The results from the primary analysis of the all-comers population in the phase III TALAPRO-2 study support the consideration of the novel combination of talazoparib plus enzalutamide versus a standard of care, enzalutamide, as a first-line treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC). Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in radiographic progression-free survival (rPFS).
The findings are reported at 2023 ASCO Annual Meeting on 4 June in Chicago, IL, US along with a simultaneous publication in The Lancet by Prof. Neeraj Agarwal of the Huntsman Cancer Institute, University of Utah in Salt Lake City, UT, US, and Prof. Karim Fizazi of the Department of Cancer Medicine, Institut Gustave Roussy, University of Paris-Saclay in Villejuif, France, and study colleagues.
Alterations in homologous recombination repair (HRR) genes, including BRCA1/2, found in approximately one-quarter of patients with advanced prostate cancer, can sensitise patients to treatment with PARP inhibitors. Talazoparib is a potent PARP inhibitor and traps PARP on single-strand DNA breaks, preventing DNA repair.
In the phase II TALAPRO-1 study, talazoparib monotherapy (1 mg/day) showed durable antitumour activity and a manageable safety profile in patients with heavily pretreated mCRPC with HRR deficiency. The phase III PROfound study with olaparib and TRITON3 with rucaparib also showed benefit using a PARP inhibitor as monotherapy for patients with pretreated mCRPC who had HRR alterations, with prolonged PFS versus control treatment.
The authors wrote in the background that co-inhibition of the androgen receptor (AR) and PARP might result in enhanced benefit with the potential to extend efficacy of PARP inhibitors to tumours regardless of HRR gene alterations. The underlying biology includes activation of PARP and the downregulation of HRR gene expression inducing so-called BRCAness by AR blockade and the role of PARP in supporting AR activity.
The phase III TALAPRO-2 study is assessing talazoparib combined with enzalutamide as first-line treatment in patients with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy in two cohorts with equally split alpha for data analysis: unselected (cohort 1, the all-comers cohort, recruited first) and selected (cohort 2, HRR-deficient only, which completed recruitment after completion of enrolment in cohort 1) for DNA damage response alterations in genes directly or indirectly involved in HRR.
In TALAPRO-2 patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0.5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient versus non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes versus no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label.
The primary endpoint was rPFS by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is ongoing. Between 7 January 2019 and 17 September 2020, 805 patients were enrolled and randomly assigned, 402 to the talazoparib group and 403 to the placebo group.
Median follow-up for rPFS was 24.9 months for the talazoparib group and 24.6 months for the placebo group. At the planned primary analysis, median rPFS was not reached (95% confidence interval [CI] 27.5 months–not reached) for talazoparib plus enzalutamide and 21.9 months (95% CI 16.6–25.1) for placebo plus enzalutamide (hazard ratio 0.63; 95% CI 0.51–0.78; p < 0.0001).
The authors commented that this performed in line with extended follow-up of rPFS with enzalutamide alone in the PREVAIL study with median 20 months (95% CI 18.9–22.1). Statistically significant and clinically meaningful improvements in rPFS were seen for the all-comers population (the primary endpoint), HRR-deficient subgroup, and HRR-non-deficient or unknown subgroup, as well as in the HRR-non-deficient subgroup by prospective tumour tissue testing only.
In addition, key secondary endpoints, including time to PSA progression, time to chemotherapy, and time to progression or death on first subsequent antineoplastic therapy, all favoured the talazoparib group. Overall survival (OS) data are immature. Final OS data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations.
Further study is ongoing to agnostically identify and explore alterations in single genes or gene pairs (entire FoundationOne panel), and more complex molecular signatures, that might be prognostic or predictive in the HRR-non-deficient population.
In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3–4 event was anaemia (46%), which improved after dose reduction, and only 8% of patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group.
In an accompanied comment, Dr. Wassim Abida of the Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center in New York, NY, US, and Dr. Gerhardt Attard of the Department of Oncology, University College London in London, UK wrote that the main strength of this study is prospective stratification via state-of-the-art genomic testing, which is key to understanding the potential benefit of the combination in non-HRR-mutated mCRPC.
TALAPRO-2 provides the most convincing evidence of benefit to date for patients without a detectable HRR alteration. Whether any AR plus PARP inhibitor combination should become standard practice for patients with mCRPC remains unclear. Ongoing studies combining these agents in the upfront setting for selected patients, including AMPLITUDE and TALAPRO-3, are examining the combination at the start of hormonal therapy.
Overall, the compelling results of TALAPRO-2 support a biomarker-driven approach for the use of PARP inhibitors in mCRPC, where the benefit of combination with a next-generation hormonal agent should be weighed against the risk of toxicity. However, the editorialists believe that future confirmation of a survival benefits for distinct molecular subgroups will shift the balance in favour of combination treatment.
The TALAPRO-2 study was sponsored by Pfizer. Astellas Pharma provided enzalutamide.
References
- Fizazi K, Azad A, Matsubara N, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol 41, 2023 (suppl 16; abstr 5004).
- Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. The Lancet; Published online 4 June 2023. DOI: https://doi.org/10.1016/ S0140-6736(23)01055-3
- Abida W, Attard G. Combining next-generation hormonal therapy with PARP inhibition in metastatic castration-resistant prostate cancer. The Lancet; Published online 4 June 2023. DOI: https://doi.org/10.1016/ S0140-6736(23)01123-6