1. Parp Inibitori nel carcinoma ovarico in pazienti con o senza mutazione di BRCA
Giorgio Valabrega
FPO IRCCS Candiolo
Università degli studi di Torino

2. Disclosure
Dr. Valabrega received honoraria from Pharmamar, Roche, Astrazeneca, Tesaro
2) Dr. Valabrega currently has flu-like syndrome

3. Agenda PARPi in BRCA 1 and 2 mutated relapsed ovarian cancers: SOLO2,
NOVA, ARIEL3
2) PARPi in HRD (NOVA and ARIEL 3)
3) PARPi in BRCA WT not HRD ( NOVA)
4) Open questions and future perspectives

4. High grade serous ovarian has frequently BRCA or other genes alterations
Not HRD
HRD
Cancer Genome Atlas Research Network. Nature. 2011;474(7353):

6. PARPi are highly effective in BRCAmut patients
From Pignata S., Biological implications for Clinical practice in ovarian cancer. ESMO discussion

7. Parpi are active also in non BRCA mutated HRD ovarian cancer

8. PFS: non-gBRCAmut HRD-positive
Treatment
PFS
Median
(95% CI) (Months)
Hazard Ratio (95% CI) p-value
% of Patients without Progression or Death
12 mo
18 mo
Nirapar ib
(N=106 )
12.9
(8.1, 15.9)
0.38
(0.243, )
p<
51%
37%
Placeb o
(N=56)
3.8
(3.5, 5.7)
13% 9%
Close out that all three primary efficacy populations with consistent durable efficacy
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.
Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016

9. ARIEL3 Population
Coleman et al, Lancet, Sept 2017

10. ARIEL3 (HRD group)
Coleman et al 2017

11. Parpi are active HRD negative ovarian cancers

12. ENGOT-OV16 / NOVA: PFS HRD-negative 0.58
Treatment
PFS
Median
(95% CI) (Months)
Hazard Ratio (95% CI) p-value
% of Patients without Progression or Death
12 mo
18 mo
Niraparib
(N=92)
6.9
(5.6, 9.6)
0.58
(0.361, ) p=
27%
19%
Placebo
(N=42)
3.8
(3.7, 5.6) 7%
Now that we have talked about primary populations, we move to exploratory analysis of the non-gBRCA cohort subgroups.
Somatic: In this subgroup, a significant treatment effect similar to that in the gBRCAmut cohort was observed with niraparib compared to placebo. Of note, the HR observed in the gBRCAmut cohort (0.27) was identical to the HR observed in this HRDpos/sBRCAmut subgroup demonstrating the consistency of the niraparib treatment effect across cohorts and in 2 independent patient populations with similar underlying tumor biology
Mirza MR et al. N Engl J Med 2016; Presidential Symposium, ESMO 2016

13. Open questions Which is the optimal clinical setting?
How can we choose among different PARPis in clinical practice (when all available)?
Why HRD negative patients benefit from Parpi?
How much do we know about resistance to PARPis?

14. Open questions
Which is the optimal clinical setting?

15. ARIEL3: rucaparib active also active in heavily pretreated patients
Coleman et al, Lancet, Sept 2017

16. OLAPARIB: SOLO 2 exploratory analysis
Efficacy of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer by number of lines of prior chemotherapy:
Phase III SOLO2 trial (ENGOT Ov-21).
Penson et al.
Abs 4670; Poster No. 932PD

17. How can we choose between different Parpi in clinical practice?
Label (niraparib for all PS newcomers in PR/CR)
Price (Unknown for Nira and Ruca)
Safety profile

18. Safety

19. Comparison of different toxicity profiles
Coleman et al, Lancet, Sept 2017

20. <1% Incidence of Grade 3-4 thrombocytopenia after Month 3*
RADAR Analysis of NOVA (Integrated Body Weight and Baseline Platelet Count Approach)
In this exploratory analysis1, two factors were identified as significant predictors for early dose modification
Baseline Body Weight:
<77 kg (170 lbs) OR
Baseline Platelets:
<150,000/µL
Higher incidence of grade 3 or 4 thrombocytopenia (39.3% vs %)
As a result of dose modifications, average daily niraparib dose was 206 mg for the first two months
Only 17% of this patient group remained on niraparib 300mg at Month 4
In patients with one of these two baseline characteristics:
An exploratory analysis of NOVA concluded that individual dose modification maintained efficacy and reduced the rate of new adverse events2
<1% Incidence of Grade 3-4 thrombocytopenia after Month 3*
Please see additional Important Safety Information on slide 14 – 18 of this presentation
*With dose modifications.
1. TESARO, Inc. Data on File Wang J, et al. Poster presentation at ESMO Abstract #933PD.

21. NOVA Elderly Patients Subgroup Analysis: Efficacy Progression-Free Survival in gBRCAmut Patients and non-gBRCAmut Patients Aged <70 and ≥70 Years
Age Group
Niraparib, n
Placebo, n
PFS HR
(95% CI)
gBRCAmut
Age <70
124 58
0.30
(0.19 – 0.47)
Age ≥70 14 7
0.09
(0.01 – 0.73)
Non-gBRCAmut
187 89
0.47
(0.34 – 0.66) 47 27
0.35
(0.18 – 0.71)
CI=confidence interval; gBRCAmut=germline breast cancer susceptibility gene mutation; HR=hazard ratio; PFS=progression-free survival;
Data represent all randomized patients
Fabbro M., et al. Presented ESMO; Sep. 8-12, 2017; Madrid, Spain. Poster# 934PD

22. NOVA Elderly Patients Subgroup Analysis: Safety
TEAEs Resulting in Dose Interruption, Reduction, or Treatment Discontinuation in Patients Aged <70 and ≥70 Years
Characteristic, n(%)
Niraparib
Placebo
Age <70
(n=306)
Age ≥70
(n=61)
(n=145)
(n=34)
Dose Interruption
210 (68.6)
34 (55.7)
22 (15.2)
4 (11.8)
Dose Reduction
211 (69.0)
42 (68.9)
6 (4.1)
3 (8.8)
Treatment Discontinuation
42 (13.7)
12 (19.7)
3 (2.1)
1 (2.9)
Dose interruptions, reductions, and treatment discontinuations occurred with similar frequency in patients regardless of age.
Treatment-emergent adverse events (TEAEs) in patients aged <70 versus ≥70 years did not show any specific safety concerns for the older population.
Grade ≥3 TEAEs occurring in ≥10% of niraparib-treated patients were consistent in patients <70 versus ≥70 years
No grade 5 TEAEs were reported
TEAE=treatment-emergent adverse event.
Data represent all patients receiving ≥1 dose of niraparib or placebo
Fabbro M., et al. Presented ESMO; Sep. 8-12, 2017; Madrid, Spain. Poster# 934PD

23. NOVA Elderly Patients Subgroup Analysis: Safety
TEAEs of Any Grade Occurring in ≥20% of Patients and TEAEs Grade ≥3 Occurring in ≥10% of Patients Aged <70 and ≥70 Years*
TEAE=treatment-emergent adverse event. Data represent all patients receiving ≥1 dose of niraparib or placebo
*There were no grade 5 TEAEs.
Fabbro M., et al. Presented ESMO; Sep. 8-12, 2017; Madrid, Spain. Poster# 934PD

24. STILL WAITING FROM REAL LIFE DATA!
(see Cecere…..)

25. Why HRD negative patients benefit from Parpi?

26. Adesso che conosco le risposte mi hanno cambiato le domande…………..
Vito Lorusso, MITO BRINDISI 2016

27. Why do SOME HRD negative patients derive benfit from PARP-inhibitors?
Other non HRD DNA repair impaired mechanisms in these patients?
The test may miss some HRD positive cases?

28. Are there other impaired non-HRD mechanisms of DNA repair?
BER (Base excision Repair)
NER (nucleotide Ex Rep)
NHEJ (non-Homologus end Joining)
PARP inhibitors inhibit PARP-1, but also PARP2 that have different functions
(PARP2 is involved in DNA repair through NER)

29. Is HRD more frequent than earlier anticipated?
Konstantinopulos PA et al Cancer Discovery 2015

30. What is statistically significant is also clinically meaningful?
Aurelia
6.7
3.4
TRINOVA 1
7.4
5.4
TRINOVA 2
7.6
7.2
GOG 213
13.8
10.4
ICON 6 11
8.7
OCEANS
12.4
8.4
SOLO-2-gBRCA
Chemotherapy
19.1
Chemotherapy
5.5
NOVA-non-gBRCA
Chemotherapy
9.3
Chemotherapy
3.9
NOVA-gBRCA
Chemotherapy 21
Chemotherapy
5.5
ARIEL 3-tBRCA
Chemotherapy
16.6
Chemotherapy
5.4
All ARIEL 3
Chemotherapy
10.8
Chemotherapy
5.4 5 10 15 20 25
Aghajanian C et al. J Clin Oncol. 2012;30:2039–45; Coleman RL et al. Gynecologic Oncol. 2015;137:386–91; Ledermann J et al. Lancet Oncol. 2014;15:852–61; Ledermann JA et al. Lancet. 2016;387:1066–74; Marth C et al. Eur J Cancer. 2017;70:111–21; Monk BJ et al. Lancet Oncol. 2014;15:799–808; Pujade-Lauraine E et al. J Clin Oncol. 2014;32:1302–8; Mirza MR et al. N Engl J Med. 2016;375:2154–64;
Coleman RL et al. Lancet. 2017;doi: /S (17)
Median PFS (months)

31. What do we know about resistance to Parpi?

32. Divergent modes of clonal spread: primary
resistance
Mcpherson Nat Gen 2016

33. Mechanisms of PARPi resistance in HR-deficient cells.
Mechanisms of PARPi resistance in HR-deficient cells. Known mechanisms conferring PARPi resistance in tumor cells and cross-resistance to cisplatin are indicated. An acquired genetic reversion of the original truncating mutations restores functional protein expression, inducing PARPi resistance. Alternatively, acquired epigenetic reversion of BRCA1 promoter hypermethylation can restore normal BRCA1 protein expression levels, conferring PARPi resistance. Hypomorphic alleles, such as BRCA1C61G or BRCA1Δ11, are unable to prevent tumor development but confer resistance to PARPi. Tumor cells may also become PARPi resistant through loss of PARP1 expression. Rescue of DNA end resection in BRCA1-deficient tumors through loss of 53BP1 or REV7 increases HR capacity and confers resistance to PARPi. Loss of CHD4, a negative regulator of translesion synthesis (TLS), enhances DNA-damage tolerance and induces PARPi resistance. Increased in P-glycoprotein (PgP)–mediated efflux, notably through ABCB1 upregulation (via fusion with SLC25A40), reduces intracellular PARPi concentrations, inducing resistance. Desmoplastic stromal reaction is associated with reduced drug uptake conferring chemoresistance. *, personal communication from Dr. Rottenberg and Dr. Guotai; **, although this mechanism has been described for cisplatin, it might also apply for PARPi.
Panagiotis A. Konstantinopoulos et al. Cancer Discov 2015;5:
©2015 by American Association for Cancer Research

34. Somatic BRCA 1-2 recovery as resistance mechanism
to PARP inhibitors olaparib
Lhereux et al JCO 2017

35. Pignata ESMO 2017

36. Conclusions Parpi are very active in BRCA mut/HRD+ EOC
Parpi are active in HRD negative EOC
Different toxicity profiles but globally safe

37. Future perspectives
Strong translational research to predict long term responders (HRD + and -) and manage primary and acquired resistance to Parpi (e.g. liquid biopsy)
Treatment
PFS
Median
(95% CI) (months)
Hazard Ratio (95% CI) P value
% of Patients without Progression or Death
6 mo
12 mo
18 mo 24 mo
Niraparib
(N=138)
21.0
(12.9, NR)
0.27
(0.173, )
P<0.0001
80%
62%
50%
42%
Placebo
(N=65)
5.5
(3.8, 7.2)
43%
16%
Pignata ESMO 2017
Mirza NEJM 2016

38. Future perspectives
Novel combinations ongoing especially in BRCA mut e HRD mut (anti angiogenics, immune checkpoint inhibitors)
Different clinical settings (platinum resistant) or different modalities of administration (Rucaparib)

39. Medicine asks you to make perfect decisions with imperfect information
S. Mukherjee, The laws of medicine