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Having said that, PARP inhibition is one of the most promising approaches for “precision therapy” so far. Within the next few years and with the help of ongoing clinical trials, we should have a better understanding of whether or not the high expectations raised will be translated into clinical reality.
Adenocarcinoma of the prostate is the most common cancer in men.[1,2] Although significant improvements have been made regarding the management of advanced disease, challenges remain concerning the optimal treatment of both hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). In the light of the recent CHAARTED and Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials,[3,4] which confirm the benefits of upfront docetaxel treatment in parallel with gonadal suppression and antiandrogen therapy in advanced prostate cancer, median overall survival may be extended by another 10 to 14 months compared with traditional “standard of care.” These results are changing the treatment paradigm for metastatic HSPC. Similar benefits in relapse-free survival were demonstrated by the Groupe d’Ãtude des Tumeurs UrogÃ©nitales (GETUG) study, although the difference in overall survival did not reach statistical significance in this trial. In later disease stages-ie, once castration resistance has occurred-rechallenge with docetaxel, second-generation antiandrogens (ie, abiraterone and enzalutamide), radium-223, cabazitaxel chemotherapy, and immune therapy with sipuleucel are efficient strategies for symptom control and prolonged survival.
Apart from the general clinicopathologic risk scoring algorithm for localized prostate cancer, however, we still mainly rely on the “one-size-fits-all” approach for the metastatic stage and have few tools for individual treatment prediction. Palmbos and Hussain confirm that we have a long way to go to realize precision-based medicine in the care of metastatic prostate cancer. A reasonable comparison could be made with breast cancer, the most common hormone-sensitive cancer in women, in which a panel of intratumoral biomarkers (human epidermal growth factor receptor 2 [HER2], estrogen receptor, progesterone receptor) has long been established as routine for guiding patients to personalized therapy with antihormonal and/or anti-HER2 targeting drugs.
Recent efforts with genome-wide analysis have created a map of genetic alterations driving metastatic prostate cancer and have identified a significant minority of patients with germline and/or acquired alterations in genes controlling DNA repair mechanisms. A broader molecular understanding of the “defect DNA repair subtype” and other subtypes of metastatic prostate cancer could form a potential basis for personalized “tailored” medicine. In a recent study, 23% of metastatic prostate cancers were found to harbor aberrations in BRCA1/2 and ATM, which are known to be key genes in the DNA repair pathway, and 8% of patients displayed germline mutations in these genes.
Concerning tumors with defective DNA repair machinery, a theoretically feasible approach is to target poly(adenosine diphosphate [ADP]–ribose) polymerase 1 (PARP1), which is the enzyme and drug target under focus in the Palmbos and Hussain review. PARP1 is an intranuclear “patroller” of DNA integrity and catalyzes the addition of poly(ADP-ribose) (PAR) groups to target proteins in a process termed PARylation that is crucial for the recruitment of DNA-repairing proteins to sites of single- or double-strand breaks. In addition, PARP1 is likely involved in transcriptional regulation of oncogenes and tumor suppressor genes and in genes encoding hormonal receptors and enzymes.
Recent studies of nonprostatic cancers, eg, breast cancer,[13-16] non–small-cell lung cancer, and ovarian cancer,[16,18-21] reveal that oral PARP inhibitors can be safely delivered in single or combination drug regimens, although efficacy data so far are equivocal. There are promising data on tumor response and prognostic improvement in platinum-sensitive advanced ovarian cancers with BRCA1/2 mutations or other signs of aberrant homologous recombination pathways.[16,18-21] On the other hand, a large phase III trial in patients with triple-negative breast cancer, which was aimed at confirming earlier phase II data, failed to reach its early efficacy endpoints and was terminated prematurely. It is important to note that BRCA1/2 status was not available in this trial. Taken together, lessons from breast and ovarian cancers indicate that PARP inhibition might be feasible, but only in patients with the appropriate biomarker status. This is in line with the results reported in the link paper from pilot data from a Hussain trial of temozolomide and veliparib in an unselected patient group with metastatic prostate cancer, in which only modest activity was seen.
In a pivotal phase II trial, Mateo et al studied 50 patients with CRPC. Fresh tumor biopsies were taken, and next-generation sequencing was performed to detect tumors with defects of the genes controlling the DNA repair machinery. All patients were treated with olaparib, an oral PARP1 inhibitor; the dosage and safety profile for this agent had been established earlier in a phase I trial. Of the 16 patients confirmed to be “biomarker-positive” (ie, carrying one or several alterations in the DNA repair genes, including BRCA1/2, ATM, Fanconi anemia genes, or CHEK2), 14 displayed an objective tumor response. The median progression-free survival in this subgroup of patients was 9.8 months, and the median overall survival reached 13.8 months, in comparison with 2.7 and 7.5 months, respectively, for the biomarker-negative patients. Considering that this was third-line therapy or beyond (ie, representing late disease stages with per-definition multidrug resistance, usually to both traditional chemotherapies and multiple lines of antihormonal treatments), these survival figures are impressive. However, this was a single-arm trial in which survival data were not primary outcomes. Until larger phase II/III randomized trials are completed, the need for cautious interpretation should be underscored.
Palmbos and Hussain further emphasize the completed but not yet reported National Cancer Institute 9012 trial, in which the combination of the PARP inhibitor veliparib and abiraterone was assessed against standard abiraterone in a randomized phase II setting. PARP1 is supposed to be involved in the formation of a fusion gene between a transcription factor gene of the ETS superfamily and the androgen-responsive gene TMPRSS2. Of these so-called ETS fusion genes, the most commonly identified example is TMPRSS2:EGR, which is present in 50% to 60% of prostate tumors; hence, this “two frontiers” precision treatment against both PARP1 and androgen signaling is biologically relevant. In addition to analysis of the ETS fusion status, a panel of DNA repair genes will be assessed, and potential biomarkers for combined PARP1/antiandrogen therapy will be identified in the trial population of 148 patients with CRPC. The results from this key study are expected to be presented at the American Society of Clinical Oncology 2016 Annual Meeting.
Palmbos and Hussain have provided an excellent review of this topic and emphasize the importance of preselection of patients as we move toward the era of targeted therapies. As they point out, significant challenges remain before a role for PARP inhibitors in the treatment of metastatic prostate cancer can be established or ruled out. Lessons from other cancers, as well as from the recent Mateo et al phase II trial, suggest that proper molecular profiling is crucial before recommending a PARP-targeting therapy. In addition, important questions remain regarding the optimal sequence and potential combinations of treatments for metastatic prostate cancer in this new era of upfront docetaxel and multiple antiandrogen alternatives, as well as isotope or immune-modulating treatments. The requirements of fresh biopsy in some cases and the delays in obtaining molecular profiling results have to be addressed as well if this strategy is to have an impact on a wider patient population in a real-life setting.
Having said that, PARP inhibition is one of the most promising approaches for “precision therapy” so far. Within the next few years and with the help of ongoing clinical trials, we should have a better understanding of whether or not the high expectations raised will be translated into clinical reality. Among the myriad promising drugs, there will undoubtedly be some that fail to live up to current hopes, but we can be optimistic that with the use of this approach of robust molecular profiling and preselection of patients within clinical trials with matched treatments, more and more drugs will find a place in protocols that can keep advanced prostate cancer at bay for longer than can be achieved at present. This approach will also help move some of these new targeted therapies to earlier stages of prostate cancer, either as single agents or in combination with established therapies within clinical trials; however, the Holy Grail of a cure is likely, in the medium term, to remain elusive for most patients.
Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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