Change in direction for mCRPC therapy with parp inhibitors

Multiple systemic options have been considered for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Despite significant advances in these therapies, the median overall survival (OS) in the first-line setting is only 3 years.1,2 Thus, there is an ongoing need to improve the standard of care for men with mCRPC. At the Uro-Oncology Asia 2020, organized by The Hong Kong Society of Uro-Oncology, Prof. Przemyslaw W. Twardowski from John Wayne Cancer Institute, United States, discussed the paradigm shift of mCRPC therapy with poly-ADP ribose polymerase inhibitors (PARPis).

The mechanism of action of PARPis in mCRPC is blocking DNA repair pathways in cells harboring homologous recombinatory repair (HRR) defects.3 Olaparib is a PARP inhibitor and being investigated as a novel monotherapy in mCRPC. The TOBARB trial has demonstrated positive outcomes with olaparib in mCRPC patients with HRR gene defects.4

The efficacy and safety of olaparib were recently explored by the randomized, open-label and phase 3 PROfound study.5 The study population composed of HRR mutation positive mCRPC patients who progressed despite hormonal therapy and without prior PARPi therapy or DNA-damaging cytotoxic chemotherapy. Olaparib provided a statistically significant and clinically meaningful radiographic-progression free survival (r-PFS), particularly in patients with breast cancer type 1 (BRCA1), breast cancer type 2 (BRCA2) and/or ATM serine/threonine kinase (ATM) mutations.5 Also, it improved clinical and patient reported outcomes, such as objective response rate (ORR) and time to pain progression (TTPP).5 Despite >80% of cross over, in an interim analysis, olaparib has shown favorable trend in OS for patients with alteration in BRCA1, BRCA2 and/or AT (HR=0.64) and in the overall population (HR=0.67).5 Additionally, olaparib was well tolerated with a comparable safety profile with other PARPis.5

During an interview with Omnihealth practice, Prof. Twardowski mentioned that with the promising results of PROfound study, PARPis are going to be the definite path forward in the future drug development for mCRPC. Responding to the best combination therapy with PARPis, Prof. Twardowski elaborated that it is important to understand the complete mechanism and the rationale for merging therapeutic agents. For example, chemotherapy induces DNA damage of specific mutated genes and combining PARPis could inhibit the repair of damaged DNA. Combination with other DNA repair inhibitors which function through different pathways like ATM or ATR could also bring synergistic effects. However, Prof. Twardowski stated, “I would say that among all these agents to be combined, I am looking forward to the combination of PARPis and immune checkpoint inhibitors.” He expects that the action of PARPis inhibiting DNA repair would allow immune checkpoint inhibitors to target gene mutations, creating a mechanistically symbiotic relationship.

When asked about how to choose specific PARPi for patients in clinical practice, Prof. Twardowski replied, “According to phase 2 data, at similar clinical settings, I don’t see a significant difference in the efficacy and safety among PARPis.” Therefore, he said choosing an agent is purely a practical decision that depends on the access, availability and patient’s preference. The most common side effects reported with PARPis are anemia and fatigue. Whilst commenting on the management of side effects, Prof. Twardowski said, “Overall, the side effects are mild and thus manageable.” Whereas, he added that management of fatigue is challenging due to the individual variations, but currently various other measures, such as exercise and acupuncture therapy, are utilized in reducing fatigue.

In conclusion, PROfound is the first positive phase 3 trial that evaluated a targeted treatment in patients with mCRPC and highlighted the importance of genomic testing in this population. Given the efficacy and safety demonstrated by olaparib, PARPis could become the next treatment of choice in mCRPC.

  1. Ryan CJ et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.
  2. Beer TM et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. 2017;71(2):151-154.
  3. Kaufman B et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244-250.
  4. Mateo J et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015;373(18):1697-1708.
  5. Hussain M et al. PROfound: Phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Annals of Oncology. 2019;30:v851-v934.
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