TALZENNA (talazoparib) is an innovative oral inhibitor of poly ADP-ribose polymerase (PARP), a critical player in repairing DNA damage. Through preclinical investigations, it has been revealed that TALZENNA effectively inhibits the activity of the PARP enzyme and sequesters it at the specific location of DNA damage. This remarkable mechanism results in a significant reduction in cancer cell proliferation and ultimately induces the demise of cancer cells. Pfizer presented the trailblazing results from the first Phase III TALAPRO-2 study of (NCT03395197) talazoparib in combination with enzalutamide in patients with mCRPC. It exists in the landscape of sequential and advancing studies of PARP inhibitors (PARPi) in prostate cancer. As per the findings presented at the ASCO 2023, during the period from January 7, 2019, to September 17, 2020, around 805 patients participated in the study and were randomly assigned to two groups: 402 patients received talazoparib and 403 patients received a placebo. The median follow-up duration for assessing radiographic progression-free survival, (rPFS) was approximately 24.9 months for the talazoparib group and 24.6 months for the placebo group, with a range of 21.9 to 30.2 months and 14.4 to 30.2 months, respectively. Notably, at the primary analysis stage, the median rPFS for the talazoparib plus enzalutamide group was not reached (95% CI 27·5 months–not reached), whereas the median rPFS for the placebo plus enzalutamide group was 21.9 months (16·6–25·1). These findings shed light on the potential benefits of talazoparib in combination with enzalutamide, highlighting the promise of improved outcomes in patients with the condition being studied.
In a major breakthrough, the TALAPRO-2 study successfully achieved its primary objective of rPFS. Moreover, the combination arm of the study, consisting of 200 patients, exhibited an impressive 55% reduction in the risk of disease progression or death. These pivotal findings highlighted the potential of combination therapy to significantly prolong patient survival and represent a significant stride forward in the battle against this condition. Apparently, in a compelling exploration of patient subgroups, a remarkable 80% reduction in the risk of disease progression or death was witnessed among those with BRCA1/2 alterations (n=155). Equally noteworthy, patients with tumors carrying HRR gene mutations but lacking BRCA1/2 alterations (n=240) also experienced significant benefits when treated with TALZENNA in combination with XTANDI, outperforming the placebo plus XTANDI group. These groundbreaking findings highlighted the potential of this therapeutic approach to revolutionize the prognosis for patients with diverse genetic profiles, opening new avenues of hope and targeted treatment strategies.
The combination arm (talazoparib + enzalutamide) demonstrated a remarkable objective response rate (ORR) of 67.1%, with an impressive 38.4% of those responses categorized as complete responses. Additionally, a stable disease rate of 26% was observed, highlighting the treatment's ability to prevent disease progression. Only a small percentage (5.6%) of patients on the combination arm experienced progressive disease. In comparison, the placebo arm exhibited an ORR of 40%, with 18.5% of responses classified as complete, 32.3% showing stable disease, and 20% experiencing disease progression. These findings underscore the substantial therapeutic impact of the combination treatment, highlighting its potential to induce robust and comprehensive responses, thereby enhancing patient outcomes and quality of life. While the data on overall survival (OS) is still in an early stage and considered immature, there is a notable trend favoring the combination of TALZENNA and XTANDI. The results regarding OS, a crucial secondary endpoint, will be disclosed upon reaching the predetermined number of survival events expected to occur in 2024. These forthcoming findings hold great promise for further understanding the potential long-term benefits of this treatment regimen, offering hope for improved survival outcomes in patients.
The safety profiles of TALZENNA and XTANDI observed in this cohort 2 analysis remained consistent with the established safety records of both medications. Notably, the grade 3-4 treatment-emergent adverse events (TEAEs) were higher in the TALZENNA + XTANDI group (66.2%) compared to the placebo plus XTANDI group (37.2%). Specifically, there was a greater occurrence of grade ≥3 hematologic TEAEs, including anemia, neutropenia, thrombocytopenia, fatigue, decreased appetite, nausea, and back pain, in the TALZENNA plus XTANDI group compared to the placebo plus XTANDI group. Moreover, discontinuation of TALZENNA due to TEAEs was observed in 10.1% of patients, slightly higher than the discontinuation rate for the placebo group, which was 7.0%. These findings shed light on the safety considerations associated with this combination therapy, emphasizing the importance of closely monitoring and managing potential adverse events for optimized patient care.
“TALAPRO-2: First-Line Talazoparib/Enzalutamide Excels in Patients With BRCA-Mutated mCRPC.” –Expert Opinion.
“Based on these data, I believe that talazoparib plus enzalutamide, if approved, should become a standard of care for patients with mCRPC HRR alterations [and] mostly those with BRCA alterations.” –Expert Opinion.
PARP inhibitors are among the most promising therapeutic classes in the Phase III pipeline for mCRPC. Two PARP inhibitors, rucaparib, and olaparib received FDA approval in May 2020 for use in mCRPC harboring selected HRR aberrations after progression on at least one NAA therapy (olaparib) and at least one NAA and one chemotherapy (rucaparib). At present, the use of these agents is contingent upon the presence of aberrations in the HRR gene as identified on a commercial assay. Talazoparib (TALZENNA, Pfizer) and niraparib (ZEJULA, Janssen) (TALAPRO-2 and MAGNITUDE, respectively) are being investigated in combination with an AR-directed therapy for first-line treatment of mCRPC, similar to olaparib and rucaparib.
The results from the TALAPRO-2 study showed that the addition of talazoparib to the existing standard of care adds significant clinical benefit to patients. In addition to delaying disease progression, this combination delayed prostate-specific antigen progression and the time to chemotherapy without adversely influencing the patient's quality of life. Although the benefit appeared strongest in patients with mutations in HR-mediating genes. Furthermore, the rPFS results from this study appear to be the longest observed in a randomized trial in this setting, which has demonstrated the potential of the TALZENNA and XTANDI combination. Within the same class, AstraZeneca and Merck’s powerhouse PARP inhibitor, LYNPARZA is now set for an upward movement into the first line treatment, where it received approval in the EU in the 4Q of 2022 and recently got approval in the US in June 2023 in combination with abiraterone. Therefore, in 2023, we may expect the launches of niraparib and talazoparib in the first line setting in the United States. The supplemental new drug application (sNDA) for the combination use of TALZENNA plus XTANDI for the treatment of mCRPC is currently under Priority Review by the US FDA. The FDA’s decision on the sNDA is expected in 2023. In addition, the marketing authorization application (MAA) for this same indication has been accepted for review by the European Medicines Agency. As the treatment landscape for prostate cancer continues to evolve, it can be anticipated that these innovative-targeted therapies could improve the outcomes for patients with HRR-positive prostate cancer. Therefore, it would be interesting to watch the uptake and competition among the PARP inhibitors market share in the first-line setting once each one of them get launch in 2023/2024. As per DelveInsight’s estimates, we expect the four PARP inhibitors (Olaparib, Rucaparib, Talazoparib, and Niraparib) to reach a peak revenue of approximately USD 1.3 billion together in 2030 in the United States in the first line setting only