Systematic review of parp inhibitors in pancreatic cancer

2
UNIVERSIDADE DE SANTIAGO DE COMPOSTELA
FACULTADE DE MEDICINA E ODONTOLOXÍA
TRABALLO FIN DE GRAO DE MEDICINA
TÍTULO
SYSTEMATIC REVIEW OF PARP INHIBITORS IN PANCREATIC
CANCER
AUTOR
LARA SILVANA GONZALEZ DIEGUEZ
TITOR: Domínguez Muñoz, Juan En ique
COTITORA: Villanue a Sil a, Ma ía José
Depa amen o i o : Apa a o Dixes i o (CHUS)
Depa amen o co i o a: Oncoloxía (CHUVI)
Cu so académico: 2020-2021
Con oca o ia: p imei a
La a Sil ana González Diéguez
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ABSTRACT
BACKGROUND: PARP inhibi o s (PARPi) ha e shown ac i i y in epi helial o a ian
cance ha bou ing homologous ecombina ion epai (HRR) de iciency. A small subg oup o
panc ea ic cance (PC) ca ies HRR de iciencies, being candida es o ea men wi h PARPi.
OBJECTIVE: To pe o m a sys ema ic e iew o summa ize all a ailable e idence wi h
PARPi in ad anced PC o assess i s e icacy and sa e y.
MATERIAL AND METHODS: An elec onic sea ch o clinical ials wi h HRR de icien
ad anced PC, published as a esea ch a icle o in abs ac o m be ween 2010 and 2020, was
pe o med. No language es ic ions we e applied. A p ede ined p o ocol was ollowed in
acco dance wi h he PRISMA guidelines. Popula ion was de ined as HRR de icien ,
mBRCA1/2, ad anced PC. In e en ion was de ined as poly(ADP- ibose) polyme ase
inhibi o s, PARPi, olapa ib, ni apa ib, ucapa ib, alazopa ib, elipa ib, clinical ial, ad anced
PC.
RESULTS: The sea ch iden i ied 135 eco ds, wi h 14 addi ional h ough e e ence sec ion
and g ey li e a u e. A e sc eening phase and eligibili y p ocess, en phase I/II-III ials we e
included o inal analysis, namely six mono he apy ials ( ou as ea men lines and wo as
main enance s a egy) and ou in combina ion wi h chemo he apy. All bu one o he ou
mono he apy s udies we e nega i e ials, speci ically he one en olling pa ien s on p og ession
o gemci abine. The wo PARPi ials as main enance s a egy, showed imp o ed p og ession
ee su i al (PFS). Combina ion ials yield se e e oxici y in wo ou o ou s udies.
In e es ing da a we e epo ed in one ial es ing ac iona ed low dose cispla in-gemci abine
egimen plus elipa ib, whi inc eased PFS and o e all su i al (OS) in an explo a o y analysis
whe e elipa ib was con inued as main enance. Combina ion o elipa ib wi h FOLFOX also
showed a 57% o e all esponse a e (ORR) in pla inum naï e pa ien s ha bo ing pa hogenic
HR-DDR mu a ions.
CONCLUSION: PARPi showed ac i i y in mBRCA ad anced PC as main enance
s a egy, some o which being long las ing. Fu u e in es iga ion is needed o ci cum en
esis ance and imp o e esul s.
Key Wo ds: panc ea ic cance , poly(ADP- ibose) polyme ase inhibi o s, PARP inhibi o ,
homologous ecombina ion epai de iciency/de icien , BRCA 1/2 mu a ion/mu a ed.
PARP inhibi o s in panc ea ic cance
3
RESUMEN
INTRODUCCIÓN: Los inhibido es de PARP (PARPi) han mos ado ac i idad en
cánce es de o a io epi eliales con dé ici de ecombinación homóloga (HRD). Un subg upo de
cánce de pánc eas (CP) ambién albe ga HRD, siendo así candida os al a amien o con PARPi.
OBJETIVO: Re isión sis emá ica pa a esumi la e idencia disponible sob e el uso de
PARPi en CP a anzado y e alua su e icacia y segu idad.
MATERIAL Y MÉTODOS: Se ealizó una búsqueda elec ónica, sin es cción de
idioma, de ensayos clínicos de CP a anzado con HRD, publicados como a ículos de
in es igación o esúmenes en e 2010-2020. Se siguió un p o ocolo p ede inido, de acue do con
la decla ación PRISMA. La población ue desc i a como HRD, mBRCA1/2 y CP a anzado y
la in e ención como inhibido es poli(ADP- ibosa) polime asa, PARPi, olapa ib, ni apa ib,
ucapa ib, alazopa ib, elipa ib, ensayo clínico, CP a anzado.
RESULTADOS: Se iden i ica on 135 egis os, con 14 adicionales encon ados en
secciones de e e encias y li e a u a g is. T as ase de c ibado y elegibilidad, diez ensayos en
ases I/II-III ue on incluidos en el análisis inal (seis como mono e apia (cua o líneas de
a amien o y dos como es a egia de man enimien o) y cua o con quimio e apia). Uno de los
ensayos de mono e apia, cuyos pacien es no habían p og esado con gemci abina, no e a
nega i o. Los es udios como es a egia de man enimien o mos a on mejo ía de la
supe i encia lib e de p og esión (SLP). Los combinados p oduje on oxicidad se e a en dos
de ellos. Se comunica on da os ele an es en un ensayo con égimen accionado de cispla ino-
gemci abina a dosis bajas más elipa ib, obse ándose aumen o de la SLP y la supe i encia
global en un análisis en el cual se con inuó con elipa ib como man enimien o. La combinación
de elipa ib-FOLFOX mos ó una asa de espues a obje i a del 57% en pacien es pla ino-
naï e, po ado es de HDR.
CONCLUSIÓN: Los PARPi mos a on ac i idad en PC a anzado con BRCAm, como
e apia de man enimien o, siendo algunas du ade as. Es necesa ia más in es igación pa a
e i a esis encias y mejo a esul ados.
Palab as cla e: cánce de pánc eas, inhibido es poli(ADP- ibosa) polime asa, inhibido es
PARP, dé ici /de iciencia ecombinación homóloga, BRCA 1/2 mu ación/mu ado.
La a Sil ana González Diéguez
4
RESUMO
INTRODUCCIÓN: Os inhibido es da PARP (PARPi) mos a on ac i idade en canc os
epi eliais de o a io cun dé ici de ecombinación homóloga (HRD). Un subg upo de canc o de
pánc eas (CP) amén p esen a HRD, sendo así candida os ao a amen o con PARPi.
OBXECTIVO: Le a a cabo unha e isión sis emá ica pa a esumi a e idencia dispoñible
sob e o uso de PARPi no CP a anzado e a alia a súa e icacia e segu idade.
MATERIAL E MÉTODOS: Realizouse unha p ocu a elec ónica, sen es ición de
lingua, de ensaios clínicos de CP a anzado con HRD, publicados como a igos de in es igación
ou esumos en e 2010 e 2020. Seguiuse un p o ocolo p ede inido, de aco do coa decla ación
PRISMA. A poboación oi desc i a como HRD, mBRCA1/2 e CP a anzado e a in e ención
como inhibido es poli(ADP- ibosa) polime asa, PARPi, olapa ib, ni apa ib, ucapa ib,
alazopa ib, elipa ib, ensaio clínico, CP a anzado.
RESULTADOS: Iden i icá onse 135 exis os, con 14 adicionais a opados en seccións de
e e encias e li e a u a g is. T as ase de c ibado e elixibilidade, dez ensaios en ases I/II-III
o on incluídos na análise inal (seis como mono e apia (ca o liñas de a amen o e dous como
es a exia de man emen o) e ca o con quimio e apia). Un dos ensaios de mono e apia, cuxos
pacien es non p og esa an con gemci abina, non e a nega i o. Os es udos como es a exia de
man emen o mos a on mello ía da supe i encia lib e de p og esión (SLP). Os combinados
p oduci on oxicidade se e a en dous de eles. Comunicá onse da os ele an es nun ensaio con
éxime accionado de cispla ino-gemci abina a doses baixas máis elipa ib, obse ándose
aumen o da SLP e da supe i encia global nunha análise na cal se con inuou con elipa ib como
man emen o. A combinación de elipa ib-FOLFOX mos ou unha axa de espos a obxec i a
(ORR) do 57% en pacien es pla ino-naï e, po ado es de HDR.
CONCLUSIÓN: Os PARPi mos a on ac i idade no PC a anzado con BRCAm, como
e apia de man emen o, sendo algunhas delas du adei as. É necesa ia máis in es igación pa a
e i a esis encias e mello a os esul ados.
Palab as cha e: canc o de pánc eas, inhibido es poli(ADP- ibosa) polime asa, inhibido es
PARP, dé ici /de iciencia ecombinación homóloga, BRCA 1/2 mu ación/mu ado.

PARP inhibi o s in panc ea ic cance
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INDEX
1. Backg ound
2. Objec i e
3. Ma e ial and me hods
4. Sea ch s a egy
5. T ial selec ion
6. Da a ex ac ion
7. Resul s
7.1. Mono he apies
7.2. Combina ion he apies
7.3. Side e ec s associa ed o immune checkpoin inhibi o he apy
8. Discussion
9. Conclusion
10. Re e ences
11. Appendix
11.1. PROSPERO-LIKE P o ocol
La a Sil ana González Diéguez
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BACKGROUND
In he pas , he medical communi y has ca ego ized cance by eason o he issue o igin,
assuming ha umo s om di e en pa ien s a ising om he same o gan sha ed simila ai s
and should be ea ed simila ly, in con as o umo s o di e en o gans, i espec i e o cellula
simila i ies.
As diagnos ic echnologies ad anced, mo e insigh on immunochemis y and molecula
pa hology o cance has been achie ed, showing ha cance s wi h he exac same
his opa hology, can ha bo impo an di e ences in molecula pa hways which a e esponsible
o di e en p ognosis. E en mo e, malignancies om di e en kind no only can sha e
molecula pa hways bu also d i e mu a ions which a e essen ial o cance su i al. The
iden i ica ion o hose ac ionable genomic al e a ions has pa ed he way o an unp eceden ed
e a o p ecision medicine, in which a ge ed ea men is d i en by he p esence o mu a ion in
key pa hway o umo su i al .(1)
These new pieces o e idence ha e iden i ied di e en a ibu es in mos cance ypes ha
ga e ise o new classi ica ions based on biological and clinical coincidences and disc epancies
among cance s o he same o igin, hus enabling be e pa ien subclassi ica ion acco ding o
p ognos ic s a i ica ion, op imized managemen by p edic i e subg oups, as well as u he isk
s a i ica ion.(1)
The iden i ica ion o mu a ions sha ed by umo s o di e en o igin, and subsequen speci ic
ea men acco ding o he mu a ion iden i ied, is a g owing end in he ield o oncology.
Pionee ing clinical ials, known as baske ials, ha e been designed in ol ing pa ien s wi h
umo s o di e en o igin ha sha e he same molecula al e a ions, and posi i e esul s ha e
been epo ed ha ha e gi en ise o a concep kwon as umo -agnos ic ea men , which is he
one di ec ed by molecula ea u es, i espec i e o umo o igin (2).
Panc ea ic cance (PC), p edic ed o be he second deadlies cance ype in he nex en
yea s, has no been an excep ion. F om a his ological poin o iew, PC can be di ided in o
endoc ine and exoc ine sub ypes, he la e being by a he mos common, which can be u he
subdi ided in o se e al subg oups. O hese, panc ea ic duc al adenoca cinoma (PDAC)
accoun s o mo e han 90% o exoc ine PCs and a ises om p ecu so s known as panc ea ic
in aepi helial neoplasia (PIN). Mos PDACs a e e e ed o as "no o he wise speci ied" (NOS).
O he a e a ian s o PDAC include adeno-squamous ca cinoma (a mix u e o squamous and
glandula di e en ia ion), acina cell ca cinoma and ca cinomas wi h mixed his ology and
panc ea oblas oma, o men ion a ew. Finally, a mino i y subg oup o exoc ine ca cinomas
o igina es om cys s, such as cys ic mucinous neoplasm and in aduc al papilla y mucinous
neoplasm (IPMN). (3)
PC molecula classi ica ion was pa icula ly challenging due o he ac ha panc ea ic
umo s con ain a ela i ely low pe cen age o malignan cells, wi h p ominen desmoplas ic
eac ion wi h a dense ib o ic s oma (4), wi h ba ely 5%–20% neoplas ic cellula i y (5), making
mu a ional analysis and gene exp ession ea u es di icul on neoplas ic cells. The Cance
Genome A las (TCGA), a landma k cance genomics p og am de i ed om a join e o ,
beginning in 2006, be ween he Na ional Human Genome Resea ch Ins i u e and he Na ional
Cance Ins i u e, o molecula ly cha ac e ize di e en cance ypes, ook he challenge o
PARP inhibi o s in panc ea ic cance
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de elop a molecula classi ica ion o PC. (6). A e de eloping special bioin o ma ic me hods,
he TCGA analysis e ealed a complex molecula landscape, wi h a small g oup o umo s
ha bo ing mul iple KRAS mu a ions, he es being KRAS wild- ype PDACs and ca ying
andom al e a ions in o he oncogenic d i e s. In e es ingly enough, soma ic and ge mline
mu a ions in DNA epai genes (BRCA1/2, PALB2 and ATM mu a ions) we e iden i ied in up
o 6 % o pa ien s in his se ies.(7). I should be no e ha only 4% o he pa ien s in he TCGA
analysis had s age 4 diseases, due o he challenge o ob aining a good umo sample in
ad anced panc ea ic cance .
Figu e 1. TCGA molecula indings in 150 panc ea ic cance samples, wi h only 4 cases wi h s age IV disease (7)
The p esence o mu a ions in DNA damage epai genes, such as BRCA1, BRCA2 and
PALB2 in PC, is o u mos impo ance owing he epo ed ac i i y o poly(ADP- ibose)
polyme ase (PARP) inhibi o s in umo s ha bo ing homologous ecombina ion epai (HRR)
gene de iciency. PARP is a senso o DNA damage, being key in he epai o single s and
DNA b eaks (SSBs). Acco dingly, PARP inhibi ion leads o he accumula ion o single- s and
b eaks, which become double-s and b eaks (DSB) du ing eplica ion. In absence o p ope
BRCA unc ion (BRCA1 and BRCA2 p o eins a e c i ical o DSB epai ) o wi h dys unc ion
in o he HRR gen pa hways, DSB canno be epai ed, igge ing cell dea h by means o
damaged cells disposal (8–10). Thus, cells ha bo ing de ec s in BRCA genes o o he
de iciencies in homologous ecombina ion DNA damage epai (HR-DDR) genes a e p one o
be hype sensi i e o PARP inhibi ion, a p ocess e med syn he ic le hali y.(11,12)
La a Sil ana González Diéguez
8
Such s a egy has al eady been success ully applied in se e al cance ypes, wi h pla inum-
sensi i e BRCA-mu a ed epi helial o a ian cance being he pa adigm o ea men wi h PARP
inhibi o s (PARPi), no only in i s line whe e imp o ed esul s ha e been epo ed, wi h
ni apa ib (PRIMA ial) (13) and olapa ib (SOLO 1 ial) (14) achie ing s a is ically and
clinically meaning ul inc ease in o e all esponse a e and p og ession ee su i al, bu also in
second lines and beyond wi h he same d ugs (15,16) as well as wi h o he PARPi such as
ucapa ib (17) and elipa ib (18). I should be no ed ha some o a ian cance pa ien s ea ed
wi h PARPi as main enance he apy expe ience long-las ing disease ee su i al, wi h yea s
on ea men .
Inc eased p og ession ee su i al has also been epo ed in BRCA ca ie s b eas cance
pa ien s wi h olapa ib (19) and alazopa ib (20), as well in BRCA mu an p os a e cance (21)
Figu e 2. Resul s o Nex gene a ion sequencing (NGS) o HR-DDR genes in solid umo s, including 2162 panc ea ic
cance s.
Bea ing in mind he dismal p ognosis o ad anced PC (APC), which o e all su i al wi h
cu en s anda d ea men s is less han one yea (22), he e is a c ucial need o imp o e hose
esul s wi h new ea men s a egies. Taking in o accoun ha oughly 9% o unselec ed PC
pa ien s a e associa ed wi h a soma ic o a ge mline mu a ion in BRCA1 o BRCA2 (BRCA1/2)
(23,24) no o men ion a heigh ened equency o soma ic mu a ions in HR-DDR genes by
mode n sequencing echniques (up o 15.4% (95% CI, 13.0%-18.0%), as epo ed in ecen
sequencing o 833 panc ea ic umo s (Figu e 2) (25), as well as he a o emen ioned meaning ul
signi ican imp o emen in su i al wi h PARPi in se e al umo s, hese agen s migh become
a miles one o APC pa ien s. The e o e, conduc ing a sys ema ic e iew on a ailable e idence
wi h PARPi in APC may shed ligh in o he op imal use o PARPi in hese pa ien s, as well as
p o ide insigh on he managemen o ad e se e ec s.
PARP inhibi o s in panc ea ic cance
15
In e ms o oxici y, 6 pa ien s (38%) expe ienced g ade III oxici y, he mos commonly
epo ed being a igue (25%), hype bili ubinemia (19%), h ombocy openia (13%), alkaline
phospha ase inc ease (13%), dehyd a ion (13%), and, hypona emia (13%).
A phase I dose-escala ion and dose-expansion clinical ial (NCT01286987) (28) s udied
he use o alazopa ib (0.025-1.1 mg daily) in pa ien s wi h ad anced BRCAm as well as
selec ed spo adic cance . The p ima y endpoin s consis ed o ORR, PFS, bes o e all esponse,
du a ion o esponse, SD and MTD. The seconda y endpoin s we e SAEs and PK pa ame e s.
Median p io egimens we e 4 and 2 in he dose-escala ion and in he wo-pa s udy,
espec i ely. Thi een ad anced panc ea ic pa ien s (3 in he escala ion pa and 10 in he
expansion coho ) we e ea ed. The maximum ole a ed dose (MTD) was 1 mg pe day. In
panc ea ic cance pa ien s, ORR wi h 1 mg pe day dose was 25.28% (2 pa ial esponde s, one
ca ying a BRCA2 mu a ion and he emaining one, a PALB2 mu a ion), wi h a CBR (SD
las ing o e 16 weeks) o 31%. Median PFS and du a ion o esponse we e no eleased o
panc ea ic cance s. Mos common g ade 3-4 AE we e anemia (23%), h ombocy openia (18%),
neu openia (10%) and a igue (3%).
Sh o e al, epo ed esul s o RUCAPANC (29), a phase II ial (NCT02042378,
comple ed in 2016) in pa ien s wi h locally ad anced o me as a ic panc ea ic cance wi h
dele e ious ge mline o soma ic BRCA mu a ion, ea ed wi h ucapa ib 600 mg wice daily as
mono he apy a e elapse o p og ession o one o wo p io chemo he apy lines, no p e ious
PARPi was allowed. The p ima y endpoin o his ial was ORR. Six een o he 19 pa ien s
bo ne a ge mline BRCAm and 3 had a soma ic mu a ion. Rega ding mu a ional ype, 78.9%
we e BRCA 2 mu a ions. P e ious pla inum-based chemo he apy had been deli e ed in 78.9%
o pa ien s, and 42.1% o pa ien s had p og essed o pla inum he apy. Response was seen in 3
o he las 4 pa ien s ec ui ed, accoun ing o an ORR o 15.8% (95% CI, 3.4% - 39.6%), wi h
2 PR and 1 a CR. O no e, ORR was 33.3% in hose pa ien s wi h only one p io line and 2 ou
o 3 umo s bea ing a soma ic mu a ion had a con i med objec i e esponse. None o he ou
esponding pa ien s had expe ienced disease p og ession on p io pla inum-based
chemo he apy (one o hem being pla inum naï e). The disease con ol a e, which includes PR,
CR o s able disease (SD) las ing mo e han 12 weeks, was 31.6% (6/19), inc easing o 44.4%
(4/9) in pa ien s who had ecei ed jus 1 chemo he apy egimen be o e he ial. As p especi ied
in he p o ocol, acc ual was s opped due o absence o esponse a e assessmen o he i s 15
ec ui ed pa ien s, wi h 13 o hem p esen ing adiological o clinical p og ession, 2
discon inuing due o AEs, 1 ha ing SD and 1 showing adiological p og ession. Mos common
G ade ≥ 3 AE we e anemia (31.6%), a igue (15.8%), and asci es (15.8%), wi h G ade ≥ 3
nausea, omi ing, abdominal pain, h ombocy openia and ansamini is, being 10.5% each.
MAINTENANCE MONOTHERAPY TRIALS
Reiss e al. epo ed in e im esul s o an ongoing phase II ial (NCT03140670) (30),
assessing ucapa ib (600mg bid) as main enance he apy, in pa ien s wi h me as a ic panc ea ic
cance and soma ic o ge mline BRCA1/2 o PALB2 mu a ions, whose cance had no
p og essed on o ollowing a leas ou mon hs o pla inum-con aining chemo he apy. Pa ien s
could also ha e ecei ed 2 p io lines o chemo he apy, bu no o he PARP inhibi o . The
ea men was deli e ed un il p og ession o unaccep able oxici y. The p ima y endpoin was
ORR (RECIST 1.1 c i e ia) and he second endpoin s consis ed o PFS, DoR, and OS.

La a Sil ana González Diéguez
16
The in e im analysis was p esen ed in 2019, a he AACR (Ame ican Associa ion o Cance
Resea ch) Annual Mee ing, wi h da a cu o as o Decembe 31s 2018, ha ing en olled 24
pa ien s o he 42 ini ially planned pa ien s, 19 o whom we e a ailable o PFS assessmen .
Dis ibu ion by mu a ional ype was 84%, 10.5% and 5.3% o BRCA1/2 ge mline mu a ions,
PALB2 ge mline mu a ions and soma ic BRCA 2 mu a ions, espec i ely.
The median PFS was 9.1 mon hs om he s a o ucapa ib he apy. The es ima ed OS was
no eached. Wi h se en esponding pa ien s ou o 19, he ORR was 36.8%, accoun ing o 6
PR and 1 CR. Disease con ol a e (CR + PR + SD las ing o a leas eigh weeks) was 89.5%.
Eigh pa ien s had been on ea men o o e 6 mon hs and wo pa ien s emained on ucapa ib
o o e a yea (13 mon hs and 15 mon hs) (28).
The phase III POLO (31) (NCT02184195) was a andomized 3:2, double-blind, mul icen e ,
in e na ional clinical ial, e alua ing Olapa ib (300 mg wice a day, able s o mula ion, in 92
pa ien s) e sus placebo (62 pa ien s), as main enance he apy, s a ing 4-8 weeks a e las
chemo he apy cycle, in pa ien s wi h ge mline BRCA-mu a ed me as a ic panc ea ic cance ,
wi hou p og ession on a leas 16 weeks o i s line pla inum-con aining chemo he apy
egimen. The ea men was deli e ed un il p og ession o unaccep able oxici y. C osso e was
no pe mi ed. The p ima y endpoin o his ial was P og ession F ee Su i al (PFS), de ined
as he ime om andomiza ion un il adiological disease p og ession o dea h. Seconda y
endpoin s we e O e all Su i al (OS), Second P og ession F ee Su i al (PFS2), Time o
Second Subsequen The apy (TSST), Time Fi s Subsequen The apy (TFST), T ea men
Discon inua ion Time (TDT), Objec i e Response Ra e (ORR), Disease Con ol Ra e (DCR),
Quali y o Li e (QoL) and Ad e se E en s (AEs).
Roughly one- hi d and wo hi d o pa ien s ca ied BRCA1 and BRCA 2 mu a ions,
espec i ely. Mos commonly used chemo he apy egimen was FOLFIRINOX (86% and 81%
in he olapa ib and placebo g oup, espec i ely. Wi h ega d o PFS, Olapa ib showed a
signi ican ly highe PFS e sus placebo (7.4 e sus 3.8 mon hs, espec i ely; haza d a io (HR):
0.53, 95% con idence in e al [CI], 0.35 o 0.82; P=0.004), he pe cen age o pa ien s ali e a e
6 mon hs, being double in he Olapa ib g oup. A an in e im analysis, wi h da a ma u i y o
46%, he analysis o OS showed no s a is ically signi ican di e ence (median, 18.9 mon hs
e sus 18.1 mon hs; HR, 0.91; 95% CI, 0.56 o 1.46; P=0.68), and he analysis o PFS2 di e ed
om 13.2 e sus 9.2 mon hs (HR: 0.76) in a o o he olapa ib g oup.
All in all, ORR was 20% in he Olapa ib g oup and 10% in he placebo a m, wi h 2 pa ien s
in he Olapa ib a m achie ing a comple e esponse (CR), bo h ongoing a he ime o da a cu o .
Response in he olapa ib g oup was independen o esponse o s abiliza ion o he i s line
pla inum-based egimen. The median ime un il esponse was 5.4 and 3.6 mon hs and he
median du a ion o he esponse (DoR) was 24.9 and 14.8 mon hs in he Olapa ib and he
placebo g oup, espec i ely. The median du a ion on ea men was 6.0 mon hs ( ange, 0.8 o
45.3) and 3.7 mon hs ( ange, 0.1 o 30.1) in he olapa ib e sus placebo g oup, espec i ely.
In e es ingly enough, 30 pa ien s in he olapa ib g oup e sus 8 pa ien s in he placebo g oup
we e s ill on ea men a he ime o da a cu o . Nine pa ien s (15%) in he placebo g oup wen
on o ecei e a PARP inhibi o a e disease p og ession du ing he ial (8 olapa ib, 1 ucapa ib,
1 elipa ib) (32).
PARP inhibi o s in panc ea ic cance
17
Se e e ad e se e en s (g ade 3-4) appea ed in 24% o he Olapa ib and in 15% in he
Placebo pa ien s, wi h anemia, as henia and dec ease appe i e being he mos common among
olapa ib pa ien s. No g ade 5 side e ec was epo ed. Dose in e up ion, dose educ ion and
ea men discon inua ion occu ed in 35% s 5%, 16% s 3%, and 5% s 2% in he olapa ib
e sus placebo a m, espec i ely. The e was no signi ican a ia ion in global quali y-o -li e
scale be ween bo h g oups.
Table 3 summa izes he esul s o mono he apy ials by endpoin ial.
Pooled e icacy analysis could no ha e been ca ied ou because o bo h, he imma u i y o
da a o he ucapa ib ial coupled wi h he ac ha pa ien s in ha s udy could ha e had
ecei ed up o wo p io lines compa ed wi h he i s line p he POLO ial.
COMBINATION TRIALS
A dose-escala ion ial ollowed by an dose-expansion phase I/II ial (NCT00515866), in
pa ien s wi h ad anced solid umo s wi h olapa ib in combina ion wi h gemci abine, including
locally ad anced/me as a ic panc ea ic cance , was epo ed in 2015 (33). In he capsule dose-
escala ion ial, pa ien s wi h up o wo p io chemo he apy lines we e included. No p io
chemo he apy was allowed in he able dose-escala ion phase, no in he expansion phase
(capsule o mula ion only). T ial ea men du ing he escala ion phase consis ed o olapa ib
capsules (50-200 mg capsules, wice daily) con inuously o in e mi en ly (days 1-14 o a 28-
day cycle) and Gemci abine (600-800 mg/m2 weekly o 3 weeks o a 4 weeks cycle) o olapa ib
able s (100 mg daily, day 1-14) plus gemci abine 600 mg/m2, o es ablish he MTD. Once he
sui able dose was de e mined, pa ien s wi h locally ad anced o me as a ic panc ea ic cance ,
i espec i e o mu a ional s a us, unde wen an unblinded andomiza ion, in a 2:1 a io, o ei he
he combina ion a m (Olapa ib capsule + gemci abine, a ole a ed combina ion dose) o
gemci abine mono he apy (1000 mg/m2).
The p ima y endpoin o his ial was o de e mine sa e y and ole abili y, es ablishing
MTD o Olapa ib + Gemci abine. Seconda y endpoin s we e iden i ica ion o DLT, assessmen
o an i umo al ac i i y (ORR, PFS, OS and change o umo size in pe cen age de e mined by
imaging) and pha macokine ics (PK) de e mina ion in he plasma o hose pa ien s ea ed wi h
Olapa ib and Gemci abine, alone o in combina ion.
La a Sil ana González Diéguez
18
Table 3. E icacy esul s wi h PARP inhibi o mono he apy in ad anced panc ea ic cance
TRIAL TYPE AND
REFERENCE
TREATMENT
INTERVENTION
POPULATION
TYPE
SIZE
PRIMARY
ENDPOINTS
SECONDARY
ENDPOINTS
OTHER OUTCOMES
PHASE II mul icen e
single a m ial.
NCT01078662 (26)
Olapa ib a e age
o 2 p io lines
Capsule
o mula ion
gBRCAm APC
BRCA1m: 21.7%
BRCA2m: 73.9%
N = 23
ORR 21.7%, 4%
CR and 17% PR
All esponse in
absence o
p og ession on
pla inum
PFS 4.6m; OS 9.8m;
> g ade 3 Aes:
Anemia (17.4%),
Fa igue (13%),
Vomi ing (4%) and
Abdominal Pain
(4%).
Response Ra e wi h p io
pla inum-based o non-
pla inum-based egimen
NSS
PHASE II non- andomized
ial (27)
Velipa ib as 2nd
o 3 d line
gBRCAm / PALB2
APC
BRCA1m: 31%;
BRCA2m: 69%
N = 16
64% p og essed
on pla inum
ORR 0%
31% SD
25% long las ing
PFS 1.7m (95% CI
1.57-1.83); OS 3.1m
(95% CI 1.9-1.4)
PHASE I dose- escala ion
and dose-expansion
NCT01286987 (28)
Talazopa ib
g/s BRCAm
/PALB2 APC
N = 13
ORR 25.28%, 2
PR. CBR 31%
G ade 3-4 AEs:
Anemia (23%),
Th ombocy openia
(18%), Neu openia
(10%) and Fa igue
(3%).
No in o ma ion on
pla inum esis ance
PHASE II single a m
NCT02042378 (29)
Rucapa ib as 2nd
o 3 d line
g/s BRCAm, APC
(16g + 3s)
BRCA2m: 78.9%
N = 19
ORR 15.8%
(3/19), 2 PR and
1 CR
42.1% o pa ien s had
p og essed o pla inum
he apy
PHASE II single a m
NCT03140670 (30)
Rucapa ib
main enance
a e 1s o 2nd
CT line
g/s BRCAm 1/2
/PALB2 APC
N = 42planned,
24 en olled, 19
a ailable o
ORR and PFS
ORR: 36.8%
(7/19) 6 PR and
1 CR
DCR 89.5%
PFS 9m (in e im
analysis, 19 p)
No p og ession o a leas
4 mon hs on pla inum
egimen
PHASE III andomized,
double blind Polo ial.
NCT02184195 (31)
Olapa ib
main enance s
placebo,
ollowing i s
line pla inum-
based CT
Table
o mula ion
gBRCAm 1/2 APC
BRCA1 m !/3
BRCA2m 2/3
N = 154
(olapa ib: 92 p,
placebo: 62 p)
PFS
7.4 s 3.8 m,
(HR): 0.53, 95%
CI, 0.35 - 0.82
OS 18.9 s 18.1 m,
NSS (imma u e
da a)
ORR 20% (2 CR) s
10%
DOR 24.9 m (95% CI, 14.8-
NC) s 3.7 mon hs (95% CI,
2.1 o NC)
APC: ad anced panc ea ic cance ; BRCAm: BRCA mu a ion; CT: chemo he apy; g: ge mline mu a ion; g/s: ge mline o soma ic mu a ion;
HR: haza d a io; m: mon hs; NC: could no be calcula ed; NSS: no s a is ically signi ican ; ORR: o e all esponse a e (comple e esponse
+ pa ial esponse); OS: o e all su i al; p: pa ien s; PFS: p og ession ee su i al;
PARP inhibi o s in panc ea ic cance
19
In e ms o sa e y, con inuous dosing o olapa ib capsules in combina ion wi h a
gemci abine dose >600 mg/m2 was deemed o be non- ole able ollowing wo DLTs [g ade 3
neu openia wi h pe sis en a igue and g ade 3 inc eased alanine amino ans e ase (ALT)] in
pa ien s ea ed wi h con inuous olapa ib capsules 100 mg wice daily and gemci abine 800
mg/m2. Olapa ib capsules (100 mg wice daily, day 1-14) plus gemci abine 600 mg/m2, was
ound o be he MTD in bo h phase o he ial. O e all, 81% o pa ien s (38 ou o 47) ea ed
wi h olapa ib capsule and gemci abine epo ed g ade ≥3 AEs, wi h wen y-nine pa ien s (44%)
epo ing se ious AEs (SAEs), he mos common being dyspnea (14%), abdominal pain (10%),
omi ing (10%) and deep ein h ombosis (10%). No SAEs was conside ed o be ela ed o
olapa ib alone and 6 o he SAES we e a ibu ed o he combina ion Olapa ib/Gemci abine.
The e we e 2 g ade 5 SAEs in he combina ion a m, one due o neu openic sepsis, being he
o he one seconda y o bac e ial pe i oni is and enal ailu e.
The phase I clinical ial e alua ed Olapa ib in associa ion wi h i ino ecan, cispla in, and
mi omycin C in pa ien s wi h ad anced panc ea ic cance (NCT01296763) (34). The p ima y
endpoin was o s udy he numbe o pa icipan s who expe ience Dose-Limi ing Toxici ies
(DLT), in o de o de e mine he Maximum Tole a ed Dose (MTD) and he second endpoin
was o analyze he numbe o yea s om cycle 1/ day 1 On-S udy o da e o dea h. The pa ien s
had o ha e an un esec able PDAC diagnosed in o de o be eligible and a li e expec ancy
g ea e han 12 weeks. The s udy did no exclude indi iduals wi hou a BRCAm bu p io i ized
Jewish indi iduals (abou 6% cases ca ied a BRCAm), pa ien s wi h amilial panc ea ic cance
(associa ed o HRR de iciencies) and pa ien s wi h diagnosed BRCAm (n=2). The e was no
limi on he numbe o p io chemo he apy egimens allowed; howe e , ea men wi h a PARP
inhibi o o mo e han one d ug o he I ino ecan-Cispla in-Mi omycin C (IMC) egimen was
an exclusion c i e ion. This ial en olled 18 pa ien s in 6 di e en dose-escala ions (-1 o 5).
Dose le el -1: Olapa ib (50mg m2) on days 1 and 8 plus I ino ecan (70mg/m2) and Cispla in
(25mg/m2) (IC). Dose le el 1 consis ed o Olapa ib (100 mg wice-daily) on days 1 and 8 plus
IC, and en olled six pa ien s. Dose le el 2: Olapa ib on days 1-3 and 8-10 plus IC, en olled six
pa ien s. Dose le el 3: Olapa ib (200 mg wice-daily) on days 1-3 and 8-10 plus IC. Dose le el
4: Olapa ib on days 1-12 and IC on days 1 and 8. Dose le el 5: Olapa ib (MTD om dose
escala ion -1 o 4) on days 1 and 8 plus ICM (5mg/m2 on day 1), en olled six pa ien s. 22% o
he en olled pa ien s discon inued ea men because o AEs, and 56% equi ed a dose educ ion
o delay due o oxici y. 4 pa ien s had o lea e he s udy because o oxici y and 1 due o clinical
p og ession, lea ing 13 pa ien s o he clinical ac i i y e alua ion. 3 pa ien s had a PR (1 in
dose le el 5 and 1 in dose le el 1) and he e was no CR. ORR in he e alua ed pa ien s was
23% and he disease con ol a e was 62%. The 2 pa ien s wi h a known BRCAm had a PR, one
las ing 4 yea s and ano he las ing 3 mon hs.
An Open-label, andomized, mul icen e , wo-a m phase II ial (NCT01585805) o i s
line gemci abine (600 mg/m2) and cispla in (25 mg/m2) wi h (a m A) o wi hou (A m B)
elipa ib (80 mg o ally wice pe day on days 1-12) in 21 day cycles, in pa ien s wi h panc eas
adenoca cinoma ca ying ge mline BRCA/PALB2 mu a ion, was epo ed in 2020.(35) No p io
pla inum agen o PARPi was allowed. The p ima y endpoin was ORR and he seconda y end
poin s we e PFS, OS, disease con ol a e (DCR), sa e y, and co ela i e analyses.
Fi y pa ien s we e e alua ed, wi h 27 pa ien s (54%) in a m A, and 23 pa ien s (46%) in
a m B. Twel e (24%) ha bo ed BRCA1 mu a ions, 35 (70%) ca ied BRCA2 mu a ions, and 3
La a Sil ana González Diéguez
20
(6%) es ed posi i e o PALB2 mu a ions The ORR o he elipa ib combina ion a m was
74.1% and 65.2% in he elipa ib ee g oup (P = 0.55); wi h bo h a ms exceeding he
p especi ied ac i i y h eshold. DCR was 100% and 78.3% in he elipa ib combina ion a m
and he elipa ib- ee g oup, espec i ely (P = 0.02). Median PFS did no s a is ically di e ed
be ween a ms, wi h 10.1 mon hs (95% CI, 6.7 o 11.5 mon hs) and 9.7 mon hs (95% CI, 4.2 o
13.6 mon hs; P = .73), espec i ely. The same was ue o median OS, being 15.5 mon hs (95%
CI, 12.2 o 24.3 mon hs) and 16.4 mon hs (95% CI, 11.7 o 23.4 mon hs; P = 0.6), espec i ely.
Explo a o y analyses o pa ien s who ecei ed 4 o mo e mon hs o pla inum-con aining
egimen and, in he absence o disease p og ession, con inued o ecei ed a PARPi as he
immedia e nex line o he apy. Ten pa ien s, 8 wi h s age IV, combined om bo h ial a ms,
ul illing hose c i e ia, had a median OS o 23.4 mon hs (95% CI, 6.5 o 53.9 mon hs).
Explo a o y analyses by BRCA mu a ional ype yielded a median PFS o BRCA1 (n = 12) o
6.8 mon hs (95% CI, 2.8 o 10.1 mon hs) and o BRCA2 (n = 35), 11.3 mon hs (95% CI, 9.8
o 12.8 mon hs). Median OS o BRCA1 was 14 mon hs (95% CI, 8.1 o 18.5 mon hs) and 20.2
mon hs (95% CI, 12.3 o 24.4 mon hs) o BRCA2.
E en hough A m A epo ed mo e myelo oxici y and mo e dose educ ions,
nonhema ologic oxici ies we e simila in bo h a ms. G ade 3 o 4 hema ologic oxici ies in
elipa ib-con aining egimen compa ed wi h elipa ib ee g oup we e as ollows: neu openia
was seen in 13 pa icipan s (48%) e sus se en (30%), h ombocy openia in 15 (55%) e sus
wo cases (9%), and anemia in 14 (52%) e sus eigh pa ien s (35%).
Pish aian and colleagues epo ed esul s o a single-a m, open-label Phase I/II s udy
( NCT01489865) o elipa ib along wi h in usional 5-FU and oxalipla in (FOLFOX, no 5FU
bolus) in pa ien s wi h me as a ic panc ea ic cance (mPDAC) (34). The dose escala ion phase
consis ed o elipa ib (40 mg-250 mg wice pe day, o 7 days o a 14-day cycle), in o de o
iden i y he ecommended dose o phase II pa . P eselec ion c i e ia o he phase 2 pa we e
ei he a pa hogenic soma ic o ge mline BRCA1/2, PALB2, ATM mu a ion, and/o a amily
his o y compa ible wi h b eas o o a ian cance synd ome. The phase II pa was di ided in o
wo coho s, namely, ea men naï e pa ien s o wi h hose who had ecei ed p io ea men .
When a ailable, soma ic o ge mline da a we e collec ed. The p ima y objec i e o he Phase
II coho s was he ORR wi h key seconda y endpoin s being median PFS and OS.
Thi y-one pa icipan s we e en olled in he dose escala ion phase. The elipa ib dose o
FOLFOX combina ion was deemed o be 200 mg wice daily. Addi ional 33 pa icipan s we e
included in he phase II pa , 15 ea men -naï e and 18 p e ea ed, wi h 78% o pa ien s being
pla inum-naï e. 69% o pa icipan s had amily his o y and 27%, a known HR-DDR mu a ion.
The ORR was 26%, wi h heigh ened ac i i y in pla inum-naï e pa icipan s (33%) as well as in
hose ca ie s o a pa hogenic HR-DDR mu a ion (50%), achie ing an ORR 57% when bo h
c i e ia we e me . O e all, he median PFS and median OS we e 3.7 and 8.5 mon hs,
espec i ely. Mos equen ly obse ed g ade 3-4 AE we e hema ologic oxici y (16%) and
nausea/ omi ing (6%).
Table 4 displays he e ie ed esul s om he combina ion ials included in his sys ema ic
e iew, showing clinical ial ype and e e ence, ea men in e en ion, popula ion ype,
p ima y and seconda y endpoin s, and o he ou comes, when a ailable.

PARP inhibi o s in panc ea ic cance
21
Table 4. E icacy esul s wi h PARP inhibi o in combina ion he apy in ad anced panc ea ic cance
TRIAL TYPE AND
REFERENCE
TREATMENT
INTERVENTION
POPULATION
TYPE
SIZE
PRIMARY
ENDPOINTS
SECONDARY
ENDPOINTS
OTHER OUTCOMES
PHASE I dose-escala ion
and dose-expansion wo
a m ial. NCT00515866
(33)
Capsule and able
o mula ion
Olapa ib +
Gemci abine
(a m A) s
Gemci abine
alone (a m B);
A e 1s o 2nd CT
line (capsule
dose-escala ion);
No p io CT in
able phase.
Locally
ad anced/me as
a ic PC
I espec i e o
mu a ional s a us
N = 46 (dose-
escala ion) and N
= 23 (dose-
expansion)
MTD: Olapa ib
(100mg wice
daily) +
Gemci abine
(600mg/m2)
Capsule
o mula ion
Dose-escala ion:
ORR 10%;
Dose-expansion 27%
(a m A) and 14%
(a m B).
81% (a m A) g ade
>3 AEs, 44% SAEs.
P olongs PFS and OS in
BRCAm pa ien s
PHASE I dose-escala ion
NCT01296763 (34)
Olapa ib +
i ino ecan +
cispla in +
mi omycin C
No limi p io
lines
Un esec able
PDAC
I espec i e
mu a ional s a us,
p io i izing Jews,
amily his o y and
BRCAm
N = 18
ORR 23% (13
e aluable
pa ien s)
PHASE II wo-a m
andomized ial.
NCT01585805 (35)
Gemci abine +
Cispla in +
Velipa ib (a m A)
s Gemci abine +
Cispla in (a m
B); No p io
pla inum agen
allowed
gBRCAm (47p)/
PALB2 (3p), PDAC
N = 50 (a m A:
27p, a m B: 23p)
ORR a m A 74.1%,
a m B 65.2%;
Non hema ologic
oxici ies simila
in bo h a ms;
A m A mo e dose
educ ions and
myelo oxici y
DCR 100% (A)/ 78.3%
(B); PFS and OS NSS;
PFS BRCA1 6.8m /
BRCA2 12.8m; OS
BRCA1 14m / BRCA2
20.2m
PHASE I/II one-a m ial.
NCT01489865 (36)
Velipa ib +
in usional 5-FU
and Oxalipla in
(FOLFOX)
g/s BRCAm/
PALB2/ ATM…,
me as a ic PDAC
N = 31
MTD (phase I):
Velipa ib 200mg
wice daily
ORR (Phase II)
26% (50% in
mu a ed)
PFS 3.7m; OS 8.5m;
G ade >3 AEs:
hema ological
oxici y (16%) and
nausea/ omi ing
(6%)
ORR heigh ened in naï e-
ea men g oup (33%) and
in HR-DDRm (50%)
PC: panc ea ic cance ; PDAC: panc ea ic duc al adenoca cinoma BRCAm: BRCA mu a ion; CT: chemo he apy; g: ge mline mu a ion; g/s:
ge mline o soma ic mu a ion; HR: haza d a io; m: mon hs; ORR: o e all esponse a e; MTD: maximum ole a ed dose; DCR: disease con ol
a e; AEs: ad e se e en s; SAEs: se ious AEs; OS: o e all su i al; p: pa ien s; PFS: p og ession ee su i al;
La a Sil ana González Diéguez
22
SIDE-EFFECTS ASSOCIATED WITH PARP INHIBITORS
Despi e he clinical bene i s o PARP inhibi o he apy, undesi able side e ec s do occu
du ing ea men . E en hough hey a e la o s o he same class d ug, each molecule has i s
own nuances as a as side e ec s a e conce ned.
F om all s udies included in his sys ema ic e iew, oxici ies associa ed wi h each
ea men ha e been ex ac ed, as speci ied in he p o ocol. Fou agen s ha e been assessed in
he mono he apy ials in his sys ema ic e iew (olapa ib, elipa ib, ucapa ib and alazopa ib).
Resul s a e displayed ough Figu es 4-7, by mono he apy agen showing he highes oxici y
le el as well as i s pe cen age.
0
1
2
3
4
5
17% 13% 4% 4%
4% 4%
Figu e 4 - AEs Olapa ib
0
1
2
3
4
5
25% 19% 13% 13% 13% 13%
Figu e 5 - AEs Velipa ib
PARP inhibi o s in panc ea ic cance
23
Figu es 4-7 show mos common side e ec s and g ades epo ed in he di e en ials g ouped by agen s, when
a ailable. Each diag am shows he mos equen ad e se e ec s, as well he mos se e e, epo ed in he ials
and g ouped by d ug.
DISCUSSION
T ea men o ad anced PDAC is con inuously e ol ing and inc easingly being guided by
genomic analysis and iden i ica ion en iched sub ypes which can bene i om a speci ic
ea men s a egy; wi h HR-DDR being a p ime example in PDAC. As such, PARP inhibi o s
0
1
2
3
4
523%
18%
10% 3%
Figu e 6 - AEs Talazopa ib
0
1
2
3
4
5
32% 16% 16% 11% 11%
Figu e 7 - AEs Rucapa ib
La a Sil ana González Diéguez
24
ha e been es ed in ad anced PDAC wi h di e se inclusion c i e ia, mos ocusing in BRCA 1
/ 2, HR-DDR de icien umo s, no only as mono he apy bu also in combina ion s a egy.
Ge mline BRCA mu a ions, inhe i ed in an au osomal dominan ashion, do no always
ansla e in o cance , i.e. i hey a e incomple ely pene an . BRCA1 and BRCA2 I a e es ima ed
o con ey a 2-4- old, and 3- o 8- old inc ease, espec i ely, in he isk o PDAC de elopmen
(37).
Mono he apy esul s wi h PARPi as second o u he lines has yielded modes esul s (26–
29) and esponse based on sensi i i y o p io pla inum ea men has yielded opposi e esul s,
wi h no esponse in pla inum- e ac o y disease in a ucapa ib mono he apy ial (29) and no
di e ence in ORR s a i ied by p io pla inum he apy in olapa ib mono he apy ial, albei
acknowledging he ac ha all esponses occu ed in pa ien s who had no p og essed on p io
pla inum egimen (26). Lowe y and colleagues epo ing esul s wi h elipa ib single agen
showed no objec i e esponses, sugges ing ha i s e ec i eness no as main enance bu a he
as ue mono he apy line is inadequa e in la e lines, a he s udied dose and schedule (27).
I was no un il popula ion selec ion h ough pla inum sensi i i y and he use o PARPi as
immedia e main enance ea men in non-p og esso s, as compa ed wi h second o u he lines
upon p og ession, ha clinical signi ican bene i begun o eme ge (30,31).
In e es ingly enough, he need o and subsequen choice o he pla inum egimen is ma e
o deba e. PDAC a ising in he se ing o a BRCA mu a ion a e hough o show inc eased
sensi i i y o pla inum compounds, such as cispla in and oxalipla in, due o induced double-
s and b eaks and seconda y inabili y o epai hose because o ine ec i e BRCA-associa ed
DNA epai . None heless, no andomized ials compa ing pla inum e sus nonpla inum-based
egimens in his PDAC subg oup ha e been published o da e. Supe io OS was epo ed in a
e ospec i e coho o pa ien s wi h ad anced BRCA-mu a ed PDAC who ecei ed pla inum-
based he apy (22 pa ien s) compa ed wi h 21 pa ien s ea ed wi h nonpla inum egimen (22 s
9 mon hs, espec i ely; p = 0.04), al hough he e ospec i e na u e o he s udy mus be kep
in mind (38). Smalle se ies ha e epo ed simila ou comes wi h pla inum agen s (39,40). A
sys ema ic e iew and me analysis on his subjec concluded in he need o u he in es iga ion
wi h andomized ials in homogenous clinical se ings (41).
Imp essed by he exceedingly good esul o he andomized phase II elipa ib ial, wi h 2-
yea (30.6%) and 3-yea (17.8%) su i al a es o he en i e coho , among he longes epo ed
in any andomized ial in PDAC o da e, one could be p one o es ablish cispla in-gemci abine
as he new s anda d in BRCAm PDCA (35). Howe e , gemci abine plus cispla in did no show
s a is ical OS imp o emen o e gemci abine mono he apy in simila phase III ials (42,43),
albei no being HDDR-selec ed popula ion. As a consequence, in absence o andomized,
p ospec i e ials compa ing di e en pla inum-based chemo he apies, i is unknown whe he
FOLFIRINOX, a s anda d pla inum-based i s line egimen in ad anced PDAC, can be sa ely
eplaced by less oxic egimens such as gemci abine wi h cispla in o FOLFOX (wi h i ino ecan
omission), wi h subsequen oxici y educ ion while main aining e icacy, in BRCA-mu a ed
pa ien s.
PARP inhibi o s in panc ea ic cance
31
APPENDIX
P ospe o like p o ocol acco ding o PRISMA guidelines
ADMINISTRATIVE INFORMATION
Ti le
Sys ema ic e iew on PARP inhibi o s in ad anced panc ea ic cance .
Regis a ion
The p o ocol o his sys ema ic e iew will no be eco ded.
Au ho s
La a Sil ana González Diéguez supe ised by he co u o , Ma ía José
Villanue a Sil a.
INTRODUCCTION
Ra ionale
PARP is a amily o nuclea enzymes which con ibu e o single s and DNA
epai . The PARP inhibi o s bind o he PARP-DNA complex p e en ing DNA
epai , lea ing cells p one o double s and b eaks. Tumo s wi h BRCA
mu a ions, such as a subg oup o panc ea ic cance , a e unable o epai
double s and b eaks, being he e o e good candida es o PARP inhibi o s,
o achie e umo con ol.
Objec i es
To pe o m a sys ema ic e iew o clinical ials o iden i y and summa ize
all a ailable e idence wi h PARP inhibi o s in BRCA mu a ed o o he
homologous ecombina ion de iciency (HRD) in ad anced panc ea ic
cance .
METHODS
Eligibili y c i e ia
Inclusion c i e ia will be clinical ials wi h PARP inhibi o s ha include
BRCA mu a ed and HRD in ad anced panc ea ic cance pa ien s, published
in abs ac o m o as a esea ch a icle be ween Janua y 2010 and
Decembe 2020. The e will be no es ic ions on he language used in he
publica ion.
In o ma ion sou ces
An elec onically sea ch will be pe o med in PubMed, Embase,
Clinical ials.go , Web o Science o a icles as well as ASCO and ESMO
mee ing da abase o abs ac s. ClinicalT ail.go websi e was also
sc u inized o ials.
Sea ch s a egy
Sea ch s a egy will include a combina ion o b oad e ms ela ed o
panc ea ic cance , ca cinoma and PARP inhibi o s, clinical ial, BRCA,
HRD, ola ap ib, ni apa ib, ucapa ib, elipa ib, alazopa ib.
Exclusion c i e ia
Exclusion c i e ia will be: (i) pa ien s wi h no ad anced/ ecu en
panc ea ic cance , (ii) clinical ials wi h BRCA o HRD umo s epo ed,
(iii) s udies ha ma ched di e en da abases, (i ) comple ed ials wi h no
published esul s, ( ) ongoing ials wi h no published esul s, ( i) case
epo s, na a i e e iews, edi o ials, news a icles, commen a ies o
le e s.

La a Sil ana González Diéguez
32
DATA
Da a i ems
Fo each included s udy we will ex ac he ollowing da a: numbe o
pa ien s en olled, design, ype o ial, s age, median pa icipan age,
pe o mance s a us, sample size, ype o PARP inhibi o used, o he d ugs
i applied, p ima y ou come, seconda y ou come, objec i es, median
ollow-up, esponse ype (comple e esponse, pa ial esponse, p og ession
o s able disease), o e all esponse a e (ORR) (pa ial (PR) plus comple e
esponse a e (CR)), clinical bene i a e (CBR), du a ion o esponse, ime
o p og ession (TTR), p og ession ee su i al (PFS), o e all su i al (OS)
and oxici y.