The efficacy of Lynparza was evaluated in PROfound (NCT02987543), randomized, open-label, multi-center trial that evaluated the efficacy of Lynparza 300 mg twice daily versus a comparator arm of investigator’s choice of enzalutamide or abiraterone acetate in men with metastatic castration-resistant prostate cancer (mCRPC). All patients received a GnRH analog or had prior bilateral orchiectomy. Patients needed to have progressed on prior enzalutamide or abiraterone for the treatment of metastatic prostate cancer and/or CRPC and have a tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway. 

Patients were divided into two cohorts based on HRR gene mutation status. Patients with mutations in either BRCA1, BRCA2, or ATM were randomized in Cohort A; patients with mutations among 12 other genes involved in the HRR pathway (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L) were randomized in Cohort B; patients with co-mutations (BRCA1, BRCA2, or ATM plus a Cohort B gene) were assigned to Cohort A. Although patients with PPP2R2A gene mutations were enrolled in the trial, Lynparza is not indicated for the treatment of patients with this gene mutation due to unfavorable risk-benefit. Patients were randomized (2:1), 256 to Lynparza arm and 131 to enzalutamide or abiraterone acetate arm; in Cohort A there were 245 (162 Lynparza arm and 83 in enzalutamide or abiraterone acetate arm) and in Cohort B there were 142 patients (94 in Lynparza arm and 48 in enzalutamide or abiraterone acetate arm). Randomization was stratified by prior receipt of taxane chemotherapy and presence of measurable disease by RECIST 1.1. Treatment was continued until objective radiological disease progression determined by BICR. Upon radiological progression confirmed by BICR, patients randomized to enzalutamide or abiraterone acetate were given the option to switch to Lynparza. Patients with HRR gene mutations were identified by tissue-based testing using the Foundation Medicine FoundationOne® clinical trial HRR assay performed at a central laboratory.

Determination of deleterious or suspected deleterious somatic or germline HRR mutation status in line with the FDA-approved mutation classification and testing criteria for the Foundation Medicine F1CDx tissue-based assay and assessment of the germline-BRCA status using the Myriad BRACAnalysis CDx blood-based assay was performed retrospectively. Representation of individual gene mutations by cohort is provided in Table 25. No patients were enrolled who had mutations in two of the 15 pre-specified HRR genes: FANCL and RAD51C.

In Cohort A+B, the median age was 69 years (range: 47 to 91 years) in both arms; 69% were White, 29% were Asian, and 1% were Black. The ECOG performance score was 0 or 1 in most patients (95%) in both arms. In patients treated with Lynparza, the proportion of patients with RECIST 1.1 measurable disease at baseline was 58%, including 17% with lung and 10% with liver metastases, respectively. At randomization, 66% of patients had received prior taxane chemotherapy, 40% had received enzalutamide, 38% had received abiraterone acetate, and 20% had received both enzalutamide and abiraterone acetate. Patient characteristics were well-balanced between arms.

The major efficacy outcome of the study was radiological progression-free survival (rPFS) (Cohort A) as determined by BICR using RECIST version 1.1 and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) (bone) criteria. Additional efficacy outcomes included confirmed objective response rate (ORR) (Cohort A), rPFS (combined Cohorts A+B) as assessed by BICR, and overall survival (OS) (Cohort A). 

PROfound demonstrated a statistically significant improvement in BICR-assessed rPFS for Lynparza compared to investigator’s choice of enzalutamide or abiraterone acetate in Cohort A and Cohort A+B. In an exploratory analysis for patients in Cohort B, the median rPFS was 4.8 months for Lynparza vs 3.3 months for comparator with a HR of 0.88 (95% CI 0.58, 1.36). The major efficacy outcome was supported by a statistically significant improvement in ORR by BICR for patients with measurable disease at baseline in Cohort A. In Cohort B, ORR by BICR was 3.7% (95% CI 0.5, 12.7) in Lynparza treated patients and 8.3% (95% CI 1.0, 27.0) in patients treated with enzalutamide or abiraterone acetate.

The final analysis of overall survival (OS) demonstrated a statistically significant improvement in OS in patients randomized to Lynparza compared to patients in the enzalutamide or abiraterone acetate arm in Cohort A.

Efficacy results of PROfound are provided in Tables 26 and 27 and Figures 10 and 11.

Figure 10 Kaplan-Meier Curves of BICR-Assessed rPFS – PROfound – Cohort A

Consistent results were observed in exploratory analyses of rPFS for patients who received or did not receive prior taxane therapy and for those with germline-BRCA mutations identified using the Myriad BRACAnalysis CDx assay compared with those with BRCA mutations identified using the Foundation Medicine F1CDx assay.

Figure 11 Kaplan-Meier Curves of Overall Survival – PROfound – Cohort A

Response data by HRR mutations for patients in the Lynparza arm are presented in Table 27. In the comparator arm of Cohorts A and B, a total of three patients achieved a partial response, including one patient with an ATM mutation alone and 2 patients with co-occurring mutations (one with PALB2+PPP2R2A and one with CDK12+PALB2).