Olaparib, potentially the first targeted treatment for metastatic castration-resistant prostate cancer patients with DNA repair gene mutations

31 Dec 2019

Prostate cancer (PCa) is the most common cancer affecting men in Europe and the United States.1 While non-metastatic PCa has a 5-year survival rate of 98.9%, the corresponding rate for metastatic PCa is less than 30%.2 There is increasing evidence that patients with PCa could have inherited predisposition, with increased risks conferred by certain mutations.3  PROfound, a randomized, open-label, phase 3 study of the poly ADP ribose polymerase (PARP) inhibitor, olaparib, reported significant improvements in radiographic progression-free survival (rPFS), in metastatic castration-resistant prostate cancer (mCRPC) patients who tested positive for DNA repair gene alterations in BRCA1, BRCA2, or ATM.4 These results were presented at the European Society for Medical Oncology.

In cancer cells already harboring multiple genetic mutations in the DNA damage response (DDR) pathway, PARP inhibition can make the cells unable to repair DNA damage, leading to cell death.5 In PCa, mutations in the genes involved in the DDR pathway, such as BRCA1, BRCA2 and ATM are relatively common, particularly in the advanced stages of the disease.5 Genetic testing for these mutations to inform cancer treatment could improve therapeutic outcomes.5

PROfound is a randomized, open-label, phase 3 trial evaluating the efficacy and safety of olaparib versus enzalutamide or abiraterone in patients with mCRPC with alterations in any of the 15 predefined genes with a direct or indirect role in homologous recombination repair (HRR).4 Patients had to have disease progression on prior new hormonal agent therapy, and were randomized in a 2:1 ratio to receive either olaparib 300mg BID or physicians choice of enzalutamide 160mg/day or abiraterone 1,000mg QD plus prednisone 5mg BID.4 Patients were divided into two cohorts, A, and B. Cohort A consisted of 245 patients with alterations in BRCA1, BRCA2, or ATM.4 Cohort B included 142 patients with any one of the 12 other HRR alterations.4 The primary endpoint was rPFS in Cohort A, assessed by blinded independent central review.4

A significant improvement was observed in median rPFS among cohort A – patients receiving olaparib had a median rPFS of 7.4 months, versus 3.6 months with hormonal therapy (HR=0.34; 95% CI: 0.25-0.47; p<0.0001).4 27.1% of patients receiving olaparib were progression free at 12 months, as opposed to 9.4% of patients receiving hormonal therapy.4 Patients receiving olaparib also had a confirmed objective response rate of 33.3% in cohort A, versus 2.3% with hormonal therapy (OR=20.86; p<0.0001).4 Time to pain progression as measured by the Brief Pain Inventory – Short Form was also significantly in favor of olaparib, with a median that was not reached versus 9.9 months (HR=0.44; p=0.0192).4

PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC.4 Principal investigator, Dr. Maha Hussain, commented that “To see such a significant effect on disease progression and other clinically relevant effects, such as pain progression and objective response, is a remarkable achievement in such heavily pretreated patients with prostate cancer.” 6 These results should encourage the greater use of genetic testing in patients with mCRPC.6 Oncologists treating breast or lung cancer already routinely carry out genetic testing on tumor tissue, as results determine which standard of care treatment is most suitable.7 While therapeutic options for advanced prostate cancer have improved over the last decade, it still remains a lethal disease.8 It is thus imperative to improve the patient care via more personalized therapeutic options.8

  1. Haberkorn U et al. New Strategies in Prostate Cancer: Prostate-Specific Membrane Antigen (PSMA) Ligands for Diagnosis and Therapy. Clin Cancer Res. 2016;22(1):9-15.
  2. Dong L et al. Metastatic prostate cancer remains incurable, why? Asian J Urol. 2019;6(1):26-41.
  3. Giri VN et al. Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol. 2018;36(4):414-424.
  4. Fizazi K et al. LBA15_PRA phase III trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04). Annals of Oncology. 2019;30(Supplement_5):mdz394.
  5. Lang SH et al. A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer. Int J Oncol. 2019;55(3):597-616.
  6. Davenport L. “Landmark” Trial in Prostate Cancer With Mutations. Medscape. Published October 4, 2019. Accessed October 23, 2019.
  7. Shin SH et al. Addressing the challenges of applying precision oncology. NPJ Precis Oncol. 2017;1. Accessed October 23, 2019.
  8. Mateo J et al. DNA Repair in Prostate Cancer: Biology and Clinical Implications. European Urology. 2017;71(3):417-425.
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