Prostate cancer treatments in era of precision oncology

Avishek Roy

Scientific Liaison Manager
4baseCare

Prostate cancer is the second most frequent cancer among males. Patients diagnosed with metastatic cancer have a poor prognosis, with a five-year survival of 30%. Recent advances in both diagnosis and therapy have indeed prolonged survival of prostate cancer patients. Prostate cancer has entered a new phase with the development of molecular markers. In the era of precision oncology, stratification of metastatic prostate cancer patients using molecular testing has played a central role. Precision medicine makes use of new diagnostic tests to treat the appropriate patient with the right treatment at the right time, based on the biology of the malignancy. Because traditional medicine’s one-size-fits-all strategy to treating prostate cancer has failed to serve patients, the need of the hour was to establish a precision medicine approach that will benefit patients in the long run. Precision diagnosis examines your tumor’s genetic and molecular markers (uniquely altered genes and uniquely expressed proteins) and using that knowledge to determine the tumor’s vulnerabilities. Precision medicine’s promise might be fulfilled by new genomic and proteomic tools, gene editing technologies, non-coding RNA diagnostics and therapies, and liquid tumor profiling.

Prostate cancer treatment is quickly evolving, with significant progress being made in understanding the genetic landscape and biology that underpins both primary and metastatic prostate cancer. Mutations in genes that repair damaged DNA (known as DDRs or DNA damage repair genes) have been found in 25%–30% of metastatic prostate cancer patients. For example, the somatic mutations in DNA repair genes such as BRCA1/2, NEIL3, ATM, and ATR have been detected in prostate cancer patients, with BRCA2 mutations (12%) being more common than BRCA1 mutations (2%) in advanced prostate cancer patients. Castro et al (2013) investigated the status of BRCA1/2 in 2019 prostate cancer patients, and they confirmed the presence of BRCA mutations in aggressive phenotype, with poor survival outcomes. Fortunately, with the advent of precision medicine patients are able to have their malignancies analyzed for mutations that make them responsive to specific medications. Treatments for mutations in genes including PTEN, PIK3CA/PIK3CB, AKT1/2/3, RAF, Wnt, CDK12, IDH1, RB, and others are being tested in clinical studies.

Early stages of the disease can be successfully managed using surgery or radiation, but no curative treatment exists for advanced-stage prostate cancer. Early research on androgen deprivation in prostate cancer showed that the androgen receptor is important for growth and survival. Androgen deprivation therapy (ADT) is the most used anti-hormone treatment for advanced prostate cancer. Apart from its initial success, ADT resistance develops in the majority of patients with advanced prostate cancer, leading to castrate-resistant prostate cancer a (CRPC). Second-generation anti-androgen medications such as enzalutamide, abiraterone, and apalutamide have been approved by the USFDA and have improved the survival of CRPC patients (metastatic and localized). Despite these treatments, the majority of patients fail to respond to initial treatment due to adaptive resistance and the activation of immunosuppressive pathways in the tumor, resulting in tumor relapse.

A few of the most exciting emerging therapies for prostate cancer treatments in the era of precision oncology are as below:

PARP Inhibitors:
For patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed despite prior therapies and have mutations in particular genes, poly-(adenosine diphosphate) [ADP]-ribose polymerase (PARP) inhibitors have been approved by the FDA. The use of PARP inhibitors for patients with mutations in DNA damage response genes have been a boon for precise and effective extrapolation of therapies for individual cancer patients. Mateo et al (2015) reported an enhanced response to PARP inhibitors in CRPC patients with somatic and germline mutations in DNA repair genes in a phase II research. In May 2020, olaparib and rucaparib, were approved by the FDA for patients with mCRPC. Two other PARP inhibitor drugs, talazoparib and niraparib, are currently in phase 3 clinical trials in prostate cancer.

Immune Checkpoint Inhibitors:
Immune checkpoint inhibitors are a type of immunotherapy that activates immune cells that attack tumors. Checkpoint immunotherapy may only work for a subset of prostate cancer patients when used alone (rather than in conjunction with other therapies), and research is underway to explore how to best identify these individuals. Pembrolizumab, a checkpoint inhibitor, was approved by the FDA in 2017 for patients with solid tumors who had mutations in mismatch repair genes (MMR), microsatellite instability (MSI), and/or a high tumor mutational load (TMB-H). Recent studies suggest that patients with advanced prostate cancer whose tumors have lost both copies of the CDK12 gene may respond to checkpoint immunotherapy. Checkpoint inhibitors, such as pembrolizumab and ipilimumab, are being tested in combination with a variety of treatments in prostate cancer, including PARP inhibitors, cancer vaccines, and radiation therapy.

CAR T Cells:
Chimeric antigen receptor (CAR) T cell immunotherapy involves the genetic modification of the patient’s own T cells so that they specifically recognize and destroy tumor cells. Preclinical studies show that combination with standard therapies, such as androgen deprivation therapy, radiotherapy or chemotherapy, can be used to enhance the efficacy of CAR T cells against prostate cancer. There are multiple ongoing early-phase clinical trials of CAR T cells targeting prostate cancer.

Cancer vaccines:
The immune system may be activated in a variety of ways to target and eliminate prostate cancer. Cancer vaccines, for example, enable immune cells to identify and kill cells that express particular prostate cancer-associated proteins. PROSTVAC is a vaccine that stimulates the immune system to recognize and attack prostate-specific antigen (PSA), a protein generated primarily by prostate cancer cells.