Introduction

Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR) genes, with about 1% exhibiting BRCA1 changes and 7%-13% showing BRCA2 alterations. These HRR alterations, especially in BRCA1 and BRCA2, are linked to a more aggressive cancer phenotype and greater tumor sensitivity to PARP inhibitors. The Phase III PROfound trial demonstrated that patients with these alterations had significantly better radiographic progression-free survival (rPFS) and overall survival (OS) with Olaparib compared to abiraterone or enzalutamide following disease progression on prior next-generation hormonal agents (NHA).

Aim

This exploratory post hoc analysis evaluated safety and efficacy outcomes in subgroup of patients with mCRPC with BRCA alterations in PROfound Trial

Patient Profile

Patients  with an alteration in a homologous recombination repair gene by tumor tissue testing and underlying BRCA alterations

Methods

• This is a Post hoc analysis of Phase III PROfound trial
• In PROfound Trial patients were randomly assigned 2:1 to
  • Olaparib monotherapy 300 mg twice a day or
  • Physician’s choice of either enzalutamide (160 mg once daily) or abiraterone (1,000 mg once daily, plus prednisone 5 mg twice a day; control), stratified by whether patients had received previous taxane (yes/no) and had measurable disease (yes/no).

  

• rPFS and OS were estimated using the Kaplan-Meier method.
• Confirmed objective response rate and safety were also assessed.

  Results

• At final analysis, median treatment duration was 9.6 months in the olaparib arm and 3.8 months in the control arm
• Olaparib was associated with longer rPFS (HR=0.22) & OS (HR=0.63) than control (Figure 1)
  • In patients with BRCA2-only alterations, the median rPFS was 10.8 months for olaparib compared to 3.5 months for control, while for those with BRCA1-only alterations, it was 2.1 months versus 1.8 months.
  • In patients with BRCA2-onlyand BRCA1-only populations, the HR for OS favoured olaparib versus control HR, 0.59 & HR, 0.42 resp

   

   

• In the final overall survival analysis, olaparib significantly reduced the risk of death in patients with BRCA alterations, with a median survival of 17.4 months versus 12.6 months (HR, 0.64) with prior taxane, and an undefined median survival without prior taxane versus 18.8 months (HR, 0.30).
• A greater percentage of patients in the olaparib group experienced reductions from baseline in target lesions, PSA levels, and CTC levels compared to the control group, suggesting that a larger number of patients in the olaparib arm responded to the treatment. (Figure 2)

  Figure 2: Confirmed ORR, PSA, and CTCs in olaparib and control arm

  

  CTC :circulating tumor cell conversion; PSA: prostate-specific antigen response

• The proportion of tumours with biallelic inactivation was high (84%) for germline (78%) & somatic (91%) BRCA alterations
• Olaparib was associated with prolonged rPFS & OS and higher confirmed ORR for patients with either germline or somatic BRCA alterations compared with control (Table 1)

  Table 1 : Efficacy Results by Germline or Somatic Status for the Population of Patients with BRCA Alterations

  	Germline		Somatic
  	Olaparib (n =42)	Control (n= 19)	Olaparib (n = 33)	Control (n= 18)
  Endpoint
  rPFS Median, months	10.4	1.9	11.1	2.3
  HR	0.008		0.16
  OS median months	20.8	15.1	18.5	16.6
  HR	0.55		0.66
  	Germline		Somatic
  Endpoint	Olaparib (n=19)	Control (n=12)	Olaparib (n=20)	Control (n=10)
  ORR % evaluable patients with a response	47.4	0	35.0	0
  OR	NC		NC

   

   

  BRCA, BRCA1 and/or BRCA2 including co-occurring alterations in other HRR genes; HR, hazard ratio; NC, not calculable; OR, odds ratio; ORR, objective response rate; OS, overall survival; rPFS, radiographic progression-free survival.

• There was an rPFS benefit with olaparib in all zygosity subgroups ( Table 2 )

  Table 2: Olaparib Efficacy in Patients with BRCA Alterations by Zygosity of the Detected Alteration

  	Biallelic/Suspected Biallelic Inactivation		Heterozygous		Unknown
  	Olaparib (n =53)	Control (n= 35)	Olaparib (n= 53)	Control (n= 35)	Olaparib (n= 53)	Control (n= 35)
  Endpoint
  rPFS Median, months	11.4	3.5	47	2.0	74	30
  HR	0.008		NA		0.30
  OS median months	26.8	18.1	16.8	9.4	17.6	13.5
  HR	0.48		NA		0.77
  ORR
  Patients evaluable for ORR, No.	28	20	1	20	12
  Patients with a response, No. (%)	17	0	0	4	0

  BRCA, BRCA1 and/or BRCA2 including co-occurring alterations in other HRR genes; HR, hazard ratio; HRR, homologous recombination repair; NA, not applicable; OR:  odds ratio; ORR, objective response rate; OS, overall survival; rPFS, radiographic progression-free survival.

• Patients with BRCA2 homozygous deletions experienced prolonged responses to olaparib (n=16; median rPFS, 16.6 mos)

Conclusion

• Treatment with olaparib enhanced outcomes for patients with mCRPC characterized by BRCA alterations, particularly in those whose disease had progressed despite prior treatment with novel hormonal agents, when compared to enzalutamide or abiraterone.
• The benefits of olaparib were evident across all evaluated subgroups, which included previous exposure to taxane therapies, transition to olaparib treatment, the germline or somatic origin of BRCA alterations, and zygosity by targeted next-generation sequencing

Reference

J Clin Oncol 42:571-583