Prostate cancer (PCa) is now recognised as one of the most important medical problems facing the male population. When advanced PCa progresses despite treatment with androgen deprivation therapy (ADT) strategies (ie, surgical or medical castration, and use of anti-androgens), or new metastases appear, the disease is referred to as castration-resistant PCa (CRPC; also known as hormone-refractory PCa, androgen-independent PCa or androgen-insensitive PCa).
Patients with CRPC currently have few treatment options, and there is an unmet medical need in this area for new compounds that target the cancer differently and offer alternative therapeutic options for patients at this late stage of PCa.
Historically, CRPC has been associated with a median survival of less than two years. Prior to 2004, there was no treatment proven to improve survival for patients with metastatic CRPC. A new regimen comprising docetaxel (taxane) and prednisone was approved for use in such patients in 2004, becoming the new standard of care for metastatic CRPC.
Given the many ways that PCa cells can adapt to cellular stressors (eg, androgen deprivation, taxane-based chemotherapy, hyperoxia, unfavourable tumour microenvironments), current and emerging therapies are now beginning to address these mechanisms individually.
There are a number of therapies currently in phase III clinical trials or in late-stage development (preregistration or recently approved) for CRPC, including novel androgen receptor (AR)-targeted therapies, inhibitors of alternative signalling pathways, inhibitors that target the bone microenvironment, and immunotherapeutic agents.
Game-changing agents
Four new agents that were approved by the US Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) during 2010 and 2011 became part of physicians’ therapeutic arsenal for metastatic CRPC in 2012. These new agents are sipuleucel-T (immunotherapeutic agent), cabazitaxel (taxane chemotherapeutic), abiraterone acetate (androgen synthesis inhibitor) and denosumab (bone-targeting agent).
Sipuleucel-T (Provenge) is an autologous prostatic acid phosphatase (PAP)-loaded dendritic cell vaccine developed by Dendreon Corporation for treatment of metastatic CRPC. It was specifically designed to stimulate destruction of cancer cells, while leaving healthy cells unharmed. Sipuleucel-T was launched in the US, its first market, in May 2010 for treatment of asymptomatic or mildly symptomatic metastatic CRPC. Dendreon is awaiting registration in the EU for this indication.
Cabazitaxel (Jevtana; sanofi) is a third-generation taxane chemotherapeutic that is available as a second-line therapy in the US, UK, Germany and France for treatment of metastatic CRPC (in combination with prednisone or prednisolone) in patients previously treated with a docetaxel-containing regimen. Approval for this indication has also been granted in the rest of the EU, Australia, Canada, Israel, Brazil and Curacao. Cabazitaxel is also being assessed in a global phase III trial (FIRSTANA) as a first-line therapy (in combination with prednisone) in patients with metastatic CRPC.
Abiraterone acetate (Zytiga, Cougar Biotechnology; Janssen Research & Development) targets the AR-directed pathway and is a potent and irreversible inhibitor of CYP17, a critical enzyme involved in testosterone production. In July 2011 it was launched in the US as a second-line therapy (in combination with prednisone) in patients with metastatic CRPC who had received prior docetaxel therapy. Janssen also submitted regulatory applications in the EU and US in June 2012, seeking approval for use as a first-line therapy (in combination with prednisone) for metastatic CRPC in patients who are asymptomatic or mildly symptomatic following failed ADT. The FDA subsequently granted priority review status for this first-line CRPC indication.
More than 80 to 90 per cent of patients with metastatic CRPC will develop bone metastases, resulting in substantial morbidity and a significant detrimental effect on quality of life. Therefore, considerable hope was offered when the US FDA approved denosumab (Xgeva; Amgen) for the prevention of skeletal-related events in patients with solid tumours (including men with metastatic CRPC) and bone metastases in November 2010.
Amgen later submitted an application seeking approval for a line extension – specifically for prevention of bone metastases in patients with non-metastatic CRPC. However, the FDA declined to approve the application in April 2012, citing an insufficient effect on metastases-free survival after considering the adverse events risk. Denosumab is already available as a treatment to increase bone mass in patients with non-metastatic PCa who are receiving ADT and are at high risk for bone fractures.
AR-targeted therapies
Evidence of persistent hormone dependence in metastatic CRPC has opened the way to the development of new antiandrogens that block testosterone synthesis not only by testes, but also by adrenal glands and prostate tumour tissue.
Enzalutamide (Xtandi) is an oral, AR antagonist under development at Medivation. In September 2012, it was launched in the US for the treatment of metastatic CRPC in patients who have previously received docetaxel. A regulatory application has also been filed in the EU for this indication.
Both the US and EU submissions were based on data from the phase III AFFIRM trial, which showed that enzalutamide was associated with a statistically significant 4.8 month benefit in overall survival, compared with placebo.
Orteronel (TAK 700; Takeda, Millennium) is an oral cytochrome P450 C17 (CYP17) inhibitor similar to abiraterone acetate that is in phase III clinical trials for both first- and second-line treatment of metastatic CRPC. CYP17 is an enzyme that catalyses two key steroid reactions in the androgen biosynthesis pathway.
AR-independent therapies
In addition to AR-mediated pathways, evidence suggests that several alternative signalling pathways may also be involved in progression of PCa. Whether or not these pathways are truly independent of the AR or downstream components of AR signalling has not been fully elucidated, but this may vary by pathway.
Cabozantinib (XL 184; Exelixis) is an orally active, small molecule chemotherapeutic agent in clinical trials for the treatment of various forms of cancer. Its mechanism of action involves inhibition of multiple tyrosine kinases, primarily c-MET, vascular endothelial growth factor receptor (VEGFR)-2 and RET.
Tyrosine kinases stimulate multiple signalling pathways responsible for basic cells functions. c-MET plays a key role in cellular proliferation, migration and angiogenesis, and is mutationally activated in various tumour types. Expression of VEGF has been observed in a variety of cancers, while RET is mutationally activated in both familial and sporadic forms of medullary thyroid cancer (lead development indication).
Patients with CRPC currently have few treatment options and there is unmet medical need …
In 2012, two pivotal phase III trials of cabozantinib for treatment of metastatic CRPC were carried out. The first trial (COMET-2) started in January and will evaluate cabozantinib versus mitoxantrone plus prednisone in 246 men from the US, Canada and the UK with previously treated symptomatic CRPC. The second, US-based trial (COMET-1) was initiated in June and will assess cabozantinib versus prednisone on overall survival in men with previously treated metastatic CRPC with bone-dominant disease.
Another oral tyrosine kinase-targeting compound in phase III development for metastatic CRPC in combination with docetaxel is Bristol-Myers Squibb’s dasatinib (Sprycel), which acts as an inhibitor of tyrosine kinase (including Src).
As with the majority of cancers, angiogenesis and the VEGFR pathway play a key role in CRPC progression and metastasis. Two late-stage candidates targeting these pathways include: tasquinimod (Active Biotech), an orally administered angiogenesis inhibitor; and aflibercept (Regeneron Pharmaceuticals), an intravenously administered VEGF-A inhibitor.
Custirsen (Teva Pharmaceutical Industries, OncoGenex Pharmaceuticals) is a second-generation antisense oligonucleotide compound that is in phase III clinical trials for both first- and second-line treatment of metastatic CRPC. Custirsen inhibits the production of clusterin, which acts as a cell survival protein and is overexpressed in a number of cancers (including PCa).
Targeted immunotherapies
Cancer immunotherapy broadly refers to approaches that attempt to treat cancer by activating an immune response against malignant cells, while overcoming tumour-induced tolerance. PCa may be considered an ideal target for immunological attack as several tissue-specific proteins are produced that may serve as tumour antigens, including prostate-specific antigen (PSA; marker of PCa) and PAP. This notion was applied to the development of sipuleucel-T, among other therapies.
A recombinant pox virus vaccine encoding human PSA called rilimogene galvacirepvec-rilimogene glafolivec (Prostvac; BN ImmunoTherapeutics, US National Cancer Institute) is another immunotherapeutic agent in phase III development for metastatic CRPC. The vaccine consists of two components that are sequentially dosed; vaccinia-PSA (V) primes/generates an initial immune response (rilimogene galvacirepvec), and fowlpox-PSA (F) boosts the response (rilimogene glafolivec).
Ipilimumab (Bristol-Myers Squibb) is an anti-CTLA-4 monoclonal antibody in phase III development as a first- and second-line therapy for metastatic CRPC. Ipilimumab blocks the effects of the negative T-cell regulator CTLA-4, which enhances T-cell-mediated immune responses to tumour cells.
Bone-targeting therapies
The vasoactive peptide endothelin-1 (ET-1) is produced by metastatic cancer cells in the microenvironment of new-formed bone, through the stimulation of the endothelin A receptor (ETAR) and its downstream pathways in osteoblastic cells. AstraZeneca is developing zibotentan, an oral, selective ETAR antagonist in phase III trials for CRPC.
Another bone-targeting agent in phase III trials of use in patients with CRPC and bone metastases is radium-223 chloride (Alpharadin; Algeta, Bayer Healthcare), a first-in-class, highly targeted alpha-emitting radiopharmaceutical.
Path to further success
The treatment paradigm for metastatic CRPC is rapidly evolving thanks to already approved and emerging therapies in clinical development. However, the availability of multiple new therapies for metastatic CRPC presents new challenges for clinicians, who now have several factors to consider when deciding on the best treatment option for their patients (eg, ideal combinations, sequencing and optimal timing).
It is becoming increasingly apparent that CRPC is a heterogeneous disease and patient subgroups are likely to exist that are characterised by the involvement of different signalling pathways in disease progression to different degrees. This suggests that a more rational or individualised approach is required to maximise potential benefits from targeted therapy for CRPC.
The Author
R&D Pipeline was written by Asha Vaidya of Adis International (Springer Healthcare) using data derived from Adis R&D Insight and Clinical Trials Insight. For further information on Adis services, please contact Daniela Ranzani on +39 02 423 4562 or email: Daniela.Ranzani@springer.com