Challenges In The Development Of Novel Therapeutics In Ovarian Cancer Tony Ho, MD Global Medicine Leader Medi4736, Vice President, AstraZeneca

Size: px

Start display at page:

Download "Challenges In The Development Of Novel Therapeutics In Ovarian Cancer Tony Ho, MD Global Medicine Leader Medi4736, Vice President, AstraZeneca"

Brenda Hutchinson
6 years ago
Views:

Vice President, AstraZeneca The views and opinions expressed

1 Challenges In The Development Of Novel Therapeutics In Ovarian Cancer Tony Ho, MD Global Medicine Leader Medi4736, Vice President, AstraZeneca The views and opinions expressed herein are my own and do not necessarily represent those of AstraZeneca

2 Ovarian Cancer Long Journey with Multiple Treatments Quiescent tumours Surgery Chemo Chemo Chemo Chemo Chemo Chemo ~6 months ~6 months Neoadjuvant Median PFS (months) Estimated cytotoxic chemo-free period (chemo ~6 months) (months) Initial treatment Second line Third line Fourth line Fifth line Hanker et al. Annals Oncol 2012;23(10); : Three Phase III randomized trials n=1620

survival Treatment side effects Disease symptoms P =0.01 P =0.06 P =0.57 P =0.40 P =0.

3 Ovarian cancer patients want a better life Live better Live longer No active treatment (n=44) Active treatment (n=43) Quality of life Overall survival Progression-free survival Treatment side effects Disease symptoms P =0.01 P =0.06 P =0.57 P =0.40 P = Mean number of tokens assigned (out of 100) Havrilesky LJ et al. SGO 2014;abst 126

4 Natural Dilution Of Overall Survival (OS) Effects As Survival Post-progression (SPP) Increases Simulation assumption Simulated PFS at HR=0.67 Median SPP (months) Median OS HR (95% CI) ( ) ( ) ( ) ( ) ( ) Lynparza Study 19: PFS HR=0.18, P<0.001, SPP months Predicted OS HR=0.83 (using exponential distribution which underestimates HR) Actual OS HR=0.73, P=0.19, with 22.6% placebo patient cross -over; OS is a reasonable primary endpoint when median SPP is short, but it is too high a bar when median SPP is long (>12 months) Broglio KR & Berry DA. J Natl Cancer Inst 2009;101:

Potential Reason For PFS But No OS A PFS Intervention B PFS Intervention Dilution of treatment effects/ crossover/new intervention Natural history Natural history

5 Potential Reason For PFS But No OS A PFS Intervention B PFS Intervention Dilution of treatment effects/ crossover/new intervention Natural history Natural history Death Time OS Death Time C PFS Intervention D PFS Intervention Natural history? Death Time No OS Death Time OS detriment Matulonis, Oza,, Ho & Ledermann. Cancer 2014;

6 Randomization Intermediate Endpoints May Be Helpful In Demonstrating Benefit Beyond PFS Randomized population Support benefit of PFS is meaningful Help address concerns: The potential impact of treatment on subsequent therapy PFS (objective) TDT (subjective) TFST (subjective) PFS2 (objective) TSST (subjective) OS Chemo Maintenance treatment Chemo Second progression Chemo PFS2, time to second progression (or death); PSR, platinum-sensitive relapse; TDT, time to discontinuation of treatment (or death); TFST, time to first subsequent treatment (or death); TSST, time to second subsequent treatment (or death)

7 Intermediate Endpoints Demonstrated Continued Benefit Of Olaparib Beyond Progression And No Impact On Subsequent Therapy PFS 4.1 months Primary endpoint 11.2 months 6.9-month difference Placebo Lynparza 400 mg bid HR=0.18 (95% CI ), P< TFST Exploratory 6.2 months 15.6 months 9.4-month difference HR=0.33 (95% CI ), nominal P< TSST Exploratory 15.2 months 8.6-month difference 23.8 months HR=0.44 (95% CI ), nominal P= OS Secondary 31.9 months 3-month difference 34.9 months HR=0.73 (95% CI ), P= Time (months) Chemo Maintenance treatment Chemo Chemo Ledermann, 2014

8 Patient Reported Outcome (PRO) A conglomerate of many things not all measured by live better Can be any one of the following: - Symptoms Symptom progression is not health-related quality of life (HRQoL), just a subjective verification of PFS Symptoms of side effects are important, but it is not quality of life - HRQoL - Health status - Adherence to treatment - Satisfaction with treatment, etc

- Well-being The notion of multidimensionality is a key component of the definition of HRQoL Paper and electronic questionnaires as a way of collecting data

9 Health-related Quality Of Life Closest to live better but can we measure this better? Subjective perception of the impact of disease and its treatment(s) on: - Daily life - Physical functioning - Psychological functioning - Social functioning - Well-being The notion of multidimensionality is a key component of the definition of HRQoL Paper and electronic questionnaires as a way of collecting data may be passé patient may not need to report it actively - Our smart devices can tell us: Whether patients are spending time with family and friends and not going to hospital Whether patients are enjoying restaurants, museums, etc

10 Mathematical Oncology We Need To Go Early At the time of diagnosis, tumours may already be heterogeneous The probability of resistant clone emergence is a function of its size cells has much less probability of developing resistance than 1 million cells - Therefore, mathematically, sequential treatment with multiplemechanism drugs theoretically has less chance of cure than concomitant treatment with multiple-mechanism drugs Tumour size Thus, not only should we consider combination from the same pathways, we should also consider combination from multiple non-related pathways ( orthogonal combination ) Probability of escape if rate of resistance is 1 in 1,000, cells 0% 3 million cells Combination within the same pathway also increases toxicity, whereas combination of unrelated pathways does not result in overlapping toxicities 100%

11 Response ORR (%) rate (%) Olaparib ORR Decreases with Increasing Number of Prior Therapies in gbrcam Ovarian Cancer Patients Lynparza pooled analysis 80% 70% 60% 50% 40% 30% 20% 10% 0% Number of prior lines of chemotherapy Matulonis et al. SGO 2015;abst 4078

guardians ready to kill these awakening tumor stem cells even at single-cell stage Tumour size Probability of

12 Mathematical Oncology We Need To Focus On Dormant Cancer Cells During the watch and wait phase of ovarian cancer therapy, cancer stem cells may awaken and grow into new recurrence Olaparib maintenance therapy may act as guardians ready to kill these awakening tumor stem cells even at single-cell stage Tumour size Probability of escape if rate of resistance is 1 in 1,000, cells 0% 3 million cells 100% Chemo Olaparib maintenance Vs. watch and wait

13 Mathematical Oncology We Need More Guardians To Go For The Cure! Lessons from HCV First generation (1991): Interferon- monotherapy Second generation (1998): SVR 28 62% - Ribavirin (nucleotide analogue) + interferon- Third generation (2011): Triple combo SVR 75% - NS3/4A protease inhibitor + PEG IFN + ribavirin Fourth generation (2013) - Nucleotide analogue polymerase inhibitor + PEG IFN + ribavirin Fifth generation (2013): Triple combo SVR 90% - NS5B RNA-dependent RNA polymerase + ribavirin ± PEG IFN Latest generation (IFN-free regimen): SVR >90% - NS5A inhibitor + NS5B RNA-dependent RNA polymerase Olaparib or other targeted therapies (eg Wee1) maintenance Immunotherapy (eg anti-pdl1, CTLA4)? Anti-VEGF? HCV, hepatitis C virus; PEG IFN, pegylated interferon; SVR, sustained virological response

Update on PARP inhibitors: opportunities and challenges in cancer therapy

Update on PARP inhibitors: opportunities and challenges in cancer therapy Vanda Salutari Unità di Ginecologia Oncologica Fondazione Policlinico Universitario A. Gemelli vanda.salutari@policlinicogemelli.it