Responses to these new approaches result in multiple clinical trials – such as moving to earlier clinical states – which is great – or through the cultivation of thoughtful combinations – or through random combinations – something that isn’t so great.
Let’s discuss parp inhibitor combination studies.
There is no question that parp inhibitors are an important new class of therapy for prostate cancer. However, some concern is warranted about the efficacy of these drugs as monotherapy in patients with DNA repair defects in their tumors. While we no doubt see some remarkably durable long-term responses to monotherapy parpi in patients with pathogenic BRCA2 and other DNA repair mutations, at times treatment is met with a tepid response or no response at all. Recent papers and presentations highlight that a tumor with a DNA repair mutation plus other canonical mutations of prostate cancer ( e.g., TP53, PTEN, etc) are more resistant than those without. Such events are disappointing for the clinician, but mostly so for the patient, who likely invested a lot of hope in the drug on the heels of a positive somatic or germline test for this gene. For reasons we haven’t yet elucidated, the promise of personalized targeted therapy does not apply equally to all.
For such patients and their treating clinicians, several questions arise from this observation. In keeping with historical tradition, the number of “parp plus X” studies open and accruing throughout the world has blossomed - and I thought it would be a good time to think about the rationale design and potential outcomes of these various strategies.
Parp plus AR inhibition.
The first combinations out of the gate have targeted potent AR suppression (with either abiraterone or enzalutamide or others) in combination with parpi and have already shown some interesting results published and detailed elsewhere. The hypothesis behind this approach is that the androgen receptor, in its normal functioning status, serves as a sort of supporting mechanism of DNA repair. AR signaling does in fact regulate transcription of some DNA repair genes- laying a biological foundation to this approach. This hypothesis rests on the assumption that the response to the loss of androgen receptor-mediated DNA repair is mediated by parp – not some other mechanism. Parp is most likely a reasonable target in this setting, as certain preclinical data suggest that PARP-1 expression increases with prostate cancer progression.
Parp plus Immunotherapy
Checkpoint inhibitor therapy in prostate cancer has been a relative disappointment and much has been written and said about the fact that prostate cancer is ‘cold’ in terms of mutations, in particular, relative to tumors such as bladder cancer, lung cancer, and melanoma – more heavily mutated and more responsive to these agents. So, the question is, can we just add another therapy to ‘jump start’ an immune response that can be enhanced by checkpoint inhibition? Preclinical work does indicate that PARPi treatment results in DNA damage, which, in turn, leads to cGAS-STING activation and interferon release, putatively recruiting effector T cells into the tumor microenvironment. Add to this the fact that biallelic mutations in CDK12 result in more immunogenic tumors and the data for combined parpi, and the argument in favor of co-targeting parp and T cells makes some sense.
DNA Damage plus Parp:
It is known to be the case that in malignant as well as benign cells DNA damage occurs at a continuous background rate. This is why individuals with germline BRCA mutations get cancer at a greater rate – over time they just can’t keep up with the need to repair the daily onslaught of DNA damage. Thus, it makes sense that damaging DNA at a more accelerated pace could be one way to enhance parpi efficacy. How do we do that? Two mechanisms come to mind -radiation, and chemotherapy. Indeed, the former approach is under study – the NiraRad study combines niraparib and radium-223 in mCRPC. Only certain chemotherapies will damage DNA as their primary mechanism of action. Platinum compounds are the best example. In ovarian cancer, the use of a parpi following response to platinum chemotherapy is a standard of care. While sequential approaches make sense, to date the combination of platinum with parp is not adequately tolerated in a prostate cancer population although alternate strategies may still be under study.
Inducing Tumor Hypoxia:
We now have many agents that can target a plethora of biological pathways in cancer and the micro-environment. Can any of them synergize with the parpi by downregulating its expression or the expression of other DNA repair proteins? Interestingly, there may be a signal with anti-angiogenic therapies. The hypoxic tumor microenvironment arising from these approaches may alter homologous repair proteins and direct VEGF blockade has been shown in preclinical studies to reduce the expression of BRCA2 and other DNA repair proteins. Translational approaches to this are underway including one study comparing the oral VEGF inhibitor cediranib with olaparib to olaparib alone.
Avoiding the combination graveyard:
A colleague has a PowerPoint slide that he loves to show of a cemetery with multiple gravestones. Each of the gravestones he has listed the name of a drug that was combined with docetaxel and compared to docetaxel alone in a failed randomized phase 3 study. I don’t know how many there were but between approximately 2003 and 2015 multiple such clinical trials were done. The over-arching rationale that failed was that a modestly active drug (for example atrasentan or calcitriol) would produce extended benefits when combined with docetaxel. Multiple rationales were produced at that time as to why these combinations would work and why we should spend our patient’s time and resources on these clinical trials. The failure of all of these stands as a testament to the efficacy of taxane chemotherapy and the fact that while altering other mechanisms may drive CRPC forward - the additional benefits did not seem to lead to improvements for patients.
As I look at these combination studies and reflect on the numerous docetaxel combination failures, I do wonder whether the rationale for the combinations was sound but perhaps the design of the clinical trials failed to bring that out. Do we need persistent dosing of both drugs? What about ‘pulsing’? For example, if inhibition of the AR leads to a transient defect in DNA repair, maybe hitting the tumor with the parpi is only necessary right at the beginning. And if that is the case, maybe we could push UP the dose of the parpi – and see greater results. Same with platinum combinations, or radium.
So many questions, but not an infinite number of trials in which to test them! I eagerly await the results, interpretations, and impact of these studies.
Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Professor of Medicine and Director of the Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota
References:
- Sabine Schmid, Aurelius Omlin, Celestia Higano, et al. "Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations." JAMA Netw Open. 2020. 3:e2021692.
- William R Polkinghorn, Joel S Parker, Man X Lee, et al. "Androgen receptor signaling regulates DNA repair in prostate cancers." Cancer Discov. 2013. 3:1245.
- Matthew J Schiewer, Jonathan F Goodwin, Sumin Han, et al. "Dual roles of PARP-1 promote cancer growth and progression." Cancer Discov. 2012. 2:1134
- Mohammad Asim, Firas Tarish, Thomas Helleday, et al. "Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer." Nat Commun. 2017. 29:374.
- Likun Li, Styliani Karanika, Guang Yang, et al. "Androgen receptor inhibitor-induced "BRCAness" and PARP inhibition are synthetically lethal for castration-resistant prostate cancer." Sci Signal. 2017. 10:eaam7479.
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