Advances in Metastatic Castration Resistant Prostate Cancer (mCRPC) Management

– By Sonali Karhana –

Despite recent diagnostic and therapeutic advances, prostate adenocarcinoma is the second most common cancer in the Western male population. One in 7 men over the age of 50 years are diagnosed with prostate cancer at some point in their lives. “The first step toward ending this disease, which takes the lives of nearly 30,000 men each year, is to raise awareness with family, friends, and in our community” says Robert Ginyard, Chairman of ZERO, a Alexandria, VA based non-profit organization that raises awareness against the fight to end prostate cancer

The majority of newly diagnosed cases (80-90%) are localized prostate cancer, and the remaining cases are advanced or metastatic disease. Advanced prostate cancer includes a wide spectrum of the disease ranging from hormone naïve or hormone sensitive to castration resistant, both containing populations of men who have demonstrable metastatic and non-metastatic states. Castrate-resistant Prostate Cancer (CRPC) is defined by disease progression despite androgen-deprivation therapy (ADT) and may present as one or any combination of a continuous rise in serum levels of prostate-specific antigen (PSA) progression of pre-existing disease, or appearance of new metastases.

There have been significant strides in the management of prostate cancer over the past decade. The US FDA has approved six new agents with varying mechanisms of action; namely

Sipuleucel-T, Abiraterone acetate, Enzalutamide, Cabazitaxel, Radium-223, and Apalutamide. There are now multiple treatment options and possible novel therapies

Compounds Targeting Androgen Signaling

Resistance to ADT calls for pharmacological intervention of androgen receptor (AR) signaling. Three trials have been completed with

(a) ADT +/ Abiraterone acetate + prednisolone and ADT +/Abiraterone acetate + prednisolone + enzalutamide in mCRPC

(b) Abiraterone acetate + prednisone/prednisolone in mCRPC post chemotherapy

There are ongoing trials with Apalutamide and Daralutamide

Signaling Pathway Inhibitors

Ongoing trials include Buparlisib, Apitolisib or Ipatasertib +/Abiraterone acetate + Prednisone/prednisolone, Sirolimus + docetaxel + carboplatin, Ridaforolimus, Ridaforolimus + bicalutamide, Temsirolimus, Temsirolimus + Cixutumumab, Everolimus + Docetaxel, Everolimus + Bevacizumab, Everolimus + Carboplatin

DNA Damage Repair Pathway

DNA damage response (DDR) defects have a comparatively high incidence in advanced prostate cancer patients. Efforts to address this liability in the clinic are based on blocking the poly ADP ribose polymerase (PARP) family. Drugs under trial include Olaparib, Veliparib, Rucaparib and Niraparib; alone or in combination with other agents

Epigenetic Mechanisms

Epigenetic events are the main cause in gene regulation and the three most epigenetic mechanisms studied include DNA methylation, histone modifications and microRNA expression. Epigenetic drugs that inhibit DNA methylation, histone methylation and histone acetylation may reactivate silenced gene expression in prostate cancer. However, further understanding of interactions of these enzymes and their effects on transcription regulation in prostate cancer is required

Targeted Alpha Therapy Approach

Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment options for many cancer types. Radium (223Ra) is the first alpha-emitting therapy proven effective in human cancer. Radium-223 dichloride is a targeted alpha therapy administered intravenously. Prospective randomized trials indicate that 223Ra, which concentrates after intravenous injection in areas of osteoblastic metastatic disease, can prolong survival in bone-dominant castrate resistant prostate cancer patient. Combination studies for radium-223 dichloride and different checkpoint inhibitors including pembrolizumab and atezolizumab are ongoing

Prostate-Specific Membrane Antigen (PSMA) Targeting Approaches

Prostate-specific membrane antigen (PSMA), a membrane-bound protease is overexpressed on malignant prostate tumor cells and its expression rate correlates with the aggressiveness of the disease. Advance research in PSMA targeting range from immunotherapeutic approaches to therapeutic small molecules. First clinical studies with a PSMA-targeting Antibody-drug conjugates had positive results but pivotal phase 3 study has not been initiated. PSMA-targeting small molecule ligands or antibodies labeled with radionuclides have been evaluated in several clinical studies. A novel alpha therapy approach deals with a thorium-227-labeled PSMA antibody.

Chemotherapy

Docetaxel and Cabazitaxel were approved by the FDA for mCRPC in 2004 and 2010, respectively. Mitoxantrone has limited survival benefit in prostate cancer patients compared to docetaxel and has significant adverse effects

Immunotherapy

Immunotherapeutics for the treatment of mCRPC has made significant progress since the autologous cell-based vaccine Sipuleucel T became the first and to date only immunotherapy for its treatment (Sipuleucel-T was approved in 2010 for mCRPC by US FDA). However, high cost of therapy and complex procedure limits its usage. Pasero et al showed that a strong immunosuppressive environment impairs NK cell function at multiple levels in prostate cancer that hypothesizes a rationale for the design of therapies that restore NK cell efficiency in the prostate tumor microenvironment.

Nonetheless, given the strong survival advantage provided by therapies with immune checkpoint inhibitors in different cancer types, the potential benefits of immunotherapy are also being evaluated in prostate cancer. First studies with the anti-CTLA4 antibody Ipilimumab showed some promising results in early clinical evaluations addressing prostate cancer patients, but no improved overall survival could be determined afterwards in larger studies even though complete remission was observed in a few cases. The anti-PD-1 antibody pembrolizumab is being investigated in two clinical trials and durable responses have already been reported in patients with metastasized prostate cancer. Importantly, pembrolizumab recently received a tissue-agnostic approval for mismatch repair-deficient solid tumors, so that advanced prostate cancer patients belonging to this group can also be treated with this drug. Early clinical studies are ongoing with anti-PD-L1 antibodies -Atezolizumab, Durvalumab and Avelumab for treatment of metastatic prostate cancer

Immune Checkpoint Inhibitors based on CTLA-4 and PD-1/PD-L1 blockade in prostate cancer

Zumutor is poised to take their IO molecule to pre-clinical studies