robert l. coleman, md - ovarianparpinhibitor.com · robert l. coleman, md professor & vice...

Robert L. Coleman, MDProfessor & Vice Chair, Clinical ResearchMD Anderson Cancer CenterHouston, [email protected]

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Assessing Currently Available and Emerging

PARP Inhibitors

Disclosures

• Grant funding:• Clovis• Astra-Zeneca• Abbvie

• Scientific Steering Committee• Clovis: ARIEL2 and ARIEL3• Astra-Zeneca: MDACC Alliance• Abbvie: GOG-3005• Tesaro

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PARP inhibitors Clinical Trials

Olaparib

− Study 1 (NCT01078662)− Phase 2 maintenance (NCT00753545)− Phase 2 trial with paclitaxel/carboplatin (NCT01081951)− SOLO-1 (NCT01844986)− SOLO-2 (NCT01874353)− SOLO-3 (NCT02282020)− Olaparib/cediranib (NCT01116648, NCT02446600, NCT02502266)− PAOLA1 (NCT02477644)

Niraparib− PRIMA (GOG 3012; NCT02655016)− NOVA (NCT01847274)− QUADRA (NCT02354586)− AVANOVA (NCT02354131)

Rucaparib− Phase 2 trial (NCT01482715)− ARIEL2 (parts 1 and 2, NCT01891344)− ARIEL3 (NCT01968213)− ARIEL4 (NCT02855944)

Veliparib − Phase 2 trial (GOG 0280, NCT01540565)− Phase 3 trial (GOG 3005, NCT02470585)

Current PARP Inhibitors

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PARP, poly(ADP-ribose) polymerase

Olaparib: Study 1 Response

• Response rate− Overall response, 34%− Partial response, 32%− Complete response, 2%

• Response duration− Median, 7.9 months (95% CI, 5.6–9.6

months)

Domchek SM, et al. Gynecol Oncol. 2016;140(2):199-203.

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Platinum Sensitivity Status Patients Responders Response Rate (95% CI)

Platinum-sensitive 38 17 45% (29–62)

Platinum-resistant 77 22 29% (19–40)

Platinum-refractory 14 2 14% (2–43)

Unknown 8 5 63% (24–91)

TOTAL 137 46 34% (26–42)

Baseline Patient Characteristics:BRCA2: 22%BRCA1: 77%Pt-resistant: 56%Pt-refractory: 10%

Response by Platinum Sensitivity (n=137)

Efficacy results (n=137)

Olaparib: Study 19 R-Ph2 Maintenance Trial in Platinum-Sensitive Recurrent Serous OC

Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392.Ledermann J, et al. Lancet Oncol. 2014;15(8):852-861.

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Primary end point: PFSSecondary end points: OS, best ORR, health-related quality of life (TOI), FACT-O, FACT-O symptom index (FOSI), time to progression, disease control rate, and safety and tolerability

• Platinum-sensitive advanced OC• Grade 2–3 serous histology or serous

component• ≥2 previous platinum regimens• CR or PR to just-completed platinum

regimen

Olaparib 400 mg PO bid

(n=136)

Placebo

(n=129)

R

bid, twice daily; CR, complete response; OC, ovarian cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PO, by mouth; PR, partial response; R, randomization

Olaparib: Randomized, Phase 2 Maintenance Trial in Platinum-Sensitive Recurrent Serous OC


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Parameter Olaparib Placebo HR P-valueAll patients 136 129

PFS 8.4 mo 4.8 mo 0.35 (0.25–0.49) <.001

OS 29.8 mo 27.8 mo 0.88 (0.64–1.21) .44

BRCA mutated 74 62

PFS 11.2 mo 4.3 mo 0.18 (0.10–0.31) <.0001

OS 34.9 mo 31.9 mo 0.73 (0.45–1.17) .19

BRCA wild-type 62 67

PFS 7.4 mo 5.5 mo 0.54 (0.34–0.85) .0075

OS 24.5 mo 26.2 mo 0.99 (0.63–1.55) .96BRCA, breast cancer susceptibility gene; HR, hazard ratio; OC, ovarian cancer; OS, overall survival; PFS, progression-free survival

Olaparib: Randomized, Phase 2 Maintenance Trial in Platinum-Sensitive Recurrent Serous OC (cont.)

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Olaparib Maintenance: All Patients


HR, hazard ratio; OC, ovarian cancer; OS, overall survival; PFS, progression-free survival

P-value

Ongoing Olaparib Monotherapy Phase 3 Trials

aincluding primary peritoneal, or fallopian tube cancers.

bid, twice daily; BRCA, breast cancer susceptibility gene; CR, complete response; GEM, gemcitabine; HR-QoL, health-related quality of life; ORR, objective response rate; OS, overall survival; PAC, paclitaxel; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PO, by mouth; PR, partial response; RECIST, response evaluation criteria in solid tumors; TDT, time from randomisation to study treatment discontinuation or death; TFST, time from randomisation to first subsequent therapy or death; TSST, time to second subsequent therapy or death

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Patient Population Study Design Study EndpointsSOLO-1 (NCT01844986)− Newly diagnosed stage III-IV ovarian cancera

− Serous or endometrioid high-grade histology− In CR or PR at end of frontline

platinum-based chemotherapy− Deleterious BRCA mutation

− Olaparib(300 mg PO bid) or placebo to progression

− Primary: PFS− Secondary: OS, time to earliest

progression by RECIST or CA-125 or death, PFS2, best ORR, HRQoL,TDT, TFST, TSST, safety/tolerability

SOLO-2 (NCT01874353)

− Platinum-sensitive ovarian cancera

− In CR or PR after ≥2 lines of platinum Tx− Serous or endometrioid high-grade histology− Deleterious BRCA mutation

− Olaparib(300 mg PO bid) or placebo to progression


progression by RECIST or CA-125 or death, PFS2, best ORR, HRQoL, TDT, TFST, TSST, safety/tolerability

SOLO-3 (NCT01844986)− Platinum-sensitive ovarian cancera

− In CR or PR after ≥2 lines of platinum Tx− Serous or endometrioid high-grade histology− Measurable disease− No prior PARP inhibitor− Deleterious BRCA mutation

− Olaparib (300 mg PO bid) or physicians choice (weekly PAC, topotecan, PLD, or GEM) to progression


progression by RECIST or CA-125 or death, PFS2, best ORR, HRQoL, TDT, TFST, TSST, safety/tolerability

Ongoing Olaparib Combination Trials

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aincluding primary peritoneal, or fallopian tube cancers.bid, twice daily; BRCA, breast cancer susceptibility gene; CARB, carboplatin; CTx, chemotherapy; FIGO, International Federation of Gynecology and Obstetrics; GEM, gemcitabine; HR-QoL, health-related quality of life; OS, overall survival; PAC, paclitaxel; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PO, by mouth; Pt, platinum

Patient Population Study Design Study EndpointsNRG GY004 (NCT02446600)

− Pt-sensitive recurrent ovarian cancera

− Endometrioid or serous high-grade histology or other histology if gBRCAmut

− Measurable disease− ≥1 prior platinum regimens− Prior antiangiogenic Tx first-line only− Progression-free ≥6 mos after last platinum

− Carboplatin-based doublet (PAC or GEM or PLD + CARB) vs Olaparib (400 mg PO bid) vs Cediranib (30 mg PO qd) + Olaparib (400 mg PO bid) to progression

− Primary: PFS− Secondary: OS, safety,

patient-reported outcomes

NRG GY005/COCOS (NCT02502266)

− Pt-resistant or -refractory recurrent ovarian cancera

− Endometrioid or serous high-grade histology or other if gBRCAmut

− ≤2 prior regimens− Prior antiangiogenic therapy first-line only− Progression-free ≤6 mos after last platinum

− Physician’s choice (PAC, PLD, GEM)

− Olaparib+ Cediranib− Cediranib− Olaparib to progression

− Primary: PFS (phase 2); OS (phase 3)

− Secondary: Safety

PAOLA-1 (NCT02477644)

− High-grade epithelial ovarian cancera

− FIGO stage IIIB-IV− At least stable disease after

surgery/chemotherapy for 6–9 cycles

− Olaparib vs placebo + CTx and bevacizumab concurrent with CTx and in maintenance

− Primary: PFS− Secondary: OS, post-

progression survival, HRQoL, safety/tolerability


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Olaparib





Niraparib: NOVA Phase 3 Maintenance Study in Platinum-Sensitive Ovarian Cancer

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• Platinum-sensitive ovarian, primary peritoneal, or fallopian tube cancer

• Serous high-grade histology or known to have gBRCAmut

• ≥2 prior platinum regimens • In CR or PR and enrolled within

8 weeks of completion of last platinum regimen

• No prior PARP inhibitor• Planned N=490

Niraparib 300 mg PO daily to

progression

Placebo once daily to

progression

Mirza MR, et al. N Engl J Med. 2016 Oct 7. [Epub ahead of print].ClinicalTrials.gov. NCT01847274. Accessed May 31, 2016.

R2:1

N=490Primary end point: PFSSecondary end points: OS, PFS2, chemotherapy-free interval, health-related quality of life, and safety and tolerabilityAnalysis to include: all patients, gBRCAmut patients, and the non-gBRCAmut cohort (first as HRD+ patients and then all non-gBRCAmut patients)

CR, complete response; gBRCAmut, germline breast cancer susceptibility gene mutation; HRD, homologous recombination deficiency; OS, overall survival; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; PO, by mouth; PR, partial response; R, randomization

aMedian duration of follow-up at time of data cutoff was 16.9 months.

ENGOT-OV16/ NOVA Trial

Mirza MR, et al. N Engl J Med. 2016 Oct 7. [Epub ahead of print].

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Platinum-Sensitive Recurrent High Grade SerousOvarian Cancer

N=553

gBRCAmutn=203

2:1 Randomization

Niraparib n=138

Placebon=65

47 Ongoing

Treatmenta

4 Ongoing

Treatmenta

Non-gBRCAmutn=350

2:1 Randomization

Niraparib n=234

Placebon=116

46 Ongoing

Treatmenta

12 Ongoing

Treatmenta

Prospective Stratification Factors for Randomization


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Characteristic

gBRCAmut Non-gBRCAmutNiraparib(n=138)

Placebo(n=65)

Niraparib(n=234)

Placebo(n=116)

Time to progression after penultimate platinum therapy, n (%)

6 to <12 mo 54 (39.1) 26 (40.0) 90 (38.5) 44 (37.9)

≥12 mo 84 (60.9) 39 (60.0) 144 (61.5) 72 (62.1)

Best response to most recent platinum therapy, n (%)

Complete response 71 (51.4) 33 (50.8) 117 (50.0) 60 (51.7)

Partial response 67 (48.6) 32 (49.2) 117 (50.0) 56 (48.3)

Prior bevacizumab use, n (%)

Yes 33 (23.9) 17 (26.2) 62 (26.5) 30 (25.9)

No 105 (76.1) 48 (73.8) 172 (73.5) 86 (74.1)

gBRCAmut, germline breast cancer susceptibility gene mutation

Progression-Free Survival: gBRCAmut

Treatment

PFSMedian

(95% CI), mo

Hazard Ratio(95% CI)P-value

% of Patients Without

Progression or Death

12 mo

18 mo

Niraparib(n=138)

21.0(12.9, NR) 0.27

(0.173, 0.410)

P<.0001

62% 50%

Placebo(n=65)

5.5(3.8, 7.2)

16% 16%

PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox

proportional hazards model, with the stratification factors used in randomization.

gBRCAmut, germline breast cancer susceptibility gene mutation; NR, not reached; PFS, progression-free survival


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Progression-Free Survival: Non-gBRCAmut


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Treatment

PFSMedian

(95% CI), mo




12 mo

18 mo

Niraparib(n=234)

9.3(7.2, 11.2)

0.45(0.338, 0.607)

P<.0001

41% 30%

Placebo(n=116)

3.9(3.7, 5.5) 14% 12%

Progression-Free Survival: Non-gBRCAmut HRD+


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Treatment

PFSMedian

(95% CI), mo




12 mo

18 mo

Niraparib(n=106)

12.9(8.1, 15.9)

0.38(0.243, 0.586)

P<.0001

51% 37%

Placebo(n=56)

3.8(3.5, 5.7) 13% 9%




Ongoing Niraparib Trials

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Patient Population Study Design Study EndpointsPRIMA (GOG 3012; NCT02655016)

− Newly diagnosed stage III-IV ovarian cancera

− HRD+ tumor− In CR or PR at end of at least 4 cycles of

frontline platinum-based chemotherapy− No prior PARP inhibitor

− Niraparib (300 mg PO) or placebo to progression

− Primary: PFS− Secondary: OS, PFS2,

HRQoL, safety/tolerability

QUADRA (NCT02354586)

− Recurrent ovarian cancera

− Serous high-grade histology− ≥3 prior chemotherapy regimens − Disease progression on most recent

chemotherapy

− Niraparib(300 mg PO) to progression

− Primary: ORR− Secondary: DOR, DCR,

PFS, safety/tolerability

AVANOVA (NCT02354131)

− Recurrent platinum-sensitive ovarian cancera

− High-grade serous or endometrioid histology− HRD-positive

− Sequential bevacizumab àniraparb vs niraparib monotherapy vs niraparib+ bevacizumab combination to progression

− Primary: PFS− Secondary: Disease control

rate


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Olaparib





ARIEL2: Phase 2, Part 1

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bid, twice daily; BRCAmut, breast cancer susceptibility gene mutation; ORR, objective response rate; PFS, progression-free survival; PK, pharmacokinetics; PO, by mouth; RECIST, response evaluation criteria in solid tumors

• Platinum-sensitive ovarian, primary peritoneal, or fallopian tube cancer

• Serous or endometrioid high-grade histology

• ≥1 prior platinum regimen• Open-label phase 2

Rucaparib 600 mg PO bid to

progression

BRCAmut

Biomarker negative

BRCA-like

Part 1 (COMPLETED) : Evaluation of HRD status/Rucaparib efficacy

Swisher EM, et al. Lancet Oncol. 2017;18(1):75-87.

N=350Primary end point: PFSSecondary end points: ORR (RECIST, RECIST+CA-125), PK, and safety and tolerability

ARIEL2: Phase 2 Study Results

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BRCA, breast cancer susceptibility gene; BRCAmut, breast cancer susceptibility gene mutation; HRD, homologous recombination deficiency; ORR, objective response rate; PFS, progression-free survival; RECIST, response evaluation criteria in solid tumors

HRD Subgroup

Median PFS (90% CI)

ORR RECIST, n (%)

ORRRECIST+CA-125,

n (%)

BRCAmut 9.4 mo (7.3–NR) 27/39 (69) 32/39 (82)

BRCA-like 7.1 mo (3.7–10.8) 22/74 (30) 33/74 (45)

Biomarker-negative 3.7 mo (3.5–5.5) 8/62 (13) 13/62 (21)

McNeish IA, et al. J Clin Oncol. 2015;33(suppl):abstract 5507.

Efficacy and Safety Populations

Criteria- Diagnosis of ovarian cancer (inclusive of primary peritoneal

and fallopian tube cancer)

- Enrolled at 600 mg bid dosing level and received ≥1 dose of rucaparib 600 mg

Criteria- Received ≥2 prior chemotherapies, including ≥2

platinum-based regimens

- Had a deleterious germline BRCA or somatic BRCA mutation

- Enrolled at 600 mg bid dosing level and received ≥1 dose of rucaparib 600 mg

Study 10(NCT01482715)

n=62

n=42

ARIEL2(NCT01891344)

n=315

n=64

Safety Population (n=377)

Efficacy Population (n=106)

Safety population visit cutoff dates: Study 10 (31 Mar 2016), ARIEL2 (29 Apr 2016). Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).bid, twice daily; BRCA, breast cancer susceptibility gene

Kristeleit RS, et al. Ann Oncol. 2016;27(suppl 6):vi296.

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Progression-free at 6 months:79%

Progression-free at 12 months:41%

Progression-Free Survival in the Efficacy Population


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Median (months) 95% CI Range10.0 7.3–12.5 0.0–22.1+

+ Censored; Censoring rate: 47%

• Of 106 patients, 50 did not have an event of disease progression or death by the data cutoff dates– Of these 50 patients, 32 were still on treatment, and 18 discontinued treatment for reasons other than disease

progression or death at the data cutoff dates

Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).CI, confidence interval

Prob

abili

ty o

f Pro

gres

sion

-Fre

e Su

rviv

al

MonthsAt risk

(events) 106 (0) 93 (9) 85 (14) 69 (19) 43 (37) 31 (40) 21 (43) 14 (49) 8 (54) 3 (55) 3 (55) 2 (56) 0 (56)

Investigator-Assessed ORR in the Efficacy Population


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Efficacy population visit cutoff dates: Study 10 Part 2a (30 Nov 2015) and ARIEL2 (29 Feb 2016).CR, complete response; GCIG, Gynecologic Cancer InterGroup; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable diseas

Parameter

Study 10n=42

ARIEL2n=64

Efficacy Populationn=106

n (%)[95% CI]

Investigator-assessed RECIST ORR(confirmed CR+PR)

25 (60)[43.3–74.4]

32 (50)[37.2–62.8]

57 (54)[43.8–63.5]

CR 4 (10) 5 (8) 9 (9)

PR 21 (50) 27 (42) 48 (45)

SD 12 (28) 24 (37) 36 (34)

PD 2 (5) 7 (11) 9 (9)

NE 3 (7) 1 (2) 4 (4)

Investigator-assessed RECIST/GCIG CA-125 ORR

75 (71)[61.1–79.2]

Ongoing Rucaparib Trials

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Patient Population Study Design Study Endpoints

ARIEL3 (NCT01968213)

− Recurrent ovarian cancera

− High-grade serous or endometrioid histology− 1 prior non-platinum regimen− Platinum sensitive− In a CR or PR at end of just-completed platinum

regimen − No prior PARP in ≥2 prior platinum regimens− No more than 1 nonplatinum chemotherapy

regimen

− Rucaparib (600 mg PO bid) or placebo to progression

− Primary: PFS− Secondary: OS, HRQoL,

safety/tolerability

ARIEL4 (NCT02855944)

− Grade II-III ovarian cancera

− ≥2 prior chemotherapy regimens and have relapsed or progressive disease

− Rucaparib (600 mg PO bid) or chemotherapy to progression

− Primary: PFS− Secondary: OS, safety/tolerability



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Olaparib





Veliparib: Phase 2 Study Design

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N=50Primary end point: investigator-assessed ORRSecondary end points: PFS, EFS, PFS6/EFS6, OS, safety/tolerability

bid, twice daily; EFS, event-free survival; gBRCAmut, germline breast cancer susceptibility gene mutation; ORR, objective response rate; OS, overall survival; PARP, poly(ADP-ribose) polymerase; PO, by mouth

• Recurrent ovarian, primary peritoneal, or fallopian tube cancer

• gBRCAmut present• <3 prior treatment regimens • Prior biologic therapy but no prior PARP

inhibitor allowed• Measurable disease

Veliparib 400 mg PO bid to

progression

Overall Best Response Patients, n (%)

RECIST (n=40)

CR 2 (5)

PR 11 (27.5)

SD 14 (35)

PD 7 (17.5)

Indeterminate 6 (15)

Disease control rate 27 (67.5)

Results

Coleman RL, et al, Gynecol Oncol. 2015;137(3):386-391.ClinicalTrials.gov. NCT01540565. Accessed June 2, 2016.

GOG 3005: Frontline Phase 3 Trial

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AUC, area under the curve; CNS, central nervous system; DRS, disability rating score; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; OS, overall survival; PFS, progression-free survival; q3wk, every 3 weeks; qwk, every week

CHOICE OF THERAPYCarboplatin AUC 6 q3wk +Paclitaxel qwk (80 mg/m2) or paclitaxel q3wk (175 mg/m2)Primary or interval cytoreductive surgery

Veliparib

PlaceboHigh-grade serous carcinoma

• Ovary, fallopian tube, primary peritoneal

• FIGO stage III or IV• No prior systemic therapy• ECOG 0-2• No CNS metastases

Arm 2veliparib PO bid +

carboplatin/paclitaxel

Arm 3veliparib PO bid +


Arm 1placebo PO bid +


(1:1:1)

N=1100R

ClinicalTrials.gov. NCT02470585. Accessed May 31, 2016.

Primary end point: PFSSecondary end points: OS, DRS scores

§ 2 PARP inhibitor currently approved (olaparib, rucaparib)

§ 2 others in active clinical trials (niraparib, veliparib)

§ Current use outside trials: gBRCAmut

Current status

§ Increasing number of agents: relative merits

Defining new patient groups to benefit§ Defining BRCA-like patients§ Combination with other targeted

agentsScope of roles in ovarian cancer§ Monotherapy in recurrent disease§ Monotherapy as maintenance after

chemotherapy § Combination therapy with

chemotherapy

Immediate future issues

PARP Inhibitors: Summary

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gBRCAmut, germline breast cancer susceptibility gene mutation; PARP, poly(ADP-ribose) polymerase

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