2 februari 2019: Bron: Journal of immuno therapy for cvancer

Durvalumab plus olaparib geeft mediaan 16 maanden progressievrije ziekte bij prostaatkankerpatienten die resistent waren geworden voor enzalutamide en / of abiraterone. De helft van de deelnemende patiënten reageerde met minimaal een jaar progressievrije ziekte met heel beheersbare bijwerkingen. Dat blijkt uit een fase II veiligheidsstudie studie bij 17 patiënten met in de botten uitgezaaide prostaatkanker.

Bijzonder aan deze studie is dat er vooraf niet geselecteerd was op DNA mutaties. Hoewel een DNA mutatie gerelateerd aan een DNA reparatie gen wel vaker voorkwam bij de patienten die goed reageerden op deze aanpak waren er ook patienten die goed reageerden zonder een DNA mutatie.

Mediane door scans bevestigde progressievrije ziekte (rPFS) voor alle patiënten is 16.1 maanden (95% CI: 4.5–16.1 months) met een 12-maanden rPFS bij 51.5% (95% CI: 25.7–72.3%) van de deelnemende patiënten. 9 van de 17 (53%) patiënten had een door scans bevestigde vermindering van de PSA waarden en tumorvermindering.

Een mooi resultaat dus want progressievrije ziekte na abiraterone en / of enzalutamide komt niet zo vaak voor.

Treatment outcomes and immune predictors of response

Nine of 17 patients (53%) had a PSA decline of ≥50% (defined as responders). Of those 9 patients, 4 had a radiographic response per RECIST v.1.1 (Fig. 1a, b). For all patients, the 12-month PFS is 51.5% (95% CI: 25.7–72.3%). The median radiographic progression-free survival (rPFS) of patients with alterations in DDR genes was 16.1 months (95% CI: 7.8–18.1 months) (Fig. 2), with 12-month PFS probability of 83.3% (95% CI: 27.3–94.5%) compared with a 12-month probability of 36.4% (95% CI: 11.2–62.7%) for those without mutations; exact p = 0.031.

An external file that holds a picture, illustration, etc. Object name is 40425_2018_463_Fig1_HTML.jpg

PSA Response. a Waterfall plot demonstrating maximum decline in PSA for each patient. Bar colors represent radiographic response by RECIST criteria: green, partial response; blue, stable disease; red, progressive disease; gray, not assessable (bone-only disease). b Spider plot of PSA responses over time

In het studierapport staat mooie grafiek over de wel en niet responders gerelateerd aan hun ziekte en mutaties.

Molecular characteristics of responders

Using a sequencing panel targeting 500 cancer-associated genes, we performed genomic analysis of germline DNA for all patients and tumor DNA for 14/17 patients (Fig. 4). Four responders harbored germline alterations in DDR genes: one with a known deleterious mutation in NBN and 3 with frameshift indels in BRCA2. The patients with germline BRCA2 indels had tumor tissue available which demonstrated somatic deletion of the second allele.

An external file that holds a picture, illustration, etc. Object name is 40425_2018_463_Fig4_HTML.jpg

Genomic Alterations. Presence or absence of alterations in DDR and other significant genes. Genomic data are from OncoVar sequencing, a capture-based sequencing panel of 500 cancer-associated genes. Copy number calls are based on read depth and minor allele frequency in the OncoVar sequencing results. All patients had germline sequencing performed. As indicated, 3 patients had insufficient tumor tissue on biopsy and no archival tissue available

Het volledige studierapport: Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations is gratis in te zien.

Hier het abstract van de studie:

 

  

Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities.

2018 Dec 4;6(1):141. doi: 10.1186/s40425-018-0463-2.

Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations.

Karzai F1, VanderWeele D2, Madan RA1, Owens H1, Cordes LM1, Hankin A1, Couvillon A1, Nichols E3, Bilusic M1, Beshiri ML2, Kelly K2, Krishnasamy V4, Lee S5, Lee MJ5, Yuno A5, Trepel JB5, Merino MJ6, Dittamore R7, Marté J1, Donahue RN8, Schlom J8, Killian KJ9, Meltzer PS9, Steinberg SM10, Gulley JL1, Lee JM11, Dahut WL12.

Abstract

BACKGROUND:

Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations.

METHODS:

Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations.

RESULTS:

Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5-16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7-72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8-18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response.

CONCLUSIONS:

Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities.

TRIAL REGISTRATION:

ClinicalTrials.gov identifier: NCT02484404 .

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Articles from Journal for Immunotherapy of Cancer are provided here courtesy of BioMed Central

durvalumab, olaparib, progressievrije ziekte, PSA waarden, prostaatkanker, botuitzaaiingen


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