Overview of Therapy for mCRPC: PARP Inhibitors

EP: 1.Overview of Improvements in Prostate Cancer Management

EP: 2.Optimizing Use of PSMA PET Imaging and PSADT in Prostate Cancer

EP: 3.Evolving Treatment Landscape of Nonmetastatic CRPC

EP: 4.Factors in Selecting Novel AR-Targeted Therapy for Nonmetastatic CRPC

EP: 5.Nonmetastatic Castration-Resistant Prostate Cancer: Quality of Life Measures

EP: 6.Monitoring Strategies in Nonmetastatic CRPC

EP: 7.Overview of Treatment for Metastatic HSPC

EP: 8.Role of Micronized Abiraterone in Metastatic HSPC

EP: 9.Selecting Optimal Therapy for mHSPC: Design of the ARASENS Trial

EP: 10.Interpreting Data From the ARASENS Trial in Metastatic HSPC

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EP: 11.Overview of Therapy for mCRPC: PARP Inhibitors

EP: 12.DNA Alterations and Selection of PARP Inhibitors in mCRPC

EP: 13.Metastatic CRPC: Utility of Imaging as a Biomarker

EP: 14.Selecting Among Novel Imaging Options in Metastatic CRPC

EP: 15.Role of 177Lu-PSMA-617 in mCRPC and Bone Metastases

EP: 16.Addressing Bone and Visceral Metastases in Metastatic CRPC

EP: 17.Results of the VISION Trial and Real-World Use of 177Lu-PSMA-617 in mCRPC

EP: 18.Prostate Cancer Management: Future Directions in Care

Transcript:

Alicia Morgans, MD, MPH: I’m really excited to start our next module on metastatic castration-resistant prostate cancer [mCRPC]. Scott, I’m wondering if you can give us an overview of the treatment landscape, complicated though it is?

Scott T. Tagawa, MD, MS, FACP: Sure. One of the nice things, essentially, about my training and my career is that I have seen a number of different advances. When I was a first-year fellow, we enrolled patients in at least a SWOG [Cancer Research Network] study that supported the approval of docetaxel, and then it was testing docetaxel combinations or re-treatment with docetaxel. But now we have a lot of different options. As I’m seeing a patient, I will describe to him and his family, the 6 categories of therapy. There is chemotherapy, and we have 2 taxanes that improve overall survival; we have hormonal therapy, a number of different agents that I’ll term the AR [androgen receptor] pathway inhibitors, specifically CYP17 or AR signaling inhibitors. We have bone-targeted therapy, both those I’d call in the supportive care realm that prolong time to skeletal-related events, as well as overall survival drugs, or at least drug, with Radium-223. We have immunotherapy with sipuleucel-T for those with minimally symptomatic metastatic CRPC, and for a small subset, which is zero if we don’t look, so we should look for MSI [microsatellite instability] in on-label use of pembrolizumab. And then molecularly selected therapy, which I would put in today’s realm as PARP inhibitors. Then other, which is generally clinical trials, and there are some novel agents in some of those categories, such as hormonal therapy. Then we have those that are clinical trials that are in different categories, for instance, PSMA [prostate-specific membrane antigen]-targeted radionuclides.

Alicia Morgans, MD, MPH: Well, the list is long, and it’s getting longer, so thank you so much for walking us through those, Scott. Evan, I’m wondering if you can share your thoughts on some of the data around those targeted treatments that are targeting the PARP inhibitor space, so DNA repair defects. Can you share with us, of course the historical data, the older data, plus the newer data on some combination therapies that seem to be making waves now in mCRPC?

Evan Y. Yu, MD: Yes, absolutely. Let’s take a step back and think about how PARP inhibitors even work. When you think about DNA repair in a cell, there are many types of DNA repair. There is mismatch repair, nucleotide excision repair, homologous recombination repair, and that’s one of the high fidelity mechanisms of DNA repair. For instance, with BRCA1 or BRCA2, there are many other genes involved, but these proteins are very directly involved in homologous recombination repair. When you think about PARP inhibitors, you have to think about the term “synthetic lethality,” where you have one pathway that’s mutated, and maybe the cell functions just fine. If you find just the right next pathway that you inhibit, or that you alter and mutate chemically, pharmacologically, genetically, etc, and you modify, what ends up happening is now you have dramatic apoptosis and cell death. That’s how to think about this.

I’ll give an example. If you have an alteration in BRCA2 in which you lose function there, and you can’t repair very well, your errors in DNA or via homologous recombination repair, and now you have to rely on other repair mechanisms. So, PARP is important for single-strand break repair, and if you introduce a PARP inhibitor, now you’re taking out another node, or another mechanism of DNA repair. So now, you have a couple of different mechanisms that are lost, and there you can get dramatic apoptosis. That’s the idea of how this works in select patients who already have an alteration in homologous recombination repair, and what we call homologous recombination deficiency state. If you rewind the clock a little bit, some of the earlier studies that were published in the New England Journal of Medicine from the de Bono [Johann de Bono, MD, MSc, PhD, FRCP] group, looking at the TOPARP trial, they had selected patients who were biomarker positive, meaning that they had biallelic alteration in some of these DNA repair genes, homologous recombination repair genes. There was a dramatic 88% response rate via their composite response criteria to olaparib in that study.

Now, if you fast forward a bit and you look at regulatory approvals, there was the PROfound study, where olaparib was studied in biomarker-positive patients and showed an overall survival benefit, essentially over switching to another novel hormonal therapy agent there. It was probably mostly driven by the BRCA1 and BRCA2 population, but it was positive overall for the entire cohort of about 16 different genes included, so they had a broad approval in patients who have one of those genes altered. I think ultimately, the label had 15 different genes on it, and it could be given in a pre- or post-docetaxel setting in the metastatic castration-resistant prostate cancer disease state. There was rucaparib as well in the TRITON2 trial that was approved on an accelerated approval pathway based on a very good response rate in the 40%-plus range. So, there is another PARP inhibitor there, not just olaparib.

If you fast forward to the recent meeting at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium], we have a couple of interesting trials there that were in combination in first-line metastatic castration resistant prostate cancer with abiraterone. There are some preclinical data to show that there might be additive or synergistic effects there. In the MAGNITUDE trial they used niraparib, a different PARP inhibitor. In that study they had a biomarker-negative and a biomarker-positive cohort, and in the biomarker-positive cohort with BRCA alterations, niraparib added to abiraterone did show an rPFS [radiographic progression-free survival] benefit. We’ll have to wait and see the overall survival data. In the biomarker-negative cohort, that was negative, unfortunately. There were interesting data also from another study, the PROpel study, which used olaparib added to abiraterone versus abiraterone alone, and that did not require biomarker positivity or negativity for assignment to cohorts up front. The patients were enrolled and testing was done after the fact, but they did show that the overall population did have an rPFS benefit with the addition of olaparib. It leads to the question of do you actually need to do testing there? Why might olaparib be working in this patient population? Of course, we’ll want to see the overall survival data there as well.

I think this field is still in evolution. Other ongoing trials are looking even earlier, perhaps in the castration-sensitive disease states, but there are still a lot of questions even with the data we have now. What sort of testing should be we doing, tissue testing, circulating tumor DNA [ctDNA] testing? Should we be doing serial testing? Do we pick up mutations to develop as part of evolution of the tumor over time? How much attention do we need to place into what the gene is? There are some data to show that maybe ATM alterations, which are common, might not respond as well to PARP inhibitors. Of course, there are more problems with CHIP [clonal hematopoiesis of indeterminate potential] when you do ctDNA testing and you find ATM alterations there just from age-related clones, or old white blood cells for instance. Then you have to ask the question about zygosity, is biallelic mandatory, or is a monoallelic alteration going to be adequate? Does it depend upon what gene alteration? There are a lot of questions. I’ll stop there because I talked a lot about PARP inhibitors to try to summarize the field.

Transcript edited for clarity.