Prostate cancer is the second most common cancer in men, with more than 1.4 million new cases and 375,000 deaths globally in 2020.1 Metastatic castration-resistant prostate cancer (mCRPC) is one of the most severe and deadly forms. Approximately 25% of men with mCRPC and other advanced prostate cancers have DNA damage response (DDR) alterations, somatic or germline, or both, that are connected to resistance to traditional therapies.2,7 Over the past decade or so, genetic and genomic testing for prostate cancer has developed significantly.
Several decisive studies in 2015 and 2016 helped lead the way:
- The Cancer Genome Atlas Research Network found that 19% of the 333 primary prostate cancers they evaluated had mutations in DNA repair genes.3
- A 2015 Stand Up to Cancer/Prostate Cancer Foundation/American Association for Cancer Research study discovered that 23% of 150 metastatic tissue biopsies collected from patients with mCRPC had alterations in DNA repair pathway genes (primarily within BRCA2, ATM, and BRCA1).3
- A 2016 multicenter study of 692 men with metastatic prostate reported that 11.8% of the patients carried a germline mutation in a DNA repair gene, much higher than the 4.6% among those with localized prostate cancer. 4
Advancing treatment for mCRPC patients
The combination of technological advances and clinical trials in recent years has created opportunities in testing and treatment that affect the management of advanced prostate cancers. Identifying biomarkers through circulating tumor DNA (ctDNA) tests and detecting germline pathogenic variants are vital to understanding prostate cancer risk and guiding clinical care, including determining early screening needs and tailoring treatment.
New poly (ADP-ribose) polymerase, PARP, inhibitors treatments have been approved for mCRPC. A subset of homologous recombination repair (HRR) genes relevant to mCRPC is critical in evaluating eligibility for these inhibitors. Three recently published phase 3 clinical trials involving PARP inhibitors and patients with mCRPC are summarized below.
PROpel, a randomized, double-blind, placebo-controlled trial, studied mCRPC patients who’d undergone anti-androgen hormone therapy that wasn’t effective. They were enrolled independent of their HRR mutation (HRRm) status. The phase 3 trial was conducted after preclinical, and phase 2 trials suggested an anti-tumor effect when abiraterone (an androgen biosynthesis inhibitor) was combined with PARP inhibitor olaparib to treat mCRPC.5 The clinical trial results showed “statistically significant improvement in imaging-based progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone.”6
Tumor tissue and blood samples were collected to determine HRRm status by tissue and ctDNA testing after randomization and before primary analysis. The genes assessed through HRRm testing were ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L.
TALAPRO-2 is a multinational, two-part study comparing PARP inhibitor talazoparib plus enzalutamide (a nonsteroidal anti-androgen medication) versus placebo plus enzalutamide to treat patients with mCRPC, with or without DDR alterations. The TALAPRO-1 study of patients with DDR alterations established “efficacy in prespecified interim analyses.”8 TALAPRO-2 is designed to demonstrate whether talazoparib plus enzalutamide can significantly improve enzalutamide’s effectiveness.
TALAPRO-2 enrolled two groups. Cohort 1 patients are not required to have DDR alterations. Cohort 2 patients have DDR alterations (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A or CDK12). DDR alterations were assessed through a blood or recent tumor tissue sample before randomization.8
MAGNITUDE is a randomized, double-blind study evaluating a combination of niraparib (PARP inhibitor), abiraterone, and prednisone versus placebo with abiraterone in patients with and without HRRm. It was created to test the hypothesis that “targeting both oncogenic pathways concurrently may improve outcomes” for both groups.10
The HRRm group included those with monoallelic or biallelic pathogenic gene alterations in one or more of the following genes: ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2. The other group included patients without detectable alterations.10
Understanding the mCRPC population is essential
These clinical trials represent the efforts to develop new treatment combinations and therapies for mCRPC patients. PARP inhibitors are shown to be effective in those with DDR alterations, which has led to the approval of new drugs for this group of patients. They also have the potential to target tumors in patients without DDR alternation when combined with other medications.2
Clinicians strive to develop their patients' most effective treatment plans through precision oncology. That requires extensive knowledge of their patient. To support a better understanding of the mCRPC patient population through genomic testing, we have released a ctDNA Prostate Reference Material. It contains variants in all related genes and other variants relevant to the biology and understanding of prostate cancer.
Sources
- https://www.wcrf.org/cancer-trends/prostate-cancer-statistics/
- https://www.tandfonline.com/doi/full/10.2217/fon-2021-0811
- https://ascopubs.org/doi/10.1200/EDBK_390384
- https://pubmed.ncbi.nlm.nih.gov/27433846/
- https://evidence.nejm.org/doi/10.1056/EVIDoa2200043
- https://pubmed.ncbi.nlm.nih.gov/37714168/
- https://ascopubs.org/doi/full/10.1200/JCO.22.01649
- https://www.tandfonline.com/doi/full/10.2217/fon-2021-0811
- https://www.tandfonline.com/doi/full/10.2217/fon-2021-0811
- https://ascopubs.org/doi/full/10.1200/JCO.22.01649