The clinical development of therapies targeting DNA repair pathways in prostate cancer is now well underway. It is a hopeful on-ramp for prostate cancer into the world of molecular oncology. We are beginning to see the emergence of consistent data and some surprises. There is a significant reason for hope, for example, that the poly ADP ribose polymerase (PARP) inhibitors will become a standard of care for patients with BRCA1 or BRCA2 alterations.
If you have been following the clinical trials in castration-resistant prostate cancer (CRPC) involving PARP inhibitors, it is easy to understand some of the excitement being generated by this new class of drugs with approximately 50% of patients experiencing objective responses and substantial declines in prostate-specific antigen (PSA). Further, delays in radiographic progression-free survival compared to other standard therapies, including a smattering of near-complete responses (CRs) and long progression-free intervals, increase enthusiasm.
Most of this excitement pertains to patients with BRCA1 and BRCA2 mutations. It is less clear what will happen with patients who harbor tumors with mutations in other members of the DNA Repair family.
One key component of our recognition of this class of genomic aberrations is the recognition that a long “tail” of mutations exists in the DNAR repair pathway curve, yet little is known about the effect of PARP inhibitors in his setting.
The term “tail” arises from the frequency graphs that consistently show that in a CRPC population the most abundantly mutated genes are BRCA2 and BRCA1, with ATM, and CDK12 not far behind, only to be followed by a long list of alterations that occur at the 1-3% range, these include mutations in BRIP1, RAD51B, RAD51C, BARD1, Chek2, PALB2, FANCA, and others.
It’s too early to conclude that list of genes on the tail, and we may never get great numbers without significant efforts to get such patients on clinical trials. That said, the early data, however, is pointing towards a generalized failure of PARP inhibitors to lead to substantial reductions in PSA in patients with one class of mutation – ATM.
So below I will discuss how ATM differs from BRCA1 and BRCA2 and how ATM patients may not be experiencing as much benefit as those with other mutations, and perhaps why.
First, the clinical data: The first study that provides some evidence as to the differential outcome based on these mutations is the PROfound study which tests olaparib (AstraZeneca) against physician's choice in post androgen receptor (AR) targeted therapy patients. In PROfound, 86 patients with ATM mutations were treated and are available for outcome analysis. Sixty-two of them received olaparib and 24 entered the “physician's choice” arm of the study. The ATM patients on olaparib did no better than those receiving the physician's choice treatment. The median radiographic progression-free survival (rPFS) was 4.70 (1.84, 7.28) in the control arm versus 5.36 (3.61 to 6.21) months in the olaparib arm. Of note, the median rPFS in the control arm for all mutation subsets was 3.55 months.
In the TRITON2 study that evaluates Rubraca® (rucaparib), Clovis Oncology in post-docetaxel patients with a variety of DNA repair defects, data from 57 patients with ATM mutation are available and were presented recently at ESMO. These patients had higher baseline PSA values than the BRCA1/2 cohort (108.7 vs 65) and fewer of them had high Gleason grade disease ( 47.4 with ≥8 versus 68.4)
Results were unimpressive for the ATM patients on this trial as well. In contrast to the BRCA1/2 group, where the PSA response rate was 52%, only 2/57 ( 3%) of patients with ATM mutations experienced a PSA decline of ≥50%. The “clinical benefit rate” in ATM was modestly higher, however, at 29% at 6 months but only 8% at 12 months. Clinical benefit rate refers to the number of patients who did not experience disease progression during the time period.
These results are disappointing despite many years' worth of preclinical data showing that, in vitro, PARP inhibitors induced synthetic lethality in ATM mutant and ATM knockout cells. What could be going wrong?
First, ATM is a DNA Damage sensor, not a DNA repair protein itself, like BRCA2 or BRCA1. In cells that are undamaged, ATM sits quietly as an inactive homodimer. Its main role is to become activated when double-strand DNA breaks occur. This is in contrast, for example, to ATR, which is activated in the context of single-strand breaks. Individuals with familial mutant ATM are known to be very sensitive to radiation and other genotoxic stresses. Patients with homozygous germline loss of ATM are those who comprise the disease known as Ataxia-Telangiectasia – so named for the frequent clinical manifestations of neurodegeneration (manifesting early as ataxia), immunodeficiency, and a substantially increased risk of lymphomas.
ATM has a more diverse portfolio of roles in the cancer cell than does BRCA2. A key component of ATM's function is to induce cell cycle arrest and that, in certain circumstances, this could be prolonged. The degree and nature of the cell cycle arrest is dependent on what part of the cycle the cell is in when the double-strand breaking damage occurs. For example, cells in G1 and S phase will arrest immediately on double-stranded DNA breakage. Those who research these mechanisms refer to “G2 Accumulation” which occurs over a long period of time, slowing down the cancer cell cycle. So how does this translate into PARP inhibitors not working? Because ATM is likely to arrest cells in G2, it seems consistent to think that an ATM damaged cell could fail to undergo cell cycle arrest, but in such cases, cell lethality should be increased, not decreased. I’m struggling to get my clinically-oriented brain around what is some very basic science.
The ongoing PARP inhibitor trials are reassessing their efforts against ATM mutated tumors. It may be that they are excluded from eventual FDA labels or they might be included (responses do occur, they are just rare). It may be that ATM mutated tumors would benefit from a combination approach that includes a PARP inhibitor, or it could be that PARP inhibitors have no role. That seems to be the direction things are heading.
What could we do for patients with ATM mutations outside of PARP inhibition? It appears that patients with ATM mutations still have defective DNA repair, albeit originating from a defect in sensing DNA damage, in particular, double-stranded breaks. So maybe the problem is that PARP is not that active in these patients and that’s not the best therapeutic target.
Perhaps we should target ATM mutant patients with more genotoxic drugs like platinum or radiation, or both. In the current era, that shouldn’t be hard to do. We have several candidates; external beam radiation, radium-223, even Lu-177 PSMA could work. Each of these could be combined with cisplatin or carboplatin.
These patients merit further attention. They comprise about 7% of the prostate cancer population1.
More to follow as the age of molecular oncology unfolds.
Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Director and Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota
Published Date: November 29th, 2019
1. Mateo, Joaquin, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues et al. "DNA-repair defects and olaparib in metastatic prostate cancer." New England Journal of Medicine 373, no. 18 (2015): 1697-1708.
Further Related Content: