14.1 Deleterious or Suspected Deleterious Germline BRCA-mutated HER2-negative Locally Advanced or Metastatic Breast Cancer

EMBRACA (NCT01945775) was an open-label study in which patients (N=431) with gBRCAm HER2-negative locally advanced or metastatic breast cancer were randomized 2:1 to receive TALZENNA 1 mg or healthcare provider's choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) until disease progression or unacceptable toxicity. Randomization was stratified by prior lines of chemotherapy for metastatic disease (0 vs 1, 2, or 3), by triple-negative disease status [triple-negative breast cancer (TNBC) vs non-TNBC], and history of central nervous system (CNS) metastasis (yes vs no).

Patients received no more than 3 prior cytotoxic chemotherapy regimens for their metastatic or locally advanced disease. Patients were required to have received treatment with an anthracycline and/or a taxane (unless contraindicated) in the neoadjuvant, adjuvant, and/or metastatic treatment setting. First-line treatment for advanced or metastatic disease with no prior adjuvant chemotherapy was allowed if the investigator determined that 1 of the 4 chemotherapy choices in the control arm would be an appropriate treatment option for the patient. Patients with prior platinum therapy for advanced disease were required to have no evidence of disease progression during platinum therapy. No prior treatment with a PARP inhibitor was permitted. Of the 431 patients randomized in the EMBRACA study, 408 (95%) were centrally confirmed to have a deleterious or suspected deleterious gBRCAm using a clinical trial assay; out of which 354 (82%) were confirmed using the BRACAnalysis CDx®. BRCA mutation status [breast cancer susceptibility gene 1 (BRCA1)-positive or breast cancer susceptibility gene 2 (BRCA2)-positive] was similar across both treatment arms.

The median age of patients treated with TALZENNA was 46 years (range: 28 to 84) and 51 years (range: 24 to 89) among patients treated with chemotherapy. Among all randomized patients, 1% vs 2% were males, 67% vs 75% were White; 11% vs 11% were Asian, and 4% vs 1% were Black or African American in the TALZENNA and chemotherapy arms, respectively. Almost all patients (98%) in both arms had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Approximately 56% of patients had estrogen receptor-positive and/or progesterone receptor-positive disease; 44% of patients had triple-negative disease, and the proportions were balanced across both treatment arms. Fifteen percent (15%) of patients in the TALZENNA arm and 14% of patients in the chemotherapy arm had a history of CNS metastases. Ninety-one percent (91%) of patients in the TALZENNA arm had received prior taxane therapy, and 85% had received prior anthracycline therapy in any setting. Sixteen percent (16%) of patients in the TALZENNA arm and 21% of patients in the chemotherapy arm had received prior platinum treatment in any setting. The median number of prior cytotoxic regimens for patients with advanced breast cancer was one; 38% received no prior cytotoxic regimens for advanced or metastatic disease, 37% received one, 20% received two, and 5% received three or more prior cytotoxic regimens.

The major efficacy outcome measure was progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by blinded independent central review (BICR). A statistically significant improvement in PFS was demonstrated for TALZENNA compared to chemotherapy. A sensitivity analysis of investigator-assessed PFS was consistent with the BICR-assessed PFS results. Consistent PFS results were observed across patient subgroups defined by study stratification factors (prior lines of chemotherapy, TNBC status, and history of CNS metastases). Efficacy data from the EMBRACA study are summarized in Table 11, and the Kaplan-Meier curves for PFS are shown in Figure 1 and final overall survival (OS) in Figure 2.

Figure 1. Kaplan-Meier Curves of PFS – EMBRACA Study

Abbreviation: PFS=progression-free survival.

Figure 2. Kaplan-Meier Curves of OS – EMBRACA Study (ITT Population)

Abbreviations: ITT=intent-to-treat; OS=overall survival.

14.2 HRR Gene-Mutated Prostate Cancer

mAPMR Prostate Cancer

TALAPRO-2

The efficacy of TALZENNA 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) mAPMR prostate cancer were randomized 1:1 to receive enzalutamide 160 mg daily plus either TALZENNA 0.5 mg or placebo daily until unacceptable toxicity or disease progression. Mutation status of HRR genes was determined prospectively using solid tumor tissue or circulating tumor DNA (ctDNA)-based next generation sequencing tests. 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). All patients received a GnRH analog or had had a prior bilateral orchiectomy and needed to have progressed on prior androgen deprivation therapy. Prior treatment with a CYP17 inhibitor or docetaxel for mAPMN/S prostate cancer was permitted. 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 mAPMN/S prostate cancer setting, 29% 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 blinded independent central review (BICR). An additional efficacy outcome measure was overall survival (OS).

Statistically significant improvements in rPFS and OS were demonstrated in patients randomized to TALZENNA with enzalutamide compared with placebo with enzalutamide. Efficacy results are presented in Table 12, and Figures 3 and 4.

Figure 3. Kaplan-Meier Curves of rPFS - TALAPRO-2 (HRRm mAPMR Prostate Cancer)

Figure 4. Kaplan-Meier Curves of OS – TALAPRO-2 (HRRm mAPMR Prostate Cancer)

Exploratory subgroup analyses of rPFS and OS for patients with BRCA-mutated (BRCAm) and non-BRCAm HRRm are presented in Table 13.

mAPMN/S Prostate Cancer

TALAPRO-3

The efficacy of TALZENNA in combination with enzalutamide was evaluated in TALAPRO-3 (NCT04821622), a randomized, double-blind, placebo-controlled, trial in which 599 patients with HRRm mAPMN/S prostate cancer were randomized 1:1 to receive enzalutamide 160 mg daily plus either TALZENNA 0.5 mg or placebo daily until unacceptable toxicity or disease progression. Mutation status of HRR genes was determined prospectively using solid tumor tissue or ctDNA-based next generation sequencing tests. 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). All patients received a GnRH analog, or had a prior bilateral orchiectomy. Patients must have initiated androgen deprivation therapy or undergone a bilateral orchiectomy in the mAPMN/S prostate cancer setting up to 3 months prior to randomization with or without an androgen receptor pathway inhibitor (ARPI) but were not allowed to have received prior docetaxel. Randomization was stratified by de novo mAPMN/S vs relapsed mAPMN/S prostate cancer, high vs low volume disease, and BRCA vs non-BRCA mutational status.

The median age was 70 years (range: 44 to 89); 100% were male; 57% were White, 39% Asian, 2% Black, 1% Other, 2% unknown/not reported; 10% were Hispanic/Latino, 87% were Not Hispanic or Latino, 3% unknown/not reported; and baseline ECOG performance status was 0 (68%) or 1 (32%). Thirteen percent of patients had received a prior ARPI in the mAPMN/S setting. There were 398 (66%) and 438 (73%) patients with high volume disease and de novo mAPMN/S prostate cancer, respectively, and 307 (51%) with both de novo and high-volume disease. The most commonly mutated HRR genes (>5%), including co-occurring mutations, were: BRCA2 (30%), ATM (28%), CDK12 (19%), CHEK2 (15%) and ATR (7%).

The major efficacy outcome measure was rPFS evaluated according to RECIST, version 1.1 and PCWG3 (bone) criteria, assessed by investigator. An additional efficacy outcome measure was OS.

A statistically significant improvement in rPFS was demonstrated in patients randomized to TALZENNA with enzalutamide compared with those randomized to placebo with enzalutamide. At the time of the rPFS analysis, OS data were immature with 28% deaths in the overall population. Efficacy results are presented in Table 14 and Figure 5.

Figure 5. Kaplan-Meier Curves of rPFS - TALAPRO-3 (HRRm mAPMN/S Prostate Cancer)

Exploratory subgroup analyses of rPFS for patients with BRCAm and non-BRCAm HRRm are presented in Table 15.