1. Niraparib in Bladder Cancer
A Phase II, Randomized, Trial of Niraparib Versus Best Supportive Care as Maintenance Treatment In Patients With Locally Advanced Or Metastatic Urothelial Cancer Whose Disease Did Not Progress After Completion Of First-line Platinum-containing Chemotherapy
Prof. Massimo Di Maio
Dott.ssa Francesca Vignani
A.O. Ordine Mauriziano
S.C.D.U Oncologia Medica

2. Orally active inhibitor of PARP
Niraparib
Orally active inhibitor of PARP
High selectivity for PARP1 (IC50=3.8 nM) and PARP2 (IC50=2.1 nM)
Poli-(ADP-ribosio)-polimerasi] è un enzima nucleare (proteina), presente in abbondanza ed è coinvolta in una serie di processi cellulari che coinvolgono principalmente di riparazione del DNA e la morte cellulare programmata (apoptosi)
Steffen JD et al. Front Oncol
IC50=median inhibition concentration.
Jones P et al. J Med Chem. 2009;52:

3. Rationale and Background
PARP1 binds damaged DNA & hydrolyzes NAD+ to produce linear branched PAR chains
Repair proteins are recruited to reseal SSBs
PARP inhibition prevents this repair leading to accumulation of SSBs
When SSBs are encountered by replication forks, they generate DSBs that need to be repaired by homologous recombination repair (HRR)
Lack of HRR leads to accumulation of DSBs and cell death.
Collapsed
replication fork
Poly(ADP-ribose) polymerase 1 (or PARP1) is an abundant nuclear protein that binds damaged DNA and hydrolyzes nicotinamide adenine dinucleotide to produce linear branched poly(ADP-ribose) chains, which recruit repair proteins to reseal single-strand breaks during base excision repair
In the absence of PARP function the replication fork stalls and ultimately generates double-strand breaks that need to be repaired by homologous recombination.
BRCA1 and 2 are involved in high-fidelity homologous recombination repair, and hence cancer cells deficient in BRCA1 and BRCA2 are selectively hypersensitive to PARP inhibitors. This provides a strong rationale for the development of PARP inhibitors for cancer treatment.
It is important to note that while BRCA deficiency is a clear indicator for PARP inhibitor sensitivity, other defects in DNA repair can sensitize the cell to these agents.
HRR pathway deficiency sensitizes cancer cells to PARP inhibition
DSB=double-strand break; HRR=Homologous recombination repair; NAD=nicotinamide adenine dinucleotide; PARP=Poly(ADP-ribose) polymerase; PAR=poly(ADP-ribose); SSB=single-strand break.
Piccart. Clin Onc , Jan 2015; 12(27) 3

4. Rationale and Background
The presence of HR defects is implicated in the sensitivity to platinum chemotherapy
Potential cross-sensitivity and cross-resistance between platinum drugs and PARP inhibitors
The platinum sensitivity of urothelial cancer (UC) tumors is thought to be related to an underlying defect in HR–mediated DNA repair
Approximately 34% of bladder UC harbored truncating and missense mutations in genes associated with the HR pathways, genes which confer PARP inhibitors sensitivity (CHEK1/2, RAD51, BRCA1/2, ATM, ATR, MDC1, and FANCF). (TCGA, Bladder Urothelial Carcinoma provisional, 2015) 4

5. Rationale and Background
A reduced capacity for HR repair is associated with increased sensitivity to PARP inhibitor and the combination of PARP inhibitor and cisplatin causes a significant increase in DNA damage versus the use of cisplatin alone in UC cell lines.
Jian W, Xu HG, Chen J, et al. Anticancer Drugs. 2014;25:
The response to neoadjuvant cisplatin chemotherapy is associated with mutations in general DNA repair genes (P<.001), some of which are strongly associated with HR (ATM and FANCC) in patients affected by UC.
Plimack ER, Dunbrack RL, Brennan TA, et al. Eur Urol. 2015;68:
The prevalence of somatic mutations in HR genes, as well as their association with platinum sensitivity represent a good rationale to consider PARP as a target for the treatment of UC in selected patients.

6. Study Design Experimental arm Random 2:1 Control arm
Niraparib 300 mg daily
plus best supportive care
until PD or unacceptable toxicity or death.
Unresectable, locally advanced or metastatic TCC of the urothelium
ECOG PS 0-1
4-6 cycles of platinum-based CT
CR, PR or SD
Random
2:1
Control arm
Best supportive care
until PD or death
TCC: transitional cell carcinoma; PS: performance status; CT: chemotherapy
CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease

7. Endpoints Primary endpoint: Progression-free survival (PFS).
Secondary endpoints:
Objective response rate.
Duration of response.
Overall survival.
Rate of progression-free survival at 6 months.
Safety and tolerability.
Patient-reported outcomes.
BRCA mutation test, HRD diagnostic test (exploratory endpoint). 7

8. Primary end point is PFS. Target Hazard Ratio: 0.57
Sample size
Primary end point is PFS.
Target Hazard Ratio: 0.57
Median PFS in control arm: 4 months
Median PFS in experimental arm: 7 months
Power 80%
One-tailed alpha: 0.10
65 events needed for final analysis
77 patients need to be randomized
26 assigned to control arm
51 assigned to experimental arm
10 Institutions will contribute to patients’ enrolment.

9. Inclusion / exclusion criteria
Inclusion criteria
Histologically / cytologically confirmed carcinoma of the urothelium.
Measurable disease prior to the start of first- line chemotherapy.
Prior first-line chemotherapy of cycles of platinum-containing regimen (cisplatin or carboplatin).
No progressive disease following completion of first-line chemotherapy
Blood sample availability to determine germline BRCA mutation status.
Archived tumor tissue sample availability to determine HRD status.
ECOG performance status 0-1
Adequate bone marrow, liver and kidney function
Exclusion criteria
Known hypersensitivity to the components of Niraparib.
Known active hepatic disease.
Prior treatment with a known PARP inhibitor agent
Persisting toxicity related to prior therapy (G >1), however, alopecia, sensory neuropathy (G ≤2), or other (G ≤ 2) adverse events not constituting a safety risk based on the investigator's judgement are acceptable.
Diagnosis of any other malignancy within 5 years prior to randomization. 9

10. Thanks for your attention! 10