Prostate cancer is the second most commonly occurring cancer in men and the fourth most commonly occurring cancer overall.1 It is estimated that more than 164,000 men in the United States will be diagnosed with prostate cancer in 2018.2 Since it occurs predominantly in older men, prostate cancer is likely to become an increasing healthcare burden in our aging population. Metastatic prostate cancer responds to androgen deprivation therapy. However, most cases become refractory after 1–3 years and resume growth despite hormone therapy and castrate serum levels of testosterone, leading to the state of castration-resistant prostate cancer (CRPC), for which the prognosis is poor, and there are no curative treatment options.3 There is an unmet need for alternative therapeutic approaches.
There is a wide variation in mortality rates in prostate cancer, which reflects the clinical and genetic heterogeneity of this disease and the different patient populations afflicted by it. Approximately 12% of patients with mCRPC have a deleterious mutation in the BRCA1 or BRCA2 genes.4 BRCA1 and BRCA2 proteins, as well as the as the ataxia-telangiectasia mutated (ATM) protein, are essential for the repair of double-strand breaks in DNA through the homologous recombination repair (HRR) pathway. An emerging treatment strategy in mCRPC, as well as a number of other cancers, involves the use of poly (ADP-ribose) polymerase (PARP) inhibitors to block HRR pathways, producing irreparable damage to cancer cells.5
Olaparib was the first PARP inhibitor to be approved by the US Food and Drug Administration (FDA) in mCRPC patients with BRCA1/2 or ATM alterations, based on the findings of the TOPARP phase II study, which recruited an unselected group of prostate carcinoma patients with disease progression after one to two lines of chemotherapy. Although the clinical activity in the cohort as a whole was not impressive, with only a 32% response rate, stratification on the basis of mutation testing found an 88% response rate in patients with mutations in HRR genes.6 This led to an explosion of interest in PARP inhibitors for mCRPC.
In October 2018, the FDA granted Breakthrough Therapy designation for a second PARP inhibitor, rucaparib, as a monotherapy treatment of adult patients with BRCA1/2-mutated mCRPC who have received at least one prior androgen receptor-directed therapy and taxane-based chemotherapy.7 Approval was based on data from the ongoing phase II TRITON study, which aims to enrol 157 patients who have progressed on one to two lines of androgen receptor-directed therapy and one prior line of taxane-based chemotherapy for mCRPC.
The first data from TRITON was presented by Clovis Oncology at the European Society for Medical Oncology (ESMO) 2018 Congress, 19–23 October 2018, in Munich, Germany.8 At the data cut-off date (6 March 2018), 52 patients had been treated with rucaparib. Of these, 26 (50%) had a BRCA1/2 alteration (BRCA patients), 12 had a CDK12 alteration, 10 had an ATM alteration and four had an alteration in another HRR gene. Among the evaluable BRCA patients, 11/23 (47.8%) had a confirmed prostate-specific antigen response. The most common treatment-emergent adverse events were nausea (48.1%; grade ≥3, 3.8%) and asthenia/fatigue (44.2%; grade ≥3, 1.9%). One (1.9%) patients discontinued due to a treatment-emergent adverse event.9
In another study presented by Clovis Oncology showing that genomic profiling of circulating tumour DNA and tumour tissue successfully identified patients with a mutation in an HRR gene for the evaluation of rucaparib in mCRPC. This has important implications in identifying patients most likely to respond to rucaparib.10 At present, there is no consensus for genetic testing in patients with prostate cancer; although, the National Comprehensive Cancer Network guidelines state that all mCRPC patients should be tested.11
One potential limitation of PARP inhibitors is the fact that the duration of response is suboptimal. A number of resistance mechanisms have been proposed, including the development of reversion mutations within the HRR pathway that restore function and allow double-strand breaks to undergo a less destructive repair pathway.12 Clearly more study is needed to elucidate these mechanisms and develop strategies to overcome them.
The early promise of PARP inhibitors has led to their investigation as front-line therapy (ClinicalTrials.gov Identifier: NCT02975934)13 and as combination therapy to maximize the durability and depth of therapeutic responses. A number of ongoing trials evaluating different PARP inhibitors in combination with immune checkpoint inhibitors (NCT03338790, NCT02484404).14,15 In addition, a recent study found that olaparib in combination with abiraterone improved progression-free survival in patients with mCRPC compared with abiraterone alone.16
References
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14. Clinicaltrials.gov. An Investigational Immunotherapy Study of Nivolumab in Combination With Rucaparib, Docetaxel, or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (CheckMate 9KD). Available at: https://clinicaltrials.gov/ct2/show/NCT03338790 (accessed 26 November 2018).
15. Clinicaltrials.gov. Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers. Available at: https://clinicaltrials.gov/ct2/show/NCT02484404 (accessed 26 November 2018).
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