Talzenna (Page 6 of 8)

14.2 HRR Gene-mutated mCRPC

The efficacy of TALZENNA in combination with enzalutamide was evaluated in TALAPRO-2 (NCT03395197), a randomized, double-blind, placebo-controlled, multi-cohort trial in which 399 patients with HRR gene-mutated (HRRm) mCRPC were randomized 1:1 to receive enzalutamide 160 mg daily plus either TALZENNA 0.5 mg or placebo daily until unacceptable toxicity or progression. All patients received a GnRH analog or had prior bilateral orchiectomy and needed to have progressed on prior androgen deprivation therapy. Prior treatment with a CYP17 inhibitor or docetaxel for metastatic castration-sensitive prostate cancer (mCSPC) was permitted. Mutation status of HRR genes was determined prospectively using solid tumor tissue or circulating tumor DNA (ctDNA)-based next generation sequencing assays. Patients were required to have a mutation in at least one of 12 genes involved directly or indirectly in the HRR pathway (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C).

Randomization was stratified by previous treatment with a CYP17 inhibitor or docetaxel (yes/no).

The median age was 70 years (range: 41 to 90); 100% were male; 68% were White, 21% Asian, 2.8% Black, 0.8% Other, 7% unknown/not reported; 12% were Hispanic/Latino; and baseline ECOG performance status was 0 (62%) or 1 (38%). Thirty-nine percent of patients had bone-only disease; 15% had visceral disease. In the mCSPC setting, 29% percent of patients had received docetaxel and 9% had received a prior CYP17 inhibitor. The most commonly mutated HRR genes (>5%), including co-occurring mutations, were: BRCA2 (34%), ATM (22%), CDK12 (19%), CHEK2 (18%), and BRCA1 (6%).

The major efficacy outcome measure was radiographic progression-free survival (rPFS) evaluated according to RECIST, version 1.1 and Prostate Cancer Working Group (PCWG3) (bone) criteria, assessed by BICR. An additional efficacy outcome measure was OS.

A statistically significant improvement in rPFS was demonstrated at the pre-specified interim analysis in patients randomized to TALZENNA in combination with enzalutamide compared with placebo in combination with enzalutamide. Consistent rPFS results were observed in patients who received or did not receive a prior CYP17 inhibitor or docetaxel. The OS data were not mature at the time of the rPFS analysis (24% of patients had died). Efficacy results are presented in Table 10 and Figure 3.

Table 10. Efficacy Results for TALAPRO-2 (HRR Gene-mutated mCRPC)
Abbreviations: BICR=blinded independent central review; CI=confidence interval; CSPC=castration-sensitive prostate cancer; HRRm=homologous recombination repair gene-mutated; mCRPC=metastatic castration-resistant prostate cancer; N=number of patients; NE=not evaluable.
*
Hazard ratio and CI were based on Cox PH model stratified by previous treatment for CSPC.
p-value was based on log-rank test stratified by previous treatment for CSPC and compared with the boundary 0.0076.

TALZENNA with Enzalutamide

(N=200)

Placebo with Enzalutamide

(N=199)

Radiographic Progression-free Survival (rPFS) by BICR

Number of rPFS events, n (%)

66 (33)

104 (52)

Median months (95% CI)

NE (21.9, NE)

13.8 (11.0, 16.7)

Hazard ratio (95% CI)*

0.45 (0.33, 0.61)

p-value

<0.0001

Figure 3. Kaplan-Meier Curve for rPFS in TALAPRO-2 (HRR Gene-mutated mCRPC)

Abbreviations: HRRm=homologous recombination repair gene-mutated; mCRPC=metastatic castration-resistant prostate cancer; rPFS=radiographic progression-free survival.
Figure 3
(click image for full-size original)

Exploratory subgroup analyses of rPFS for patients with BRCA -mutated (BRCA m) and non-BRCA m HRRm are presented in Table 11.

Table 11. Exploratory rPFS Subgroup Analyses by BRCAm Status for TALAPRO-2 (HRR Gene-mutated mCRPC)
Abbreviations: BRCA m=breast cancer susceptibility gene-mutated; CI=confidence interval; HRRm=homologous recombination repair gene-mutated; NE=not evaluable; rPFS=radiographic progression-free survival.
*
Includes 4 patients who were incorrectly randomized in the HRRm stratum who did not have HRR gene mutations.

BRCA m

Non-BRCA m HRRm*

TALZENNA with Enzalutamide

N=71

Placebo with Enzalutamide

N=84

TALZENNA with Enzalutamide

N=129

Placebo with Enzalutamide

N=115

rPFS

Number of events, n (%)

15 (21)

54 (64)

51 (40)

50 (43)

Median months (95% CI)

NE (NE, NE)

11.0 (8.3, 11.1)

24.7 (16.4, NE)

16.7 (13.8, 27.7)

Hazard ratio (95% CI)

0.20 (0.11, 0.36)

0.72 (0.49, 1.07)

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