DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
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 [ADP]-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.).
From the Institute of Cancer Research (J.M., S.C., S.S., S.M., H.M., R.P.-L., D.N.R., A.O., N.T., G.B., N.P., P.F., A.G., I.F., C.P., G.S., D.B., J.G., Z.Z., C.T.W., R.F., R.R., B.E., G.F., D. Roda, W.Y., R.B., H.P., R.A., A.S., R.E., G.A., C.J.L., A.A., E.H., J.S.B.), the Royal Marsden NHS Foundation Trust (J.M., S.S., R.P.-L., A.O., N.T., D.B., Z.Z., R.F., D. Roda, R.E., G.A., J.S.B.), and University College London Hospital (U.M.), London, Queen's University, Belfast (S.J.), University of Leeds, Leeds (C.R.), Churchill Hospital, Oxford (A.P.), University of Liverpool, Liverpool (S.H.), Beatson West of Scotland Cancer Centre, Glasgow (R.J.), and Christie Hospital, Manchester (T.E.) - all in the United Kingdom; the University of Michigan, Ann Arbor (D. Robinson, Y.-M.W., X.C., L.P.K., F.Y.F., A.M.C.); Weill Cornell Medical College, New York (M.A.R.); and Thomas Jefferson University, Philadelphia (K.E.K.).
Joaquin
J
Mateo
Suzanne
S
Carreira
Shahneen
S
Sandhu
Susana
S
Miranda
Helen
H
Mossop
Raquel
R
Perez-Lopez
Daniel
D
Nava Rodrigues
Dan
D
Robinson
Aurelius
A
Omlin
Nina
N
Tunariu
Gunther
G
Boysen
Nuria
N
Porta
Penny
P
Flohr
Alexa
A
Gillman
Ines
I
Figueiredo
Claire
C
Paulding
George
G
Seed
Suneil
S
Jain
Christy
C
Ralph
Andrew
A
Protheroe
Syed
S
Hussain
Robert
R
Jones
Tony
T
Elliott
Ursula
U
McGovern
Diletta
D
Bianchini
Jane
J
Goodall
Zafeiris
Z
Zafeiriou
Chris T
CT
Williamson
Roberta
R
Ferraldeschi
Ruth
R
Riisnaes
Bernardette
B
Ebbs
Gemma
G
Fowler
Desamparados
D
Roda
Wei
W
Yuan
Yi-Mi
YM
Wu
Xuhong
X
Cao
Rachel
R
Brough
Helen
H
Pemberton
Roger
R
A'Hern
Amanda
A
Swain
Lakshmi P
LP
Kunju
Rosalind
R
Eeles
Gerhardt
G
Attard
Christopher J
CJ
Lord
Alan
A
Ashworth
Mark A
MA
Rubin
Karen E
KE
Knudsen
Felix Y
FY
Feng
Arul M
AM
Chinnaiyan
Emma
E
Hall
Johann S
JS
de Bono
D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005221:Fatigue / Q000139:chemically induced; D024522:Genes, BRCA2; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010793:Phthalazines / Q000009:adverse effects / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C531550:olaparib