SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.
Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as Bicalutamide (CASODEX®), Nilutamide (NILANDRON®) and Flutamide (EULEXIN®) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPIs), which include Abiraterone (ZYTIGA®), Enzalutamide (XTANDI®), Apalutamide (ERLEADA®) and Darolutamide (NUBEQA®).
For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Pathway Inhibitors (ARPIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.
DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HRR pathway. At least 15 genes are involved in the HRR pathway including BRCA1, BRCA2 and ATM genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Recently published data has shown that deleterious Germline and/or Somatic mutations in BRCA1, BRCA2, ATM, or other Homologous Recombination DNA-repair genes, are present in about 30% of patients with advanced prostate cancer, including metastatic CRPC. Patients with metastatic CRPC harboring BRCA alterations and other HRR gene alterations have poor outcomes, and earlier resistance to commonly used systemic therapies.
The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in HRR genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death. PARP inhibitors have demonstrated significant activity in patients with prostate cancer and HRR gene alterations, with the greatest clinical benefit noted in BRCA1/2 mutation carriers.
Talazoparib (TALZENNA®) is a PARP inhibitor presently approved for HRR Gene-Mutated CRPC and for Germline BRCA- mutated advanced breast cancer.
TALAPRO-2 trial is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study that enrolled 1,035 unique patients with mCRPC (who had not received new life-prolonging systemic treatments after documentation of mCRPC) at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. The study included two patient cohorts: Cohort 1 included all comers (N=805, of whom 169 had HRR mutations and 636 did not) and Cohort 2 included those with HRR gene mutations (N=399, including 169 patients from Cohort 1 and 230 enrolled in Cohort 2). A total of 805 patients in Cohort 1 were randomized in a 1:1 ratio to receive either Talazoparib 0.5 mg daily plus Enzalutamide 160 mg daily (N=402) or placebo plus Enzalutamide (N= 403). Randomization was stratified based on HRR gene alteration status and prior Abiraterone or Docetaxel (yes/no) for castration-sensitive prostate cancer. Eligible patients had asymptomatic or mildly symptomatic mCRPC, ECOG PS 1 or less, ongoing Androgen Deprivation Therapy, and no prior life-prolonging therapy for CRPC. All patients underwent tumor tissue testing before enrollment, and approximately 20% were found to have HRR alterations. Specific gene mutations, including BRCA1, BRCA2, ATM, and CDK12, were evenly distributed across treatment arms, with BRCA1 and BRCA2 alterations found in approximately 7% of patients. The Primary endpoint of the study was radiographic Progression-Free Survival (rPFS), and Overall Survival (OS) was a key Secondary endpoint. The researchers had previously reported that TALAPRO-2 trial met its Primary endpoint, showing improved radiographic PFS for Talazoparib plus Enzalutamide compared to placebo plus Enzalutamide as first line treatment in patients with mCRPC unselected for HRR gene alterations (Cohort 1). The final OS data, updated rPFS, and extended safety follow-up in Cohort 1 was reported in this publication
The final OS analysis demonstrated a statistically significant and clinically meaningful improvement in survival for patients treated with Talazoparib plus Enzalutamide compared to Enzalutamide alone. The median OS in the Talazoparib plus Enzalutamide group was 45.8 months versus 37.0 months in the placebo arm, representing a 20% reduction in the risk of death (HR=0.796; P=0.0155). Patients with HRR-deficient tumors had a greater reduction in the risk of death (38%), with a median OS improvement of 14 months (HR=0.622; P=0.0005). The median OS with Talazoparib plus Enzalutamide was 45.1 months and 31.1 months in the placebo plus Enzalutamide group. Patients without HRR mutations still benefited from an approximate 9-month OS gain.
In patients with BRCA1/2 alterations, the median OS was not reached in the Talazoparib plus Enzalutamide group versus 28.5 months in the placebo plus Enzalutamide group (HR=0.497; P =0.0017). For those with non-BRCA1/2 HRR alterations, the median OS was 42.4 versus 32.6 months (HR=0.727; P=0.0665).
The updated rPFS data continued to favor Talazoparib plus Enzalutamide. The median rPFS was 33.1 months versus 19.5 months in the placebo arm (HR=0.667; P<0.0001). In the HRR-deficient cohort, median rPFS was 30.7 months versus 12.3 months (HR=0.468; P <0 .0001).
No new safety signals emerged with extended follow-up. The most common adverse event was anemia. Grade 3-4 anemia occurred in 49% of the unselected population and 43.4% of the HRR-deficient population. Talazoparib discontinuation due to adverse events was 21.6% in the unselected population and 13.1% in the HRR-deficient cohort. Anemia-related discontinuations were 8.5% in the unselected population and 4.5% in the HRR-deficient group.
It was concluded from this study that Talazoparib plus Enzalutamide significantly improved OS and rPFS compared to Enzalutamide alone in both HRR-deficient and non-deficient populations. The findings support the broad use of this combination as a new standard of care for treatment-naïve patients with mCRPC.
Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. Agarwal N, Azad A, Carles J, et al. J Clin Oncol. 2025,43(suppl 5):LBA141. doi:10.1200/JCO.2024.42.4_suppl.LBA18.
