Talazoparib/Enzalutamide Improves Imaging-Based PFS in Metastatic CRPC, Regardless of HRR Status

Neeraj Agarwal, MD

Talazoparib (Talzenna) plus enzalutamide (Xtandi) in the frontline setting yielded a clinically meaningful improvement in imaging-based progression-free survival (PFS) among patients with metastatic castration-resistant prostate cancer, regardless of homologous recombination repair (HRR) status, compared with placebo plus enzalutamide. Moreover, the treatment was found to delay time to worsening global health core and quality of life in this setting, according to an analysis of the phase 3 TALAPRO-2 study (NCT03395197).¹

Findings presented at the 2023 American Society for Clinical Oncology Genitourinary Cancers Symposium showed that treatment with talazoparib plus enzalutamide resulted in a 37% reduction in the risk of progression or death as assessed by blinded independent central review (HR, 0.63; 95% CI, 0.51-0.78; P < .001). The median rPFS was not reached (NR; 95% CI, 27.5-NR) in the combination arm (n = 402) compared with 21.9 months (95% CI, 16.6-25.1) for patients in the placebo arm (n = 403). The median follow-up for rPFS was 24.9 months and 24.6 months in the combination and placebo groups, respectively.

Patients with HRR-deficient mCRPC treated with talazoparib plus enzalutamide (n = 85) achieved a median rPFS of 27.9 months (95% CI, 16.6-NR) vs 16.4 months (95% CI, 10.9-24.6) for those treated with placebo (n = 84; HR, 0.46; 95% CI, 0.30-0.70; P < .001). In those who were did not have HRR-deficient tumors or for whom this was unknown, the median rPFS was NR (95% CI, 27.5-NR) for those who received talazoparib plus enzalutamide (n = 317) compared with 22.5 months (95% CI, 19.1-30.5) for placebo plus enzalutamide (n = 319; HR, 0.70; 95% CI, 0.54-0.89; P = .004).

The median rPFS was NR (95% CI, 25.8-NR), for patients with HRR-nondeficient mCRPC confirmed by prospective tumor tissue testing who received talazoparib plus enzalutamide (n = 198) compared with 22.1 months (95% CI, 16.6-NR) for those treated in the placebo arm (n = 214; HR, 0.66; 95% CI, 0.49-0.91; P = .009).

“We [saw] a consistent effect with talazoparib plus enzalutamide in prespecified subgroups, such as by age, performance status, Gleason score, site of metastasis, HRR status, or prior abiraterone [acetate (Zytiga)] or docetaxel,” lead study author Neeraj Agarwal, MD, a professor of medicine and a presidential endowed chair of Cancer Research at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, said in a presentation of the data.

Prior data from the phase 2 TALAPRO-1 trial (NCT03148795) showed that talazoparib monotherapy at 1 mg per day produced durable antitumor activity and manageable safety in heavily pretreated patients with mCRPC harboring HRR gene alterations.²

TALAPRO-2 evaluated talazoparib in combination with enzalutamide in the first-line setting for patients with mCRPC who were unselected for HRR status. Patients were required to have an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to receive talazoparib at 0.5 mg plus enzalutamide at 160 mg per day or placebo plus enzalutamide at 160 mg per day. Stratification factors included prior abiraterone or docetaxel in the castration-sensitive setting (yes vs no) and HRR gene alteration status (deficient vs nondeficient or unknown).

The primary end point was rPFS. Overall survival (OS) served as the trial’s key secondary end point, and other secondary end points included time to cytotoxic chemotherapy, time to progression on next line of therapy (PFS2) by investigator assessment, objective response rate (ORR), patient-reported outcomes (PROs), and safety.

Patient characteristics were well balanced between the 2 treatment arms. The median age in both arms was 71 years, and the median prostate-specific antigen (PSA) was 18.2 ng/mL (range, 0.1-2796.0) and 16.2 ng/mL (range, 0.1-2285.1) in the talazoparib and placebo arms, respectively. Metastatic disease sites included bone (86.8% and 84.9% in the talazoparib and placebo arms, respectively), lymph node (36.6% and 41.4%), visceral lung (11.2% and 15.1%), and visceral liver (3.0% and 4.0%).

In the talazoparib and placebo arms, 64.4% and 67.2% of patients had an ECOG performance status of 0, respectively. Additionally, 27.1% of patients in the talazoparib group had prior abiraterone (5.2%) or docetaxel (21.4%), compared with 27.3% in the placebo group (6.2% for abiraterone and 23.1% for docetaxel). HRR status was nondeficient or unknown for 78.9% and 79.2% for patients in the talazoparib and placebo arms, respectively.

For patients treated with talazoparib plus enzalutamide, 86.3% had tumor tissue assess for baseline HRR gene status, 14.2% had tissue and circulating tumor DNA (ctDNA) assessed, and no patients had ctDNA alone assessed. For patients treated with placebo plus enzalutamide, those rates were 86.1%, 14.1%, and 0.2%, respectively.

In the talazoparib arm, 21.1% of patients had 1 or more alterations in the corresponding HRR gene. Gene alterations were well-balanced and consistent with prior reports. These included the following: CDK12 (5.7%), BRCA2 (5.7%), ATM (5.7%), CHEK2 (1.5%), BRCA1 (1.2%), and other (ATR, ANCA, MLH1, MRE11A, NBN, PALB2, RAD51C; 3.5%). In the placebo arm, 20.3% of patients had 1 or more alterations in the corresponding HRR gene, including CDK12 (7.2%), BRCA2 (6.9%), ATM (3.5%), CHEK2 (1.2%), BRCA1 (1.0%), and other (3.2%).

Additional data from an interim analysis of OS showed that the median OS was 36.4 months (95% CI, 33.5-NR) for talazoparib plus enzalutamide vs NR (95% CI, 33.7-NR) for placebo plus enzalutamide (HR, 0.89; 95% CI, 0.69-1.14; P = .35). These data were 31% mature.

The median time to PSA progression was 26.7 months (95% CI, 21.2-30.4) in the talazoparib arm and 17.5 months (95% CI, 14.1-20.8) in the placebo arm (HR, 0.72; 95% CI, 0.58-0.89; P = .002). The median time to cytotoxic chemotherapy was NR (95% CI, 37.0-NR) and NR (95% CI, 32.3-NR) for the talazoparib and placebo groups, respectively (HR, 0.49; 95% CI, 0.38-0.65; P < .001). The median PFS2 for talazoparib plus enzalutamide was 36.4 months (95% CI, 33.5-NR) vs 35.3 months (95% CI, 28.6-NR) for placebo plus enzalutamide (HR, 0.77; 95% CI, 0.61-0.98; P = .04).

Evaluable patients treated with talazoparib plus enzalutamide (n = 120) experienced an ORR of 61.7%, including a complete response (CR) rate of 37.5%, a partial response (PR) rate of 24.2%, a stable disease rate of 30.0%, and a progressive disease rate of 5.8%. The ORR for evaluable patients treated with placebo plus enzalutamide (n = 132) was 43.9%, with a CR rate of 18.2%, a PR rate of 25.8%, a stable disease rate of 28.8%, and a progressive disease rate of 22.7%.

Regarding safety, 98.5% and 94.5% of patients experienced any treatment-emergent adverse effect (TEAE) in the talazoparib and placebo arms, respectively. The rates of any treatment-related TEAEs were 89.7% and 69.6%, respectively. Serious AEs were reported in 39.4% of patients in the talazoparib arm, including 19.6% who had serious treatment-related AEs (TRAEs). In the placebo arm, serious AEs and serious TRAEs occurred in 26.7% and 3.0% of patients, respectively.

The rates of grade 3/4 TEAEs were 71.9% and 40.6% for the talazoparib and placebo groups, respectively. Grade 5 TEAEs occurred in 3.3% of patients in the talazoparib arm compared with 4.5% in the placebo arm. No grade 5 TEAEs were deemed treatment related in the talazoparib arm compared with 0.5% in the placebo arm.

Dose interruptions, reductions, and discontinuations of talazoparib occurred in 75.4%, 56.0%, and 19.1% of patients in the experimental arm, respectively. Interruptions, reductions, and discontinuation of placebo were reported in 23.4%, 7.2%, and 12.2% of patients in the control arm, respectively.

Regarding TEAEs of special interest for talazoparib, 1 patient in the experimental arm experienced myelodysplastic syndrome during the safety reporting period, and another patient had acute myeloid leukemia during the follow-up period. Pulmonary embolism occurred in 2.5% of patients (9 out of 10 cases were grade 3) in the experimental arm 0.7% of patients (all grade 3) in the control arm.

The most common TEAEs leading to a dose reduction of talazoparib included anemia (43.2%), neutropenia (15.1%), and thrombocytopenia (5.5%). Notably, 49.0% of patients have grade 1/2 anemia at baseline. Grade 3/4 anemia was reported in 46.5% of patients in the experimental arm, the median time to onset was 3.3 months, and 8.3% of patients discontinued talazoparib due to anemia. However, the median relative dose of talazoparib remained above 80%.

PROs showed that talazoparib plus enzalutamide significantly prolonged time to definitive clinically meaningful deterioration of global health status/quality of life. The median time to deterioration was 30.8 months (95% CI, 27.0-39.6) for talazoparib/enzalutamide (n = 395) compared with 25.0 months (95% CI, 22.9-30.4) for placebo/enzalutamide (n = 398; HR, 0.78; 95% CI, 0.62-0.99; P = .04).

“Results from the primary analysis of the TALAPARO-2 trial support the use of talazoparib plus enzalutamide as a first-line treatment of men with mCRPC, regardless of HRR gene alteration status,” Agarwal concluded.

In a discussion following the presentation, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga in Spain, said that although Agarwal and colleagues concluded that results from TALAPRO-2 support the use of talazoparib plus enzalutamide as a first-line treatment for patients with mCRPC, regardless of HRR status, a better understanding is needed regarding the combination of an ARS inhibitor with a PARP inhibitor, since the balance between benefit and AEs may depend on HRR status and other potential factors.

“We know that alterations in HRR genes sensitize patients to response to [a] PARP inhibitor, and, as Dr Agarwal saw, there is a difference in the magnitude of the benefit for patients with HRR alterations and patients without [HRR alterations]. I think HRR status matters,” Castro said.

References

1. Agarwal N, Azad A, Carles J, et al. TALAPRO-2: phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl 6):LBA17. doi:10.1200/JCO.2023.41.6_suppl.LBA17
2. de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250-1264. doi:10.1016/S1470-2045(21)00376-4