At this year’s recently concluded ESMO conference, new developments related to the PARP inhibitor talazoparib in precision diagnosis and treatment were announced. Precision diagnosis has become a leading trend in the field of prostate cancer, and biomarker research is receiving increasing attention. In this context, this publication invited Professor Guiming Zhang from Qingdao University Affiliated Hospital, a well-known young expert in the field of prostate cancer, for an in-depth interview to explain the three new developments related to talazoparib’s precision treatment recently announced at ESMO. Here, we provide a summary of the interview for the readers.
TALAPRO-2 Study: Exploration of Homologous Recombination Repair (HRR) Mutations and Their Potential Association with Antitumor Activity from Germ Line (g) and Somatic (s) Sources
Background and Objectives
l TALAPRO-2 (NCT03395197) is the first Phase 3 study aimed at evaluating the PARP inhibitor talazoparib in combination with enzalutamide as a first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC).
l Prospective testing allocated HRR mutation-positive patients in a 1:1 ratio to receive either talazoparib at 0.5 mg daily (0.35 mg daily for moderate renal impairment; n=200) or placebo with enzalutamide at 160 mg daily (n=199).
l The primary endpoint of the study was Radiographic Progression-Free Survival (rPFS) assessed by blinded independent central review (BICR).
l In the HRR mutation-positive population, the combination of talazoparib and enzalutamide did not reach the median rPFS (95% CI, 21.9 months to not reached), while the median rPFS for the placebo plus enzalutamide group was 13.8 months (95% CI, 11.0-16.7) (HR=0.45; 95% CI, 0.33–0.61; P<0.0001).
l Overall survival data are not yet mature; the trend in overall survival favors the combination of talazoparib and enzalutamide (HR=0.69; 95% CI, 0.46–1.03; P=0.07).
l The most common adverse reactions with talazoparib in combination with enzalutamide were anemia, fatigue, and neutrophil count decrease.
l This study aimed to evaluate the potential association between the source (germ line vs. somatic) of HRR gene mutations and efficacy in the Phase 3 TALAPRO-2 study.
Methods
l The study assessed the frequency of germ line HRR mutations in patients who could be evaluated using saliva sequencing with the Ambry CustomNext-Cancer panel (9 out of 12 genes from the HRR12 tumor gene panel in TALAPRO-2).
l For the intention-to-treat population, tumor mutation source was assessed using saliva data (with tumor cell germ line heterozygosity prediction when saliva results were insufficient) to evaluate the relationship between germ line and tumor tissue HRR mutations and efficacy.
l Stratified log-rank tests were used to assess correlations with rPFS.
l Data cutoff date was October 3, 2022.
Results
Out of 302 evaluable patients for germ line HRR mutations, 91 patients (30.1%) had one or more HRR gene mutations in their saliva.
In the talazoparib plus enzalutamide group, there was no significant difference in median rPFS between patients with germ line and somatic mutations (HR=0.69; 95% CI, 0.36–1.34; two-sided P=0.28). However, in the placebo plus enzalutamide group, patients with germ line HRR mutations had shorter rPFS (HR=2.27; 95% CI, 1.32–3.91; P=0.003).
Conclusion
l In the TALAPRO-2 study, approximately one-third (30.1%) of mCRPC patients with HRR mutations had germ line HRR mutations.
l In patients receiving talazoparib in combination with enzalutamide, there was no association between antitumor activity and the source of HRR gene mutations, whether germ line or somatic.
l Patients with germ line HRR mutations had shorter rPFS when treated with placebo plus enzalutamide.
Talazoparib (TALA) Plus Enzalutamide (ENZA) Treatment for mCRPC: Subgroup Analysis of the TALAPRO-2 Study Full Population Cohort by HRR Mutation Status
Background and Objectives
l Simultaneously inhibiting AR and PARP may increase the benefit of prostate cancer treatment, regardless of the presence of HRR gene mutations.
l TALAPRO-2 is the first Phase 3 study aiming to evaluate talazoparib in combination with enzalutamide as a first-line treatment for mCRPC patients. In the unselected full population, regardless of HRR gene mutations, the study demonstrated statistically and clinically significant improvements in rPFS compared to placebo plus enzalutamide (HR=0.63; 95% CI, 0.51–0.78; P<0.0001).
l This study explores the relationship between patient baseline characteristics and secondary efficacy endpoints in the full population cohort of the TALAPRO-2 study, stratified by HRR mutation status.
Methods
l Exploratory subgroup analysis of secondary efficacy endpoints was conducted based on HRR gene mutation status (classified as HRR+ vs. HRR-/unknown).
l Post hoc analyses of rPFS (as assessed by BICR) were performed based on previous receipt of second-generation ARPi treatment, abiraterone or apalutamide, or docetaxel treatment.
l Kaplan-Meier methods summarized time-to-event endpoints, and stratified log-rank tests were used to compare treatment groups. However, due to the small number of patients in some subgroups, non-stratified models were used for the pre-specified analysis of rPFS. All reported p-values are two-sided.
Results
Analysis based on baseline disease characteristics showed that HRR+ patients had a shorter time from initial diagnosis of prostate cancer to randomization, higher Gleason scores (≥8), higher median baseline serum PSA, and higher rates of lymph node involvement.
Objective response rates for HRR gene mutation status are shown in the following figure:
Second interim analysis of overall survival (OS) and analysis of other secondary efficacy endpoints based on HRR gene mutation status demonstrated that, although the OS data are not yet mature, talazoparib in combination with enzalutamide had a trend toward OS benefit in the full population, with a more significant benefit in the HRR+ subgroup. Talazoparib plus enzalutamide extended PSA progression time, time to initiation of cytotoxic chemotherapy, and PFS2, with benefits in both HRR+ and HRR-/unknown subgroups.
Patients who had received abiraterone treatment during the hormone-sensitive prostate cancer (HSPC) stage and then received talazoparib in combination with enzalutamide had a 43% reduction in the risk of radiographic progression rPFS or death (with only 6% of patients in each treatment group having received abiraterone treatment). Patients who had previously received docetaxel treatment had a 49% reduction in the risk of progression in the talazoparib plus enzalutamide group.
Conclusion
l Analysis based on baseline disease characteristics showed that HRR+ patients had a shorter time from initial diagnosis of prostate cancer to progression to mCRPC.
l In mCRPC patients, talazoparib in combination with enzalutamide improved secondary efficacy endpoints compared to enzalutamide alone as a first-line treatment, especially in the HRR+ subgroup.
l While the OS data are not yet mature, the mid-term data support combination therapy in the HRR+ subgroup.
New Emerging Circulating Tumor DNA (ctDNA) Variants and Dynamic ctDNA Load Correlations with the Potential Antitumor Activity of Talazoparib in TALAPRO-1
Background and Objectives
l The TALAPRO-1 study assessed the efficacy and safety of talazoparib in mCRPC patients with HRR mutations (11 genes, including BRCA1/2, PALB2, and ATM), who had received at least one taxane-based chemotherapy and one non-hormonal therapy (NHT).
l This study aimed to explore newly emerging ctDNA variants of HRR and PARP genes, the proportion from ctDNA (tumor fraction), and their correlation with the antitumor activity of talazoparib.
Methods
l Serial ctDNA samples and safety follow-up assessments at weeks 1, 9, and 25 were evaluated using FoundationOne® Liquid CDx (Foundation Medicine, Cambridge, MA, USA).
l The data cutoff date was September 4, 2020 (primary completion date).
Results
At weeks 1, 9, 25, and safety follow-up (SFUV) week, the complexity of BRCA2 mutations (allele number/number of BRCA2m patients) was 18/16 [1.1], 12/10 [1.2], 62/11 [5.6], and 57/14 [4.1], respectively. The median number of BRCA2 variants was 2 (range, 1-18; 3 patients had ≥15 variants) at week 25. The complexity of BRCA1 and PALB2 mutations increased, while ATM mutation complexity remained stable.
Newly emerging PARP1 variants were predicted to truncate PARP1 and/or inhibit binding with talazoparib.
Among 27 patients, 15 had quantifiable tumor fractions (TF) at week 1, ranging from 10% to 68%, and TF changes could be assessed at week 9. In these 15 patients, 10 had TF below the limit of quantification (BLQ) at week 9, 1 patient had a ≥50% TF decrease, and 4 patients had no change in TF at week 9 (change <50%). Among these patients, 4 out of 4 with partial response (PR), 2 out of 2 with non-complete response (non-CR) or non-progressive disease (non-PD), 3 out of 5 with stable disease (SD) (one additional patient had a ≥50% reduction), and 1 out of 4 with progressive disease (PD) showed a reduction below the limit of quantification (BLQ) at week 9.
Conclusion
l The increase in mutation complexity of BRCA1, BRCA2, and PALB2 during treatment aligns with ctDNA results reported in other clinical studies involving PARP inhibitors and may suggest partial restoration of HRR gene function through mutation recovery.
l The emergence of PARP1 variants predicted to truncate PARP1 or inhibit binding with talazoparib supports the hypothesis that the ability of PARP to capture DNA damage is a major mechanism of cancer cell killing.
l Numerically supporting the use of ctDNA load as a candidate predictive biomarker for early tumor shrinkage in patients with antitumor responses.
Professor Guiming Zhang ‘s Comments
Prostate cancer is the second most common cancer in men worldwide (second only to lung cancer), and over half of prostate cancer patients in China already have metastasis at the time of initial diagnosis. mCRPC is the final stage of prostate cancer, and at the molecular level, tumor cells exhibit heterogeneity. Harmful mutations in DNA repair genes are present in 20% to 30% of mCRPC patients. Previous treatment approaches such as novel hormonal therapy and chemotherapy cannot fully meet the clinical needs of patients, and more innovative and precise treatment approaches are urgently needed. Therefore, precision diagnosis and treatment have become hot topics and trends in advancing the survival benefits of prostate cancer patients, enabling the effective identification of targets and prediction of patient benefits.
Previously, there have been few studies investigating the prognosis differences between germ line and somatic HRR mutations in prostate cancer. The results of the “TALAPRO-2 Study: Exploration of Homologous Recombination Repair (HRR) Mutations and Their Potential Association with Antitumor Activity from Germ Line (g) and Somatic (s) Sources” presented at ESMO are refreshing. The study found that patients with germ line HRR mutations had shorter rPFS when treated with enzalutamide alone, without significant differences between germ line and somatic mutation patients. However, in patients receiving talazoparib in combination with enzalutamide, there was no association between antitumor activity and the source of HRR gene mutations. This suggests that adding talazoparib on top of novel hormonal therapy may reverse the poor prognosis of patients with germ line mutations, equalizing the prognosis between germ line and somatic HRR mutation patients.
In the “TALAPRO-2 Study: Subgroup Analysis of Talazoparib (TALA) Plus Enzalutamide (ENZA) Treatment for mCRPC,” we are pleased to see that, although overall survival data are still immature, there is a clear OS benefit in the HRR mutation population. In the final study, we also see more exploration of the correlation between ctDNA mutation load and efficacy.
It’s worth mentioning that the indication for talazoparib in combination with enzalutamide for the treatment of mCRPC patients with HRR mutations has received FDA approval. We look forward to its approval and availability in China, benefiting a large number of prostate cancer patients and bringing new choices and breakthroughs in precision diagnosis and treatment for prostate cancer.
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Doctor of Medicine, Postdoctoral Fellow,
Chief Physician, Master’s Supervisor
Chinese Urological Association (CUA) Youth Committee Member of the Tumor Group;
Youth Committee Member of the Chinese Anti-Cancer Association Genitourinary System Tumor Committee (CACA-GU);
Member of the Prostate Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO);
Standing Committee Member and Tumor Group Member of the Shandong Provincial Medical Association Urology Branch;
Deputy Director and Standing Committee Member of the Youth Committee of the Shandong Provincial Anti-Cancer Association Genitourinary System Tumor Branch;
Member of the Geriatric Medicine Research Committee of the Shandong Provincial Medical Association Urology Branch;
Member of the Qingdao Urology Association;
Outstanding Young Medical Expert in Qingdao.
