In recent years, there have been groundbreaking advancements in the exploration of treatment modalities for prostate cancer, particularly in the use of PARP inhibitors in combination with novel hormonal therapies, offering new hope for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The TALAPRO-2 study has demonstrated that the combination of talazoparib with enzalutamide significantly improves radiographic progression-free survival (rPFS) in the overall mCRPC patient population (HR=0.63; 95% CI, 0.51–0.78; P<0.0001) and in mCRPC patients with homologous recombination repair (HRR) gene defects (HR=0.45; 95% CI, 0.33–0.61; P<0.0001) compared to placebo in combination with enzalutamide[1]. As a result, the combination therapy of talazoparib and enzalutamide received FDA approval on June 20th of this year for first-line use in mCRPC patients with HRR gene mutations.
At the recently concluded European Society for Medical Oncology (ESMO) Annual Meeting, updated patient outcomes, drug exposure, safety, and efficacy-related analyses of the TALAPRO-2 study were presented. We are fortunate to have invited Professor Aili Zhang from the Fourth Hospital of Hebei Medical University to provide an in-depth interpretation of the updated results of TALAPRO-2 for our readers.
Patient-reported outcomes (PRO) for mCRPC patients with HRR mutations receiving talazoparib (TALA) + enzalutamide (ENZA) vs. placebo (PBO) + ENZA: Results from the Phase III (TALAPRO-2 Cohort 2) study[2]
TALAPRO-2 (NCT03395197) is an international, multicenter, randomized, double-blind, placebo-controlled Phase III clinical trial. It aims to assess the efficacy, safety, and patient-reported outcomes of talazoparib in combination with enzalutamide versus enzalutamide in the first-line treatment of mCRPC. Cohort 1 included 805 patients in the overall population who were not preselected for HRR mutations (402 in the experimental group and 403 in the control group), while Cohort 2 included 399 patients with HRR mutations (200 in the experimental group and 199 in the control group). The primary endpoint was rPFS assessed independently by blinded central review, with key secondary endpoints being overall survival, PRO, and safety outcomes, among others. The specific design of Cohort 2 is outlined as follows (Figure 1).
PRO was evaluated as a secondary endpoint using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the EORTC Prostate Cancer-Specific Quality of Life Questionnaire (QLQ-PR25). PRO assessments were performed at baseline, regular visits (every 4 weeks until week 53, then every 8 weeks) until progression, at the end of treatment due to safety concerns, and during long-term follow-up (every 12 weeks). The treatment evaluation results are as follows.
Compared to PBO+ENZA, the TALA+ENZA group had a significantly longer time to complete deterioration in quality of life (27.1 months vs. 19.3 months, HR=0.69 (0.49-0.97), P=0.032) and a significantly prolonged time to urinary symptom deterioration (not reached vs. 30.2 months, HR=0.56 (0.34-0.93), P=0.022) (Figure 2).
During treatment, there were favorable differences in body function, emotional function, cognitive function, pain, urinary system symptoms, and intestinal symptoms in favor of TALA+ENZA, but they did not reach the predefined threshold of clinical significance (≥10 points) (Figure 3).
Exposure-safety correlation analysis of talazoparib in mCRPC patients from the TALAPRO-2 study[3]
Previous results from the TALAPRO-2 study showed that in the TALA+ENZA group of the overall population, 62% and 53% of patients experienced interruptions and reductions in the TALA dose (58% and 52%, respectively, in the HRR-deficient cohort). This analysis aims to describe the relationship between TALA exposure in mCRPC patients in the TALAPRO-2 study and selected safety endpoints, including ≥Grade 3 anemia, neutropenia, and thrombocytopenia.
Daily TALA exposure is influenced by ENZA and its N-desmethyl metabolite and may change during treatment due to dose adjustments based on patient safety responses. To describe changes in TALA exposure over time, the analysis used time-varying average daily concentration (Cavg,t).
The results showed that higher TALA exposure was associated with an increased risk of ≥Grade 3 anemia, thrombocytopenia, and neutropenia. Lower baseline hemoglobin and higher baseline lactate dehydrogenase were also associated with a higher risk of ≥Grade 3 anemia. Lower baseline weight and higher baseline alkaline phosphatase were associated with a higher risk of ≥Grade 3 anemia. Lower baseline weight and lower baseline absolute neutrophil count were associated with a higher risk of ≥Grade 3 neutropenia (Figure 5).
Exposure-efficacy correlation analysis of talazoparib in mCRPC patients in the TALAPRO-2 study
In addition, the conference also revealed the relationship between TALA exposure and rPFS in the TALAPRO-2 study, regardless of HRR gene mutation status, and identified potential prognostic factors for rPFS.
The results showed that patients who did not experience rPFS events had higher TALA exposure compared to those who did experience rPFS events, indicating that higher TALA exposure may be associated with longer rPFS (Figure 6).
In the PBO+ENZA group, patients with HRR gene mutations had significantly shorter rPFS (P=0.011), while in the TALA+ENZA group, there was no significant difference in rPFS among patients with different HRR statuses (P=0.62) (Figure 7).
When comparing mCRPC patients with HRR gene defects receiving TALA+ENZA treatment to patients without HRR defects in the control group, a trend toward longer median rPFS was observed in the TALA group (P=0.16), further indicating the additional benefit of TALA in combination with ENZA for mCRPC patients (Figure 8).
The final analysis results of the Cox Proportional Hazard model (Figure 9) showed that higher TALA exposure was associated with longer rPFS. Lower baseline lactate dehydrogenase levels and lower baseline alkaline phosphatase levels were associated with longer rPFS. Lower baseline lymphocyte count was associated with shorter rPFS. Having measurable disease was associated with longer rPFS compared to non-measurable disease. Being limited to bone metastasis was associated with longer rPFS than metastasis in other sites.
With the approval of PARP inhibitor combination therapy in the first-line indication for mCRPC, the treatment landscape for advanced prostate cancer is gradually evolving, and there is hope for further improvements in the survival of late-stage prostate cancer patients. Talazoparib is a new generation PARP inhibitor and is currently known to be the most potent PARP inhibitor reported. Previous clinical studies have already demonstrated that the addition of talazoparib significantly reduces the risk of progression or death by 37% in the overall mCRPC patient population compared to enzalutamide monotherapy, and for patients with HRR mutations, the risk of progression or death is reduced by 55%[1]. Apart from these objective clinical endpoints, improvements or maintenance of patient-reported outcomes in quality of life are benefits relatively independent of tumor control, reflecting a patient-centered approach. Talazoparib significantly extends the time to complete deterioration in quality of life and urinary symptom deterioration, while also improving patients’ physical function, emotional function, cognitive function, pain, urinary symptoms, and gastrointestinal symptoms, enhancing the quality of life for patients.
The conference also reported the relationship between TALA exposure and hematological adverse events and efficacy. Higher TALA exposure was associated with an increased risk of ≥Grade 3 anemia, thrombocytopenia, and neutropenia, but at the same time, higher TALA exposure was also associated with longer rPFS. This suggests that in clinical practice, the impact of drug exposure on adverse events and efficacy should be considered holistically. Anemia, neutropenia, and leukopenia are the most common hematological adverse events of PARP inhibitors. However, it’s worth noting that in the TALAPRO-2 study, almost half of the patients (49%) had Grade 1-2 anemia at baseline, and Grade 3-4 anemia mostly occurred after 3-4 months of treatment[1]. These data suggest that blood cell counts should be closely monitored in the first 3-4 months of TALA treatment based on individual patient baseline conditions, and appropriate dosing should be determined for long-term treatment. Grade 1-2 adverse events can be improved through symptomatic supportive measures to maximize efficacy. If not tolerated, dose adjustments can also be made to improve the hematological adverse events in patients.
Preclinical studies have shown that inhibiting androgen receptor signaling suppresses the expression of HRR genes, including BRCA1, leading to a “BRCAness” phenotype and increased sensitivity to PARP inhibitors in the absence of PARP inhibitors. Therefore, in the absence of PARP inhibitors, such as in the PBO+ENZA group, the HRR gene mutation status becomes an important prognostic factor. However, in the TALA+ENZA group, regardless of HRR gene defects, there was no significant difference in patients’ rPFS. Even in the TALA+ENZA combination therapy group, there was a trend towards longer rPFS in patients with HRR gene defects compared to patients without HRR defects in the PBO+ENZA treatment group, indicating the synergistic effect of talazoparib and enzalutamide.
The combination of AR and PARP inhibitors inducing synthetic lethality has opened a new chapter in the first-line treatment of mCRPC, and it is expected that future data from longer-term follow-up on overall survival in the TALAPRO-2 study will further demonstrate its long-term benefits for patients, benefiting a large number of advanced prostate cancer patients.
Medical Doctor, Doctoral Supervisor, Professor of Urology, Chief Physician
Vice President of the East Hospital, The Fourth Hospital of Hebei Medical University
Standing Committee Member of the Male Reproductive System Tumor Special Committee of the Chinese Anti-Cancer Association
Standing Committee Member of the Prostate Cancer Special Committee, Urothelial Carcinoma Special Committee, and Kidney Cancer Special Committee of the Chinese Society of Clinical Oncology
Standing Committee Member of the Urology Special Committee of the Chinese Primary Health Care Foundation
Member of the Urology Physician Branch of the Chinese Medical Doctor Association
Vice Chairman and Secretary-General of the Hebei Cancer Prevention and Control Association
Chairman of the Male Reproductive System Tumor Special Committee of the Hebei Cancer Prevention and Control Association
Chairman of the Urological Tumor Special Committee of the Hebei Cancer Prevention and Control Association
Chairman of the Kidney Cancer Special Committee of the Hebei Clinical Oncology Society
Vice Chairman-Elect of the Urology Physician Branch of the Hebei Medical Doctor Association
Vice Chairman of the Urology Branch of the Hebei Medical Association
Head of the Urological Oncology Group of the Oncology Branch of the Hebei Medical Association
Chairman of the Urology Special Committee of the Shijiazhuang Medical Association
Editorial Board Member of “Hebei Medicine,” “Journal of Modern Integrated Traditional Chinese and Western Medicine,” and “Electronic Journal of Comprehensive Cancer Treatment”
Editorial Board Member of “JCO Chinese Edition Special Issue on Male Reproductive System Tumors”
References
1. Agarwal N, Azad AA, Carles J, Fay AP, Matsubara N, Heinrich D, Szczylik C, De Giorgi U, Young Joung J, Fong PCC, Voog E, Jones RJ, Shore ND, Dunshee C, Zschäbitz S, Oldenburg J, Lin X, Healy CG, Di Santo N, Zohren F, Fizazi K. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023 Jun 2:S0140-6736(23)01055-3. doi: 10.1016/S0140-6736(23)01055-3. Epub ahead of print. PMID: 37285865.2. Fay A, et al. ESMO 2023. Poster Number 1811P3. Azad A,et al. ESMO 2023. Poster Number 1829P 4. Azad A,et al. ESMO 2023. Poster Number 1834P
