A LOOK TO THE FUTURE: WHAT'S NEXT FOR PARP INHIBITORS? - ISABELLE RAY-COQUARD, MD, PHD - PRIME ONCOLOGY
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A Look to the Future:
What’s Next for PARP Inhibitors?
Isabelle Ray-Coquard, MD, PhD
Centre Léon Bérard
Lyon, France
Where Are We Going in Ovarian Cancer?
• First-line maintenance in newly diagnosed ovarian cancer
(all comers)
• PARPi after PARPi
• Combination
– PARPi and VEGF inhibitors (olaparib and cediranib or
niraparib and bevacizumab)
– PARPi and DDR & PARPi and PD-L1/PD-1
DDR, DNA damage response; PARPi, poly ADP-ribose polymerase inhibitor; VEGF, vascular endothelial growth factor
PRIMA Evaluates Niraparib Maintenance Following First-Line
Chemotherapy in Patients With Advanced Ovarian Cancer
• PRIMA is a global, randomized, multicenter, placebo-controlled phase III study
Randomize within
12 weeks of first Global study in 20 countries and 195 trial sites
• Newly diagnosed FIGO III-IV day of last
HGSOC or high-grade chemotherapy cycle
endometrioid ovarian cancer* Primary
Niraparib
endpoint
PO 300 mg
• CR or PR following first-line Secondary
Randomize BICR PFS in: endpoints
(adjuvant or neoadjuvant)
2:1 Secondary
platinum-based CTX
Planned N ≈ 620 HRD PFS2 endpoint
population HRQoL
• Patients with stage III disease OS
should have residual disease Safety
Stratification by: Placebo ITT population
after primary surgery; all stage
• Use of NACT
IV disease eligible • Response (CR/PR)
to first-line platinum-
• Agree to undergo central tumor based chemotherapy
HRD testing • HRD status Clinicaltrials.gov identifier: NCT02655016
Status: Enrollment complete
*Including ovarian, fallopian or primary peritoneal cancer
BICR, blinded independent central review; CR, complete response; CTX, chemotherapy; FIGO, International Federation of Gynecology and Obstetrics; HGSOC, high-grade serous
ovarian cancer; HRD, homologous recombination deficiency; ITT, intention to treat; NACT, neoadjuvant chemotherapy; OS, overall survival; PFS, progression-free survival; PFS2, time to
second progression; PO, by mouth; PR, partial response
1. Gonzalez MA, et al. Ann Oncol. 2017;28(5s): Abstract 986TiP. 2. National Institutes of Health. https://clinicaltrials.gov/ct2/show/study/NCT02655016.
Accessed 25 January 2019.
Rationale to Combine PARPi & Anti-VEGF • All comers • Pre-clinical data • CP+Bev followed by Bev maintenance is a standard of care in 1st-line in many countries • Liu & coll publication with cediranib + Olaparib (JCO 2016)
PAOLA-1 Evaluates Addition of Maintenance Olaparib to Standard of
Care in Patients With Newly Diagnosed Advanced Ovarian Cancer
• PAOLA-1 is an ENGOT/GCIG sponsored, randomized, placebo-controlled phase III trial
• FIGO stage III–IV high-grade Olaparib
ovarian cancer (serous or 300 mg† PO bid +
endometrioid)* or Bevacizumab**
15 mg/kg q 3 w Primary endpoint
nonmucinous BRCAm
15 months • PFS1 (RECIST 1.1)
• No evidence of disease or CR
or PR following first-line
BRCA testing Secondary endpoints
platinum-based chemotherapy Randomize 2:1
prior to • PFS2
plus bevacizumab N = 806
randomization
• TSST
• A minimum of 3 cycles of
platinum-based chemotherapy Placebo • OS
Stratification by tumor BRCA status +
plus bevacizumab (2 after • Safety
and first-line outcome
interval debulking) Bevacizumab** • PRO/HRQoL
15 mg/kg q 3 w
• ECOG PS 0–1 15 months
Clinicaltrials.gov identifier:
NCT02477644
*Includes patients with primary peritoneal and/or fallopian tube cancer. **Bevacizumab concurrent with platinum-based chemotherapy and then as maintenance treatment.
†Tablet formulation (2 tablets twice daily)
ECOG PS, Eastern Cooperative Oncology Group performance status; ENGOT, The European Network for Gynaecological Oncological Trial groups; FIGO, International Federation
of Gynecology and Obstetrics; GCIG, Gynecologic Cancer Intergroup; HRQoL, Health-related quality of life; OS, overall survival; PRO, patient-reported outcome; RECIST,
Response Evaluation Criteria in Solid Tumors; TSST, time to second subsequent therapy
1. Ray-Coquard I, et al. J Clin Oncol 2016;34(15s): Abstract TPS5607. 2. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02477644.
Accessed 25 January 2019.
MITO 25 Evaluates Maintenance Rucaparib Plus Carboplatin, Paclitaxel, ±
Bevacizumab in Patients With Newly Diagnosed Advanced Ovarian Cancer
• MITO 25 is an open-label, randomized, placebo-controlled phase II study
Carboplatin/paclitaxel
AUC5/175 mg/m2, q 3 w, 6 cycles +
Bevacizumab**
Primary endpoint
15 mg/kg q 3 w, 22 cycles
• FIGO stage III–IV high-grade • PFS1 (RECIST 1.1)
ovarian cancer (serous
or endometrioid)* Carboplatin/paclitaxel
AUC5/175 mg/m2, q 3 w, 6 cycles + Secondary endpoints
• No prior anticancer treatment Randomize 1:1:1 • PFS2
Bevacizumab**
• Archival tumor tissue available N = 225 15 mg/kg q 3 w, 22 cycles + • ORR
• Measurable and nonmeasurable Rucaparib maintenance† • OS
disease 600 mg bid, PO, 24 cycles
• LOH/efficacy
Stratification by:
• ECOG PS 0–1 • Residual tumor at • Safety
primary surgery Carboplatin/paclitaxel
• PRO/HRQoL
• Stage of disease AUC5/175 mg/m2, q 3 w, 6 cycles +
• HRD status (BRCAm vs Rucaparib maintenance†
BRCA-like vs 600 mg bid, PO, 24 cycles Clinicaltrials.gov identifier: NCT02655016
biomarker negative)
*Includes patients with primary peritoneal and/or fallopian tube cancer. **Bevacizumab concurrent with platinum-based chemotherapy and then as maintenance treatment.
†Maintenance following chemotherapy
LOH, loss of heterozygosity
1. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT03462212. Accessed 25 January 2019. 2. MITO 25 Trial Presentation.
https://slideplayer.com/slide/10603743/. Accessed 25 January 2019.
Where Are We Going in Ovarian Cancer?
• First-line maintenance in newly diagnosed ovarian cancer
(all comers)
• PARPi after PARPi
• Combination
– PARPi and VEGF inhibitors (olaparib and cediranib or
niraparib and bevacizumab)
– PARPi and DDR & PARPi and PD-L1/PD-1
Exploratory Subgroup Analysis:
Median PFS Post CT Under PARPi
ARIEL3: Rucaparib Maintenance, ITT Population1 SOLO2: Olaparib Maintenance2
Median (months) 95% CI
1.0 PFS events,* n (%)
Olaparib (N=110)
57 (52)
Placebo (N=62)
44 (71)
Rucaparib (n=231) 10.4 8.2–13.1 1.0 Median PFS, months 22.1 5.7
patients event-free
0.9
Probability of PFS
HR (95% CI) 0.38 (0.26–0.57)
Placebo (n=124) 5.4 5.3–5.6 0.8
0.8
Proportion of
0.7 Olaparib 300 mg BID
70% to 90% continue
HR, 0.42; 0.6 Placebo BID
95% CI, 0.32–0.55 2 prior lines 0.5
0.4
2 prior lines 0.6 0.3
to be candidates for 0.2
0.1
0.0
0.4
Platinum after PARPi 0
Number of patients at risk:
3 6 9 12 15 18 21 24
Time from randomisation (months)
27 30 33 36
Olaparib 300 mg BID 110 103 92 81 71 62 53 50 23 20 3 2 0
0.2
maintenance Placebo BID 62 45 28 18 14 13 13 11 6 5
Olaparib (N=60)
0 0
Placebo (N=20)
0
PFS events,* n (%) 34 (57) 19 (95)
1.0
0.0 Median PFS, months 16.9 5.1
patients event-free
0.9 HR (95% CI) 0.24 (0.13–0.42)
0.8
0 6 12 18 24 30 36
Proportion of
At risk (events) 0.7 Olaparib 300 mg BID
Months 0.6 Placebo BID
Rucaparib 231 (0) 138 (70) 77 (117) 43 (132) 15 (137) 2 (141) 0 (141)
Placebo 124 (0) 46 (69) 10 (103) 6 (106) 2 (109) 1 (109) 0 (109)
3 prior lines 0.5
0.4
0.3
Median (months) 95% CI 0.2
1.0 0.1
0.0
Rucaparib (n=144) 11.1 8.3–13.8
Probability of PFS
0 3 6 9 12 15 18 21 24 27 30 33 36
Placebo (n=65) 5.3 3.4–5.4 Number of patients at risk: Time from randomisation (months)
0.8 Olaparib 300 mg BID 60 55 47 37 32 29 26 24 7 7 0 0 0
HR, 0.28; Placebo BID 20 15 5 2 2 2 1 1 1 1 0 0 0
95% CI, 0.19–0.41 Olaparib (N=25) Placebo (N=17)
≥3 prior lines 0.6 PFS events,* n (%) 16 (64) 17 (100)
1.0 Median PFS, months 17.0 5.4
patients event-free
0.9 HR (95% CI) 0.26 (0.13–0.51)
0.4 0.8
Proportion of
0.7 Olaparib 300 mg BID
0.6
≥4 prior lines 0.5
Placebo BID
0.2 0.4
0.3
0.2
0.1
0.0 0.0
At risk (events) 0 6 12 18 24 30 36 0 3 6 9 12 15 18 21 24 27 30 33 36
Months Number of patients at risk: Time from randomisation (months)
Rucaparib 144 (0) 90 (41) 51 (69) 22 (85) 11 (89) 3 (93) 0 (93) Olaparib 300 mg BID 25 24 17 16 15 13 10 8 2 2 0 0 0
Placebo 65 (0) 17 (45) 3 (57) 1 (58) 0 (58) Placebo BID 17 10 4 2 2 2 0 0 0 0 0 0 0
1. Lorusso D, et al. Ann Oncol. 2018;29(suppl_8):viii332-358. 2. Penson R, et al. Ann Oncol. 2017;28(suppl_5):v330-v354.
OReO Evaluates Olaparib (Tablets) as Maintenance Retreatment
in Patients With Platinum-Sensitive Relapsed Ovarian Cancer
• OReO is a phase IIIb trial of two independently powered cohorts
Cohorts Olaparib
• All epithelial Entry based on length of first
300 mg**
ovarian cancer* PARP inhibitor exposure
PO bid Primary outcome
• 1 prior PARP BRCAm → gBRCAm or
Randomize • PFS†
inhibitor sBRCAm
• PARP inhibitor ≥18 mo 2:1
maintenance N ≈ 136 Placebo Secondary outcomes
(after first-line CT)
period
• PARP inhibitor ≥12 mo • TFST
• Known BRCA Stratification
(after second-line CT) factors: • TSST
status
• Prior bevacizumab Olaparib • FACT-O
PLUS Non-BRCAm → • 3 vs ≥4lines of 300 mg** • Safety and AEs
Response ≥PR to • PARP inhibitor ≥12 mo chemotherapy PO bid
• OS
most recent (after first-line CT)
NonBRCAm
platinum CT (not • PARP inhibitor ≥6 mo after Randomize
all-comers Placebo
bevacizumab) second- or later-line CT 2:1 Clinicaltrials.gov identifier:
N ≈ 280
NCT03106987
Status: Recruiting
*Not restricted to high-grade serous ovarian cancer. **Tablet formulation. †Powered 80% for PFS primary endpoint (BRCAm HR=0.5 [74 events]; nonBRCAm HR=0.65 [191 events]).
AE, adverse event; FACT-O, Functional Assessment of Cancer Therapy - Ovarian Cancer; TFST, time to first subsequent therapy; TSST, time to second subsequent therapy
1. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT03106987. Accessed 25 January 2019.Where Are We Going in Ovarian Cancer?
• First-line maintenance in newly diagnosed ovarian cancer (all comers)
• PARPi after PARPi
• Combination
– PARPi and VEGF inhibitors (olaparib and cediranib or niraparib and bevacizumab)
– PARPi and DDR & PARPi and PD-L1/PD-1
HR 0.55
HR 0.32
P = .002There Are Several PARPi + VEGF Combination Trials Ongoing
Patient Primary
Trial Name Phase Population Study Treatment Endpoint
Platinum-sensitive relapse trials
Olaparib
GY0041 III PSR OC Cediranib + olaparib PFS
Carboplatin + paclitaxel OR gemcitabine OR PLD
Chemotherapy + cediranib cediranib + olaparib
ICON-92 III PSR OC PFS/OS
Chemotherapy + cediranib / placebo cediranib + placebo
Niraparib
AVANOVA (Part 2)3 II PSR or BRCAm OC PFS
Niraparib + bevacizumab
AVANOVA (Part 1)3 I PSR or BRCAm OC Niraparib + bevacizumab RP2D
Platinum-resistant relapse trials
Olaparib
Cediranib
GY005 (COCOS)4 II/III PRR OC PFS
Cediranib + olaparib
Paclitaxel OR PLD OR topotecan
OC, ovarian cancer; PRR, platinum-resistant/refractory relapsed; PSR, platinum-sensitive relapsed; RP2D, recommended phase II dose; PLD, pegylated liposomal doxorubicin hydrochloride
1. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02446600. Accessed 25 January 2019. 2. National Institutes of Health.
https://clinicaltrials.gov/ct2/show/NCT03278717. Accessed 25 January 2019. 3. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02354131.
Accessed 25 January 2019. 4. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02502266. Accessed 25 January 2019.Schematics of DDR: Leading to G1 Arrest,
S-Phase Delay, and G2 Arrest
• Rationale for targeting CHK1, CHK2, ATR, and WEE1
WEE1 kinase inhibition
prevents cell cycle
arrest at G2/M and
therefore damaged DNA
cannot be repaired
PARP inhibition
causes DNA
double-strand
breaks in S phase
1. Quynh-Thu Le, et al. Clin Cancer Res. 2015;21:3393-3401. 2. Hamilton EP, et al. J Clin Oncol. 2016;34(suppl): Abstract 5562.Olaparib + AZD1775 (WEE1 Inhibitor) Combination
• NCT02511795 is a phase Ib multicenter study of AZD1775 combined with olaparib
administered in patients with refractory solid tumors
• Adults with refractory solid tumors Olaparib
100 mg/200 mg PO bid days 1–14
• ECOG 0-1
• Patients must have a confirmed response (either PR +
Primary objective: MTD
or CR) to first-line platinum therapy and then N = 135
relapsed after completing that treatment AZD1775
125, 150 or 175 mg PO bid days 1–3
– Patients who progressed whilst on platinum- and 8–10
containing treatment (platinum refractory)
are not eligible 21 day cycles
Preliminary outcomes:
• n = 13; median age 59 years
• 1 PR (rectal cancer); 9 SD (3 EOC); 1 PD (colon) on 11 patients
• Grade 3 toxicity (hematologic, diarrhea, transaminases, & fatigue)
• Expansion in multiple tumor settings is planned once the optimal dose and schedule have been determined
EOC, epithelial ovarian cancer; MTD, maximum tolerated dose; SD, stable disease
Hamilton EP, et al. J Clin Oncol. 2016;34(suppl): Abstract 5562.Rationale for Combining PARPi
and PD-L1/PD1 Inhibitors
• It is hypothesized that PARPi induces DNA damage and genomic instability in HRD-mutated
tumors, which results in enhanced immunogenicity and response to PD1/PD-L11-2
Immunologically active
Immunologically paused PARP inhibitor
• Replication stress
• Apoptosis
• TumorAg release
Immunologically absent
1. Hartlova A, et al. Immunity. 2015;42(2):332-343. 2. Nolan E, et al. Sci Transl Med. 2017;9(393):eaal4922. 3. Angell H, et al. J Immunother Cancer.
2017;5(suppl_2): Abstract P257.PARP Inhibitor and Immune Checkpoint Modulator
Combination Trials in Progress
Patient Primary
Trial Name Phase Population Study Treatment Endpoint Preliminary Efficacy
RP2D, niraparib 200 mg od +
DLT / RP2D pembrolizumab 200 mg IV Q3W
TOPACIO/
I/II rEOC Niraparib + pembrolizumab
KEYNOTE-1621-3 ORR ORR 25%
DCR 68%
AST Olaparib + durvalumab
DCR / ORR ORR 72%; DCR 81%
MEDIOLA4 I/II including Olaparib + durvalumab +
gBRCAm OC Safety NR
bevacizumab
Durvalumab + olaparib
AST
RP2D 9 evaluable patients (all BRCAwt):
including Durvalumab + cediranib
NCT024844045,6 I/II 1 PR (6+ months), 5 SD ≥4 (4–6+) months
advanced ORR
Durvalumab + olaparib + DCR: 67%
OC cediranib
Advanced DLT / RP2D
NCT031012807 I/II Ocs (mBRCA Rucaparib + atezolizumab NR
or HRD+) Safety
AST, advanced solid tumors; BRCAwt, BRCA wildtype; DCR, disease control rate; DLT, dose limiting toxicities; NR, not yet reported; ORR, objective response rate; rEOC,
recurrent epithelial ovarian cancer
1. Konstantinopoulos P, et al. J Clin Oncol. 2016;34(15s): Abstract TPS5599. 2. National Institutes of Health. https://clinicaltrials.gov/ct2/
show/NCT02657889. Accessed 25 January 2019. 3. Konstantinopoulos PA, et al. Gynecol Oncol. 2018;149(246):246. 4. National Institutes of
Health. https://clinicaltrials.gov/ct2/show/NCT02734004. Accessed 25 January 2019. 5. National Institutes of Health. https://clinicaltrials.gov/ct2/
show/NCT02484404. Accessed 25 January 2019. 6. Lee JM, et al. J Clin Oncol. 2016;34(15s): Abstract 3015. 7. National Institutes of Health.
https://clinicaltrials.gov/ct2/show/NCT03101280. Accessed 25 January 2019.PARP Inhibitor and Immune Checkpoint Modulator
Combination Trials in Progress in EOC
• ANITA evaluates concurrent atezolizumab followed by maintenance niraparib ±
atezolizumab in patients with recurrent ovarian cancer1,2
Platinum-Sensitive Relapsed (PSR) Ovarian Carcinoma
If CR,
PR, SD
Niraparib
Platinum doublet +
• Platinum-sensitive recurrent +
Placebo
HGS or endometrioid, Placebo
or undifferentiated Randomize
ovarian cancer* 1:1
If CR, Primary outcome: PFS
Planned N ≈ 414
• ≥2 prior lines of chemotherapy PR, SD
Niraparib
Platinum doublet +
• ECOG 0–1 +
Atezolizumab
Atezolizumab
*Includes patients with primary peritoneal and/or fallopian tube cancer.
1. Gynecologic Cancer Committee Agenda Chicago 2017 June. https://gciggroup.com/system/files/1_2018%20Spring%20Ovarian%20GA%20report.pdf.
Accessed 25 January 2019. 2. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT03598270. Accessed 25 January 2019.Specific Population: ROSCAN Evaluates Chemotherapy or
Niraparib ± TSR-042 in Patients With Advanced Ovarian or
Endometrial Carcinosarcoma
• ROSCAN is a multicenter, randomized, open-label, phase II/III study
Part 1 Part 2
SOC CTX TPC Primary outcome
• Progressive or recurrent uterine N = 10 N = 59
• RR at 4 months
or ovarian carcinosarcoma
• OS
• ≥1 prior lines of platinum-
chemotherapy (could be Niraparib Secondary outcomes
adjuvant setting) Randomize 200 mg – 300 mg od • PFS
2:2:1 N = 20 Keep the • TSST
• ECOG 0–1 Planned N ≈ 196 winner
(ORR 20%) Best arm • PFS2
• Recent (within 3 months) N = 117 • ORR
Niraparib
archival tumor tissue • PRO/HRQoL
200 mg – 300 mg od +
available/agree to provide TSR-042 • Safety
a tumor biopsy 400 mg IV d1 q 3 w
(4 cycles) then Clinicaltrials.gov identifier: NCT03651206
1000 mg d1 q 6 w Status: Not yet recruiting
N = 20
SOC CTX, standard of care chemotherapy; TPC, treatment of physicians' choice; ORR, objective response rate; RR, response rate
1. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT03651206. Accessed 25 January 2019.PARP Inhibitor and Immune Checkpoint Modulator
Combination Trials in Progress in EOC
• ANITA evaluates concurrent atezolizumab followed by maintenance niraparib ±
atezolizumab in patients with recurrent ovarian cancer1,2
Platinum-Sensitive Relapsed (PSR) Ovarian Carcinoma
If CR,
PR, SD
Niraparib
Platinum doublet +
• Platinum-sensitive recurrent +
Placebo
HGS or endometrioid, Placebo
or undifferentiated Randomize
ovarian cancer* 1:1
If CR, Primary outcome: PFS
Planned N ≈ 414
• ≥2 prior lines of chemotherapy PR, SD
Niraparib
Platinum doublet +
• ECOG 0–1 +
Atezolizumab
Atezolizumab
*Includes patients with primary peritoneal and/or fallopian tube cancer.
1. Gynecologic Cancer Committee Agenda Chicago 2017 June. https://gciggroup.com/system/files/1_2018%20Spring%20Ovarian%20GA%20report.pdf.
Accessed 25 January 2019. 2. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT03598270. Accessed 25 January 2019.There Are Several First-Line Combination
Trials Ongoing or About to Start
Patient Primary
Trial Name Phase Population Study Treatment Endpoint
SOC* placebo
FIRST1 III Stage III/IV OC SOC* niraparib PFS
SOC* + TSR-042 niraparib + TSR-042
CTX + bevacizumab bevacizumab
DUO-O2 III Stage III/IV OC CTX + bevacizumab + durvalumab bevacizumab + durvalumab PFS
CTX + bevacizumab + durvalumab bevacizumab + durvalumab + olaparib
Rucaparib + nivolumab
Stage III/IV OC
Rucaparib + placebo
ATHENA3 III Response to PFS
1st line Nivolumab + placebo
platinum-CTX Placebo + placebo
Paclitaxel/carboplatin + placebo + placebo
Stage III/IV OC
BGOG2 III Paclitaxel/carboplatin + pembrolizumab + placebo TBC
BRCAwt
Paclitaxel/carboplatin + pembrolizumab + olaparib
*SOC, standard chemotherapy with paclitaxel/carboplatin ± bevacizumab and bevacizumab maintenance per local practice
TBC, to be confirmed
1. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT03602859. Accessed 25 January 2019. 2. Gynecologic Cancer Committee
Agenda Chicago 2017 June. https://gciggroup.com/system/files/1_2018%20Spring%20Ovarian%20GA%20report.pdf. Accessed 25 January 2019.
3. National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT03522246. Accessed 25 January 2019.Searching the Keys to Cure Ovarian Cancer
• PARP inhibitors are a major progress in HGOC
and are moving in first-line maintenance
• Anti-angiogenics improve PFS (and OS for
some subgroups) in all lines
• Combination versus sequential use?
• Other candidates for combination
– Immunotherapies in combination are
candidates for the next step ahead
– DDR drugs
• What about preplanned translational research
in all these trials?You can also read
