-trials/toparp

olaparib beeld 2(2)

Bedenk hierbij dat alle deelnemende patiënten (N=50) alle andere behandelingen voor prostaatkanker al hadden gehad, waaronder hormoonremmers, chemo met docetaxel en/of cabazitaxel, Abiraterone, enzalutamine enz. En dan alsnog een verdubbelde levensverlenging is echt opzienbarend.

Studie opzet en resultaten:

In deze studie werden 50 patiënten opgenomen en behandeld met olaparib (400 mg twee keer per dag) Alle patiënten waren eerder behandeld met docetaxel, 98% van de patiënten met abiraterone (Zytiga) of enzalutamide (Xtandi) en 58% met cabazitaxel.

Het primaire doel was de response, dus bij wie zou de olaparib nog iets doen, gedefinieerd als objectieve response, wanneer er een vermindering in de PSA - prostate-specific antigen level van gelijk of meer dan 50% zou worden gezien of een bevestigde vermindering van circulerende tumorcellen zoals geregistreerd in het bloed van ≥ 5 per 7.5 mL bloed tot <5/7.5 mL. Gerichte next-generation sequencing, exome en transcriptome analyses, en digitale polymerase chain reactie testen (= receptoren- en DNA onderzoek) werden uitgevoerd op bioptweefsel van alle patienten voordat de behandeling startte.

Response cijfers en overleving:

Overall response werd gezien bij 16 van de 49 evalueerbare patiënten (response rate = 33%, 95% confidence interval = 20%–48%). Next-generation sequencing identificeerde homozygous deletions, deleterious mutaties, of beide in de genen voor DNA-herstel, incl. BRCA1/2, ATM, Fanconi’s bloedarmoede genen, en CHEK2,  kwamen voor bij 16 (335 afwijkingen) van de 49 patiënten. Van deze 16 hadden er 14 positieve biomarkers (88%, P < .001) versus patienten die een negatieve biomarkerscore hadden) en hadden een therapeutisch effect door de olaparib, inclusief alle 7 patiënten met een BRCA2 mutatie (vier met biallelic somatic verlies, drie met germline mutaties) en 4 van de 5 met ATM afwjikingen.

Mediane radiologische bevestigde progressievrije overleving was 9.8 maanden in patiënten met positieve biomarkers versus 2.7 maanden bij patienten (P < .001) met negatieve biomarkers. Mediane overall overleving was 13.8 maanden versus 7.5 maanden (P = .05) respectievelijk.

De meest voorkomende bijwerkingen van graad 3 en 4 waren bloedarmoede (20%) en vermoeidheid (12%).

Olaparib bij prostaatkanker grafiekOlaparib bij prostaatkanker DNA mutaties

Conclusie:

De onderzoekers concluderen: "Behandeling met de parpremmer olaparib bij patiënten welke hun prostaatkankertumoren niet langer meer reageren op standaardbehandelingen en die defecten lieten zien in genen voor DNA-herstel geeft hoge response cijfers".

Het volledige studierapport: DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer is gratis in te zien. Als u klikt op de video plaatje naast het abstract / studierapport kunt u in een korte video zien hoe olaparib werkt en hoe het wordt toegediend.

Hier het abstract van deze studie met referentielijst onderaan:

“Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA repair genes led to a high response rate.”

Original Article

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

Joaquin Mateo, M.D., Suzanne Carreira, Ph.D., Shahneen Sandhu, M.D., Susana Miranda, B.Sc., Helen Mossop, M.Math.Stat., Raquel Perez-Lopez, M.D., Daniel Nava Rodrigues, M.D., Dan Robinson, Ph.D., Aurelius Omlin, M.D., Nina Tunariu, M.D.Res., Gunther Boysen, Ph.D., Nuria Porta, Ph.D., Penny Flohr, B.Sc., Alexa Gillman, B.Sc., Ines Figueiredo, B.Sc., Claire Paulding, B.Sc., George Seed, M.Sc., Suneil Jain, M.D., Christy Ralph, M.D., Andrew Protheroe, M.D., Ph.D., Syed Hussain, M.D., Robert Jones, M.D., Ph.D., Tony Elliott, M.D., Ph.D., Ursula McGovern, M.D., Ph.D., Diletta Bianchini, M.D., Jane Goodall, B.Sc., Zafeiris Zafeiriou, M.D., Chris T. Williamson, Ph.D., Roberta Ferraldeschi, M.D., Ph.D., Ruth Riisnaes, F.I.B.M.S., Bernardette Ebbs, B.T.E.C., Gemma Fowler, B.Sc., Desamparados Roda, M.D., Wei Yuan, Ph.D., Yi-Mi Wu, Ph.D., Xuhong Cao, M.S., Rachel Brough, Ph.D., Helen Pemberton, Ph.D., Roger A’Hern, Ph.D., Amanda Swain, Ph.D., Lakshmi P. Kunju, M.D., Rosalind Eeles, M.D., Ph.D., Gerhardt Attard, M.D., Ph.D., Christopher J. Lord, Ph.D., Alan Ashworth, Ph.D., Mark A. Rubin, M.D., Karen E. Knudsen, Ph.D., Felix Y. Feng, M.D., Ph.D., Arul M. Chinnaiyan, M.D., Ph.D., Emma Hall, Ph.D., and Johann S. de Bono, M.B., Ch.B., Ph.D.

N Engl J Med 2015; 373:1697-1708 October 29, 2015 DOI: 10.1056/NEJMoa1506859

Comments open through November 4, 2015

Background

Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate –ribose) polymerase (PARP) inhibition with olaparib.

Methods

We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.

Results

Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes — including BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2 — in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.

Conclusions

Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.)

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