Saturday, October 30, 2010

The Prostate Cancer: New drugs in the post “Abiraterone-Jevtana-Provenge” world

The success of three new drugs (Abiraterone, Jevtana and Provenge) for castration-resistant prostate cancer (CRPC) this year, each targeting different pathways, and all showing an overall survival benefit, has raised the bar for those dreaming to join the club.  There is at least one riding the popularity vote, MDV3100, which may complete phase 3 next year.  Still, many struggle and plough through phase  1 and 2.  One way to understand, what may make some of them unique – and the reason they may evolve into serious competition one day – is to lay them out in separate classes or targets.  This is what I have done below.

Background: CRPC patients have failed the first-line treatment, surgical (orchiectomy) and/or biochemical (LHRH agonists or antagonists) castration.  Antiandrogens provide CRPC patients small-term relief before the disease ramps up again.  Most patients, having exhausted all options and who die from prostate cancer, die from fracture-prone tumors in the bone – prevention of bone metastasis is also a serious “goal” in this battle.  In CRPC, the cancer cells develop AR receptor alterations (higher expression levels or mutations that make them androgen-independent or responsive to other steroids including drugs used as competitive agents to testosterone), PTEN loss, upregulation of angiogenic and other growth factors, co-activators, etc – these are the potential achilles' heels for designing and developing newer drugs.  Docetaxel (Taxotere; Sanofi-aventis) increases survival in CRPC patients, who may have failed antiandrogen therapy, by 18 months.  Docetaxel has been the standard of care, up until the big three – Abiraterone, Jevtana and Provenge – emerged on the scene. 

What else is on the horizon.

Chemotherapeutics (Epothilones):
  • Cabazitaxel (Jevtana; Sanofi-Aventis) is a taxane that binds and stabilizes tubulin, interfering with cell division, and differs from other chemo drugs which generally target DNA.  It has set a bar for this class by showing improved survival in the phase 3 TROPIC trial (15.1 months with cabazitaxel plus prednisone  vrs 12.7 months in the mitoxantrone plus prednisone, Sept 2010)  [...][...]
  • In pipeline:  Patupilone, ixabepilone and sagopilone are also microtubule binding agents like cabazitaxel.  These compounds have shown activity in phase 2.

Androgen production inhibitors
  • Abiraterone acetate (Johnson & Johnson) inhibits CYP450c17 blocking androgen production in testis, adrenals and elsewhere.  So far, best in its class, it improved survival in recent phase 3 trial (14.8 mo abiraterone plus prednisone vrs 10.9 mo prednisone plus placebo, Oct 2010) [...]

Androgen Receptor antagonists, competitive inhibitors etc.
This is a big class with many compounds out in clinic but they have limited efficacy.
However, CRPC tumors are not uniformly hormone resistant.  Therefore, several 2nd generation anti-androgen and AR blockers are in pipeline.
  • MDV3100 (Medivation and Astellas Pharma), a 2nd generation AR antagonist, inhibits androgen binding to AR, nuclear translocation of AR and also blocks binding of AR to DNA.  It may turn out to be the best in this class.  Phase 3 results are expected soon. [...][...]
  • ARN-509 (Aragon) also a 2nd generation AR antagonist, is in phase 1/2 [...]
  • Apoptone (HE3235; Harbor Biosciences) is an androstenediol analog; it reduces AR gene expression, steroidogenesis (T and DHT) in tumor tissue and inhibits conversion of cholesterol to pregnanolone (steps upstream of androgenesis).  It is in phase 2 trial. [...][...][...]

Angiogenesis and growth factor antagonists
  • Anti-VEGF therapies developed (and some already FDA approved) for other solid tumors are now also being tested in CRPC trials.  VEGF inhibitors, bevacizumab, aflibercept (VEGF-trap; Regeneron) and multikinase inhibitors, sunitinib and sorafenib, and pan-VEGFR ihhibitor, cediranib are in phase 2 or 3 trials. Lenalidomide (a thalidomide analog) is in phase 3 in combination with docetaxel.
  • Atrasentan (ZD4054; AstraZeneca ) is an endothelin A (ETA) receptor antagonist.  It is in phase 3 metastatic CRPC trial ENTHUSE which started in Sept 2007 [...]  Endothelin-1 (ET-1) binds ETA and regulates various functions, including, hormone production and prostate endothelial and cancer cell proliferation.
  • KX2–391 (Kinex), a small molecule Src inhibitor, is in Phase 2 trials for bone-metastatic CRPC.
  • Dasatinib (Sprycel, BMS-354825; Bristol Myers Squibb), an inhibitor of BBRC/ABL kinase and p60Src, and AZD0530 (targets Src and Abl tyrosine kinase) are in early trials for prostate cancer.

Alternate escape pathways
Pathways – epigenetic, heat-shock proteins, HDAC, repair enzymes, etc –  that are induced as a consequence of antiandrogen, anti-angiogenic treatments.
  • Romidepsin (Istodax, FK228, FR901228; Celgene), an HDAC inhibitor, was tested in phase 1.
  • OGX-427 (OncoGenex ), an antisense agent, reduces production of Heat Shock Protein 27 (Hsp27).  It is in phase 2 advanced prostate cancer trial (Sept 2010). [...]
  • Custirsen (OGX-011/TV-1011, OncoGenex and Teva) is an antisense mRNA targeting clustrin mRNA.  Clusterin is a stress-induced chaperone protein.  It is in phase 3 SYNERGY trial as a first line therapy for CRPC [...]

Immunotherapies, vaccines and anti-prostate antigen antibodies
  • Sipuleucel-T (Provenge, Dendreon) is now the yardstick for others in this class.  It is an autologous cellular immunotherapy.  The patient's peripheral mononuclear cells are isolated and exposed to the prostate antigen Prostate Acid Phosphatase (PAP) and GM-CSF; the activated cells (vaccine) are then injected back in to the patient.  In phase 3, it extended median survival by 4.1.  It was FDA approved in April 2010 [...
  • PROSTVAC-VF vaccine (BN ImmunoTherapeutics, Inc., of Mountain View, Cal.) contains poxvirus expressing PSA and three immno costimualtory molecules on vector's surface.  Promising results were obtained in phase 2 (Jan 2010) [...]
  • TroVax (Oxford BioMedica), a gene therapy approach,  is a Modified Vaccinia Ankara (MVA) containing a prostate antigen 5T4.  Promising reults were obtained in phase 1/2 (Oct 2008) [...]
  • Ii-key hybrid HER2/neu peptide and AE37 vaccine peptide (Antigen Express, a wholly owned subsidiary of Generex) is being tested in phase 2 trials. [...]  The target of AE37 is Her2.  AE37 peptide vaccine stimulates the immune system to recognize tumor cells expressing HER2, including those with a lower expression of HER-2 (unlike Herceptin, that requires overexpression of Her-2/neu)
  • PORxin (PRX302) (Protox and Kissei Pharma) is a PSA activable pore-forming prodrug delivered directly in to the prostate.  It is in phase 2 trial for localized prostate cancer.
  • GDEPT or “gene-directed enzyme pro-drug therapy” (Broadvector, Australia) is in early trials. [...]
  • One online recent report (BioPortfolio)  lists 30 vaccine candidates in development [...]

Others and alternate therapies
  • Alpharadin (Algeta of Norway and Bayer Schering Pharma AG) is an injectable treatment based on Radium-223, an alpha-particle emitting pharmaceutical.  It has entered phase 3 (Nov 2010) [...]
  • Denosumab (Amgen) increases bone density, cuts fracture risk in prostate cancer survivors and is being tested to see if it can also prevent bone metastasis (Aug 2009)[...]
  • Zyflamend (sold by New Chapter) is an herb-based therapeutic; it is on its way to Phase 2 [...]
  • Asentar (DN-101; Novacea) a.k.a. ‘Sunshine Pill’ contains 50-100 times the normal vitamin D supplement pill.  In the phase 2 trials, Asentar significantly improved survival rates by 9 months compared to patients taking chemotherapy drugs (taxotere) alone.  It was in phase 3 (Jan 2007) [...]

Further Reading
Castration-refractory prostate cancer: New Drugs in the pipeline (2010) Adv Ther 27(5) | DOI | Scholar |

Algeta, Oslo, Norway - Alpharadin
Amgen, Thousand Oaks, Calif - Denosumab
Antigen Express,  Worcester, Mass - AE37
Aragon Pharmaceuticals, San Diego, Calif - ARN-509
Astellas Pharma US, Inc - MDV3100
AstraZeneca - Atrasentan, Cediranib
Bayer - Sorafenib, Sagopilone (ZK-EPO)
Bayer Schering Pharma AG  - Alpharadin
BN ImmunoTherapeutics (Bavarian-Nordic), Mountain View  Calif - PROSTVAC-VF
Bristol Myers Squibb - Dasatinib, ixabepilone
Broadvector Ltd., Melbourne, Australia - GDEPT
Celgene Corp. - Romidepsin, Lenalidomide
Dendreon Corp., Seattle, WA - Provenge
Genentech - Avastin
Generex Biotechnology Corp. - AE37
Harbor Biosciences, San Diego, Calif - Apoptone
Johnson & Johnson - Abiraterone acetate
Kissi Pharmaceutical Co Ltd, Japan
Kinex Pharmaceuticals, Buffalo, NY- KX2–391
Medivation, Inc, San Francisco, Calif - MDV3100
New Chapter, Brattleboro, VT- Zyflamend
Novacea Inc, South San Francisco, Calif - Asentar 
Novartis - patupilone  (EPO906)
OncoGeneX Pharmaceuticals, Bothell, WA and Vancouver, British Columbia - OGX-011, OGX-427
Oxford BioMedica, Oxford, UK - TroVax
Pfizer - Sunitinib  
Protox Therapeutics, Vancouver, BC - PORxin 
Regeneron - Aflibercept 
Sanofi-aventis, Bridgewater, NJ - Jevtana , Taxotere 
Teva Pharmaceuticals, Petach Tikva, Israel - Custirsen 

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