These data help us enter a new era and clearly indicate the importance of PARP inhibition in the surprisingly high percentage of patients with advanced prostate cancer and DNA-repair defects.
Oliver Sartor, MD
New data on molecular biomarkers in advanced prostate cancer are accumulating at a fast pace. The studies in this area can now be broadly grouped in two distinct areas—those that broadly relate to androgen signaling and those that relate to DNA-repair pathways.
The Androgen-Signaling Pathway
With regard to investigations concerning the androgen-signaling pathway, there have been several provocative studies indicating that the androgen receptor variant-7 (AR-V7) mRNA expression in circulating tumor cells is important in predicting resistance to enzalutamide (Xtandi) and abiraterone (Zytiga) in patients with metastatic castration-resistant prostate cancer.1 This concept, originally observed in a single-institution study, is now being evaluated in several prospective studies. A phase III trial with eligibility dependent on AR-V7—circulating tumor cells mRNA expression is now underway (NCT02438007).
Additional provocative studies have been published on circulating free DNA, and studies by multiple groups have now implicated resistance to both enzalutamide2 and abiraterone3 in patients with an increased copy number of the androgen receptor. Smaller studies have also implicated amplification of the CYP17 gene in abiraterone resistance.4 Selected deleterious mutations in the androgen receptor are also implicated in both abiraterone resistance and enzalutamide resistance.2,3 Thus, various aberrant androgen receptors are now beginning to be viewed in the context of clinically relevant alterations.
Recent significant discoveries have implicated germline and somatic DNA-repair defects in metastatic castration-resistant prostate cancer as a predictive biomarker for poly ADP-ribose polymerase (PARP) inhibitors such as olaparib (Lynparza). In an elegant study reported by Mateo and colleagues5 in The New England Journal of Medicine and reviewed in this issue of The ASCO Post, 50 patients were enrolled in a study with olaparib at a dose of 400 mg twice daily. All patients had previously received docetaxel, 98% had received abiraterone or enzalutamide, and 58% had received cabazitaxel (Jevtana); thus, these patients comprised an extremely heavily pretreated population. A total of 49 patients could be evaluated for response, and 16 of these patients responded.
Next-generation sequencing identified a variety of genetic alterations in either germline or tumor DNA, and alterations included homozygous deletion, various mutations, or both. A variety of DNA-repair genes were examined, and 16 of the 49 evaluable patients were found to have significant alterations in genes including BRCA1/2, ATM, Fanconi anemia, CHEK2, and/or others including PALB2.
Of the 16 patients with genetic alterations in DNA-repair genes, 14 (88%) responded to olaparib, including all 7 patients with BRCA2 alterations and 4 of 5 with ATM alterations. Of the 33 patients with no DNA-repair defect detected, only 2 responded to olaparib (6%). In addition to a higher response rate in the subset of men with DNA-repair defects, there were also olaparib-associated improvements in progression-free and overall survival. Taken together, these findings point to the potential importance of olaparib activity in this subset of patients.
An Important Step Forward
These data help us enter a new era and clearly indicate the importance of PARP inhibition in the surprisingly high percentage of patients with advanced prostate cancer and DNA-repair defects. Although the estimates vary, perhaps as many as 25% of patients with metastatic castration-resistant prostate cancer have tumors harboring DNA-repair defects. It is noteworthy that preliminary data also implicate DNA-repair defects with sensitivity to platinum-based regimens.6 Treatment with various forms of radiation therapy might also have interesting implications for these patients.
Despite the importance of the PARP inhibitor studies, there are certain limitations. Although germline analysis is relatively straightforward, biopsy of metastatic tumors in prostate cancer is neither routine nor easily performed. Further, accurate next-generation sequencing in metastatic tumor-derived DNA is not trivial, and thus these studies may be difficult to generalize into a wider non-academic settings.
Despite these shortcomings and the limitations of a small study, the findings by Mateo and colleagues represent an important step forward. Larger and more-definitive studies exploring the interaction between PARP inhibitors and DNA-repair defects in patients with advanced prostate cancer are warranted and are being planned. ■
Disclosure: Dr. Sartor reported no potential conflicts of interest.
1. Antonarakis ES, Lu C, Wang H, et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 371:1028-1038, 2014.
2. Azad AA, Volik SV, Wyatt AW, et al: Androgen receptor gene aberrations in circulating cell-free DNA: Biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res 21:2315-2324, 2015.
3. Romanel A, Tandefelt DG, Conteduca V, et al: Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med 7:312re10, 2015.
4. Salvi S, Casadio V, Conteduca V, et al: Circulating cell-free AR and CYP17A1 copy number variations may associate with outcome of metastatic castration-resistant prostate cancer patients treated with abiraterone. Br J Cancer 112:1717-1724, 2015.
5. Mateo J, Carreira S, Sandhu S, et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 373:1697-1708, 2015.
6. Cheng HH, Pritchard CC, Boyd T, et al: Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer. Eur Urol December 24, 2015 (early release online).
In the TOPARP-A phase II trial reported in The New England Journal of Medicine, Joaquin Mateo, MD, of the Institute of Cancer Research and The Royal Marsden in London, and colleagues, found that the PARP inhibitor olaparib (Lynparza) produced a high response rate in patients with previously treated ...