1. Vidaurri, Vincent

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We've always known that prostate cancer is a hormonal-driven cancer and some of the treatments have always been to target the hormonal axis," said Eddy S. Yang, MD, PhD, Professor and Vice Chair for Translational Science; ROAR Southeast Cancer Foundation Endowed Chair, Deputy Director and Associate Director for Precision Oncology at Hugh Kaul Precision Medicine Institute; and Program Co-leader, Experimental Therapeutics at O'Neal Comprehensive Cancer Center at UAB.


Since testosterone fuels tumor progression in metastatic castrate-resistant prostate cancer (mCRPC), current treatments suppress testosterone synthesis and block androgen receptors; however, these treatments provided limited durability.


Despite androgen deprivation-testosterone levels below 50 ng/mL-mCRPC develops in about 2-3 years, demonstrating the need for additional treatment options other than antihormonal therapies (Oncology (Williston Park) 2016;30:187-195).


Because of the dominance of antihormonal therapy, prostate cancer has been slow to adopt therapies targeting genomic mutations compared with other cancers.


"Until next-generation sequencing technology came about, there really wasn't an actionable target to discover a new therapy. When it was found that [PARP inhibitors were active against] patients with defective DNA repair, it was only then that trials started happening for prostate cancer," according to Yang.


In 2015, researchers showed 90 percent of prostate cancers have actionable molecular targets and approximately 20 percent involved defects in DNA repair genes BRCA1, BRCA2, or ATM, and other DNA repair genes-such as FANCA, RAD51B, and RAD51C-accounted for an additional 3 percent (Cell 2015;161:1215-1228).


PARP Inhibitor Studies

Since discovering targetable mutations, studies showed the benefit of PARP inhibitors against mCRPC harboring DNA repair aberrations.


Trial of PARP inhibitors in Prostate Cancer (TOPARP-A) showed olaparib, a PARP inhibitor, to be most effective in mCRPC harboring impaired DNA repair mechanisms after progressing on one or two regimens of chemotherapy (N Engl J Med 2015;373:1697-1708).


In the phase II study, a total of 49 patients enrolled and 33 percent responded overall. But patients with DNA-repair gene aberration had a response rate of 88 percent.


Progression-free survival for the biomarker positive group was 9.8 months compared with 2.7 months for the negative group. Overall survival was also extended in the biomarker positive group to 13.8 months compared with 7.5 months.


After these promising results, the FDA granted olaparib breakthrough status.


As a follow-up, Trial of PARP inhibitors in Prostate Cancer (TOPARP-B) treated mCRPC patients-who progressed after at least one taxane chemotherapy-with DNA damaged repair and reported an overall response rate of 54 percent for the olaparib 400 mg cohort and 37 percent for the 300 mg cohort (J Clin Oncol 2019;37:15_suppl, 5005).


Subgroup analysis of specific gene alterations showed a response rate of 80 percent for BRCA1/2, 57 percent for PALB2, and 37 percent for ATM. BRCA1/2 and PALB2 also decreased PSA by 50 percent or more in 73 percent and 67 percent of cases, respectively.


Other altered genes that responded to treatment included CDK12, ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, and WRN. All these genes are part of the homologous repair pathway.


The overall median progression-free survival (PFS) was 5.4 months, and subgroup analysis reported median PFS was 8.1 months for BRCA1/2, 6.1 months for ATM, and 5.3 months for PALB2.


Both TOPARP-A and B studies suggest olaparib may be beneficial in patients with mCRPC, harboring DNA repair alterations.


Rationale for Molecular Targeting

The most likely candidates for targeted therapy are those with homologous recombination (HR) defects like BRCA1, BRCA2, or ATM.


Repair of DNA double-strand breaks occurs through two possible pathways: 1) HR, and 2) non-homologous end joining (NHEJ). When harboring HR defects like BRCA1, BRCA2, or ATM mutation, DSBs must be shuttled to NHEJ for repair, but NHEJ, inherently, introduces more errors than HR, which result in DNA instability.


The PARP family is a group of 17 nuclear proteins. PARPs play a critical role in DNA repair. PARP-1 facilitates the repair of nearly 90 percent of single-strand breaks (SSBs), PARP-2 and PARP-3 promoting the other 10 percent. PARP-1 binds to SSBs and covalently attaches polymers of adenosine diphosphate-ribose to the DNA-an enzymatic process known as PARylation.


To conduct PARylation, PARP-1 uses nicotinamide as a co-factor. PARylated DNA recruits machinery for repair, arranges the DNA into a favorable conformation, and adds poly ADP-ribose onto itself, through auto-PARylation. Auto-PARylation causes PARP-1 to release from the DNA; this allows the repair process to commence.


In addition to PARPs helping DNA repair, Yang mentioned, "PARPs can act as a co-regulator of transcription factors related to carcinogenesis and metastasis." And of particular interest in prostate cancer, "preclinical data suggests that PARPs can co-active the androgen receptors."


PARP Inhibitors

PARP inhibitors work in two distinct but complementary ways: 1) they compete with nicotinamide to prevent PARylation (the catalytic activity of PARP), and 2) they trap PARP-1 onto the DNA to create a PARP-1/DNA complex.


All approved PARP inhibitors are nicotinamide analog, and since nicotinamide is the essential co-factor, PARP inhibitors compete with nicotinamide to restrict PARylation.


"DNA trapping of the PARP enzyme," is the main mechanism for PARP inhibitors, according to Yang.


Under normal circumstance, after recruiting the repair machinery, PARP-1 is released from DNA to allow for DNA repair. But when PARP inhibitors are present, they freeze PARP-1 onto DNA, creating a PARP-1/DNA complex and trapping PARP-1, which destabilizes DNA repair and generates DSBs.


These DSBs must then pass through NHEJ repair, rather than HR to correct the breaks, but along with repairing the breaks, this process manufactures errors into the DNA, promoting instability.


From the above, it would follow that a PARP inhibitor causes more cytotoxicity in cells with aberrations in homologous recombination repair, and so far the data suggests cancer cells, not normal cells, harboring BRCA1, BRCA2, and ATM mutation acquire PAPR inhibitor sensitivity.



"Because standard treatments work pretty well, PARP inhibitors will probably be in the metastatic castrate-resistant setting. But efforts of clinical studies are to move them closer to the frontline setting and possibly combined them with other modalities like radiation," Yang stated.


Although it's the early stages of using molecular targeted therapy in prostate cancer, PARP inhibitors show promise for a subset of mCRPC patients, and with the number of actionable mutations available, more trials are being conducted to build available therapies.


"The hope would be that we generate enough data, especially with the TOPARP-B study that validates the actual biomarkers, that we can actually treat patients with a PARP inhibitor," Yang concluded.


Vincent Vidaurri is a contributing writer.