Prostate Cancer - Newer Antiandrogens & Emerging Therapies Targeting a “Watchful Waiting” and Resistance Population

Prostate Cancer - Newer Antiandrogens & Emerging Therapies Targeting a “Watchful Waiting” and Resistance Population

Xtandi – Replacing competitor from Zytiga to Casodex (Bicalutamide) for a bigger pie in Prostate cancer & Finding its niche in crowded BC market

Xtandi + Zytiga vs. ARN-509 + Zytiga - Who will win the race?

Rising star Anti Androgens – Third generation Antiandrogens- What left for AR-V7 mutants after TOK-001 failure?

Late Stage Prostate Cancer Pipeline drugs – AKT inhibitors or PARP inhibitors or a new MoA combination with Antiandrogen or IO combo - Competing to Xtandi/Zytiga or targeting Xtandi/Zytiga Resistance Population?

Increase in prevalence of Prostate cancer and availability of new treatment options (Zytiga, Xtandi, Cabazitaxel and Xofigo) in last few years has extended role of newer oral Antiandrogens to treat metastatic CRPC patient populations where the unmet need was high. This has expanded WW market size of Prostate cancer drugs to $7b in 2016 from $2.5b in 2011. Now nmCRPC, HSPC and Xtandi/Zytiga resistance population are the markets where in new pipeline drugs are under development.

Reported PhII clinical data of Xtandi, ARN-509 and ODM-201 in nmCRPC when indirectly compared demonstrate the bar is high for ARN-509 to compete against Xtandi in nmCRPC market and while ODM-201 is few years behind in clinical development. While in mHSPC reported clinical results of STAMPEDE study opens door for docetaxel combination approach as standard of care in first line setting.

Around 8 plus drugs are in PhIII development for Prostate cancer treatment and 26 plus drugs are in PhII development (21 small molecules) - success of a few (ARN-509, ODM-201, AZD 5363, GX301) in coming years will expand nmCRPC ($3.5be), mHSPC market ($1be) and Xtandi/Zytiga resistant population ($1be) market by 2023. Longer duration of therapy and high prevalence makes earlier setting market more attractive and bigger for newer options than the late stage if they succeed.

For drugs targeting through androgen pathway - Now trials and clinical development is underway for second and third generation androgen receptor inhibitors (ARN-509, ODM-201, ODM-204, EPI-506, VT-464, TAS-3681 and DR103). While androgen synthesis inhibitors still needs a proof of concept in clinic due to failure of TAK-700 & TOK-001. Expected data from VT-464 (Apr 2017) & ASN-001 will be important to watch to taste the success for this class. Androgen receptor degrader is another MoA in development from a decade and success of in clinic compound GTX-758 (Data expected anytime from now as study completed in March 2016- less likely to succeed) will decide the proof of concept.

Other than pipeline drugs targeting androgen pathway, NCE targeting AKT pathway (AZD5363, Ipatasertib) appears to be more promising to succeed in late stage, while drugs acting through PARP inhibition (Olaparib, Niraparib) still needs a taste of success. Other interesting pipeline asset is LHRH agonist LMIS 50 mg, which is designed to overcome the drawbacks of the commercial depot products containing GnRH agonists by using a proprietary delivery system.

Also 6 therapeutic vaccines are in clinical development to treat prostate cancer. Recently launched PD-L1 IO therapy has increased hope of treating cancer in much safer way. Current ongoing studies of late stage IO mab are in Ph I/II clinical development and would be able to answer of PTEN hypothesis for role of PD-1, PD-L1 inhibitor to treat prostate cancer in coming years.

Resistant development is another challenge with long term use of Xtandi/Zytiga and needs to be addressed by pipeline second/third generation Antiandrogens/ combination approach with IO/PARP/AKT inhibitors to treat mCRPC. Increase in pricing pressure in developed market again put inference on Combination approach unless the advantage is significant and improve the Q0L in earlier setting. Due to that, drugs targeting adjuvant setting has high bar to deliver (Atezolizumab, GX301, Mipsagargin and Olaparib) in the clinical development to add significant value.

This report details current unmet need, changing regulatory requirement, reimbursement challenges & market dynamics of Prostate Cancer drugs. Report mention pipeline Antiandrogens, late stage prostate cancer pipeline drugs/new Mechanism of action & major companies developing Prostate cancer drugs. It also provides insight on clinical development strategy of combination pipeline/marketed drugs & therapeutic competitive landscape to find treatment paradigm fit & market potential of new drugs for treatment of Prostate Cancer

1. Executive Summary
Antiandrogens- Expanding Role of new Oral Antiandrogens in early treatment armamentarium of Prostate Cancer and Other indications-
Current Role of Oral antiandrogen therapy and its limitations
nmCRPC and HSPC- Next growth driver of New Oral Antiandrogens – ARN-509 or Xtandi or ODM-201- Who will win the race?
WW Targeted Patient population and expected Market size expansion of Anti androgens in each stage
Zytiga patent expiry – Game Changer in Antiandrogen Class
New Pipeline early stage Antiandrogens
Targeting Xtandi and Zytiga Resistance population- A way to Fast track drug development?
Immuno-Oncology drug –Potential in Prostate Cancer and ongoing combination studies with Antiandrogens & with Pipeline Prostate Cancer drugs
ther Late stage Pipeline drugs for treatment of Prostate Cancer- AKT inhibitors or PARP inhibitors or a new MoA combination with Antiandrogen- Competing to Xtandi/Zytiga or targeting Xtandi/Zytiga Resistance Population?
2. Prostate Cancer
Stages of prostate cancer
Signs and symptoms of prostate cancer
Causes of prostate cancer
Treatment of prostate cancer
Unmet need of prostate cancer
Current market size of prostate cancer
3. Xtandi
Xtandi – current uptake
Xtandi current US prescription trend and its uptake
Xtandi Price issue
Xtandi uptake in Europe
Xtandi uptake in Japan
Xtandi- additional opportunities in Prostate Cancer
Xtandi in nmCRPC- PROSPER study
Urology opportunity / Xtandi as a preferred urology drug
Xtandi Market Potential in nmCRPC
Xtandi Price Issue in nmCRPC
Xtandi duration of therapy in nmCRPC
Xtandi – additional clinical trials in Prostate Cancer
Xtandi in M1 Hormone Sensitive patients
Xtandi in Mo Hormone Sensitive patients
Xtandi other ongoing clinical studies
Xtandi with Pfizer early stage Prostate cancer Pipeline drug
Xtandi in Other Indications
Xtandi Potential in Breast Cancer
Xtandi in Hepatocellular Carcinoma
Xtandi in combination with New pipeline drugs
Xtandi with IO combo- please refer chapter no. 7
4. Zytiga +ARN-509- How big is it has potential to change the treatment paradigm of Prostate Cancer? A competitive threat post Zytiga patent expiry for Xtandi?
Zytiga generic entry: An opportunity for ARN-509 or A threat for JNJ?
Zytiga patent Expiry- more worries for early entry in US market than Ex-US
Use patents of Zytiga : the 438 Patent
ngoing clinical trial of Zytiga with ARN-509
ngoing clinical trials of Zytiga with Xtandi
New formulation under development for Zytiga/Xtandi
Combination studies of Zytiga with other targeted therapy vs. combination study of Xtandi with other targeted therapies, Ongoing Clinical trials
Combination of Zytiga with Onapristone
5. Pipeline Antiandrogens: Androgen Receptor Inhibitors vs. Androgen Synthesis inhibitors-
Androgen Receptor inhibitors: Who could be the major threat to Xtandi?
ARN-509- A better Xtandi is in making
Ongoing Clinical trials of ARN-509 and our expectations
ARN-509- Clinical data comparison vs. Xtandi and other pipeline candidates
ODM-201- Does its safety differentiate it against ARN-509/Xtandi?
ODM-201 and ODM-204 has potential to challenge current leader Xtandi and Zytiga
EPI-001 and EPI-506
GT0918 (Proxalutamide)
ther early stage pipeline Antiandrogens and our view –
HE3232 (Apoptone)
Androgen Synthesis inhibitors: TAK-700 and TOK-001 Failure in clinical trials creates “No hope” for VT-464 & other Cyp17 lyase inhibitor?
TAK-700- How it is different from Zytiga?
Selective Androgen Receptor Degraders
Indirect near term key competitors to Zytiga/Xtandi in Post chemo setting:
PROTAC (Proteolysis Targeting chimera) platform of ARVINAS pharmaceutical
6. Targeting Xtandi and Zytiga Non Responder and Resistant population
Causes of resistance -Emerging mechanisms of Resistance to Xtandi/Zytiga
How do the Mechanism of resistance to the Zytiga and Xtandi differ and do some of them overlap?
Can AR-V7 splice biomarker be used to determine whether Xtandi and Zytiga will work??
What other studies are looking at different ways to overcome resistance??
Who will win the race for AR-V7 variant mCRPC??
7. Combination of drugs with IO therapy
Durvalumab with or without Tremelimumab
Atezolizumab (Tecentriq)
8. New pipeline drugs
AZD 5363
ADXS31-142 (ADX-PSA)
[68Ga]RM2 or Ga-bombesin
Recombinant adenovirus (Ad5-SGE-REIC/Dkk3)
Mobilan (M-VM3)
Dendritic cells DCVAC
LMIS 50 mg
DX (Osteodex)
BHR-200 (transdermal estradiol gel)
Mipsagargin (G-202)
99mTc-MIP-1404 injection
PectaSol –C Modified Citrus Pectin
laparib (Lynparza)
TAK-385 (Relugolix)
Ipatasertib (GDC-0068, RG7440)
Zoptrex (Zoptarelin doxorubicin)
Companies mentioned:
Valeant pharmaceuticals
Turing pharmaceuticals
Johnson & Johnson
Tokai pharmaceuticals
Bayer pharmaceuticals
Teva pharmaceuticals
Bind therapeutics
NanoString Technologies
Zenith Technologies
Par pharmaceuticals
Citron pharma
Dr. Reddy’s Laboratories
Sun pharma
Amneal pharmaceuticals
West-ward pharmaceuticals (Hikma pharmaceuticals)
Hetero Labs.
BTG International Ltd.
Janssen pharmaceuticals
Amerigen pharmaceuticals
Aragon pharmaceuticals
Arno Therapeutics
Invivis pharmaceuticals
Orion pharmaceuticals
Endo pharma
ESSA pharma
Jiangsu Hengrui Medicine Co.
Suzhou Kintor pharmaceuticals Inc.
Allchem pharma
Harbor Bioscience
Bristol-Myers Squibb pharma
Takeda pharma
Viamet pharmaceuticals
Innocrin pharmaceuticals
Asana Bioscience
GTx pharma
OncoGenex pharmaceuticals
Taiho Oncology
Arvinas pharmaceuticals
Roche pharmaceuticals
Merck pharmaceuticals
Sotio pharma
Foresee pharmaceuticals
Progenics pharmaceuticals
Bavarian Nordic
Mediolanum S.p.A
Piramal Imaging S.A
Panacela Labs
BHR pharma
DexTech Medical AB
ATLAB pharma
Madison Vaccines
Millennium pharmaceuticals
Eli Lilly Company
Inspyr Therapeutics
Momotaro-Gene Inc.
Tyme Technology
Aeterna Zentaris Inc.

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