In this podcast, experts discuss the evolving role of PARP inhibitors in metastatic prostate cancer, with a focus on the biologic rationale for PARP inhibition in tumors with HRR alterations, the importance of germline and somatic genomic testing, and the clinical evidence supporting PARP inhibitor monotherapy and combinations with ARPI. The discussion highlights data from trials including AMPLITUDE and TALAPRO-3, considers how specific HRR alterations may influence treatment selection across metastatic disease settings, and reviews practical strategies for monitoring and managing adverse events such as anemia and nausea.
In this podcast episode, Neeraj Agarwal, MD, FASCO, and Emmanuel S. Antonarakis, MD, discuss the evolving role of PARP inhibitors in metastatic prostate cancer, emphasizing early molecular testing to identify appropriate patients for PARP-directed therapy and proactive adverse event management to support treatment continuation, including:
Presenters:
Neeraj Agarwal, MD, FASCO
Medical Oncologist, Dana-Farber Cancer Institute
Co-Director, Prostate Cancer Program, Harvard Cancer Consortium
The Lank Center for Genitourinary Oncology
Boston, Massachusetts
Emmanuel S. Antonarakis, MD
Clark Endowed Professor of Medicine
Director of GU Oncology, Associate Director of Translation
Division of Hematology, Oncology and Transplantation
University of Minnesota, Masonic Cancer Center
Minneapolis, Minnesota
Link to full program:
https://bit.ly/4dtT35U
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
PARP Inhibitors in Metastatic Prostate Cancer: Biomarker Testing, Treatment Strategies, and Toxicity Management
Dr. Neeraj Agarwal: My name is Dr. Neeraj Agarwal. I am a GU medical oncologist at the Dana‑Farber Cancer Institute in Boston. Here I have my esteemed friend and colleague, Dr. Emmanuel Antonarakis, a very well‑known authority in the field of prostate cancer. We will be talking about PARP inhibitors in prostate cancer today. Welcome, Emmanuel.
Dr. Emmanuel Antonarakis (University of Minnesota): Thank you, Neeraj. Let us start with current needs. Why we need something more for patients with metastatic castration-resistant prostate cancer, now known as metastatic androgen pathway modulator‑resistant prostate cancer?
Dr. Antonarakis: Neeraj, for all of us in the clinic, seeing patients, no one is cured from metastatic androgen pathway modulator‑resistant prostate cancer, formerly CRPC. And we are all accustomed to using androgen receptor‑directed therapies, taxane chemotherapies, and now radioligand therapies such as lutetium‑177–PSMA‑617. However, unfortunately, our patients are still progressing, and our patients are still dying.
We are entering the genomic revolution across cancers, including in prostate cancer, and I believe that we are scratching the surface as to new approaches that we can use for metastatic APMR prostate cancer patients, including but not limited to PARP inhibitors, but of course there are many other exciting things coming, including T‑cell engagers and other androgen receptor protein degraders. But today our focus will be on the PARP inhibitor class and the genomic mutations that sensitize patients to PARP inhibitors.
Dr. Agarwal: Talking about the PARP inhibitors, could you tell us mechanism of action of PARP inhibitors in patients with prostate cancer who have those particular types of mutations known as homologous recombination repair mutations?
Dr. Antonarakis: We now have at least four PARP inhibitors that are approved for various stages of metastatic prostate cancer. We have olaparib, rucaparib, niraparib, and talazoparib. Some of those are approved also in other cancers, for example, breast cancer, ovarian cancer, and pancreatic cancer.
The key is that these are not drugs that we will use for molecularly unselected patients. These drugs are only effective, or mostly effective, when the cancer has an underlying homologous recombination deficiency mutation. It is easy to remember the BRCA1 and BRCA2 genes. Those are the most famous ones, and actually those are the genes that increase the sensitivity to this class of drugs the most, but in the case of some PARP inhibitors, we have a broader FDA label that includes either 12 genes or 14 genes. It is as broad as 14 genes, and they are all in the same family.
We also have PALB2, we have ATM, we have CDK12, and others. It gets a bit difficult to remember all of them, and it gets a bit difficult to remember which PARP inhibitor or PARP inhibitor combination is approved for which gene set, but we will try to deconvolute that for the audience here today.
These drugs also work in patients who have germline inherited gene mutations in the HRR genes, for example, a man with metastatic prostate cancer that was born with a germline BRCA2 alteration. That patient may also benefit from these drugs.
Dr. Agarwal: If they have these mutations, how do PARP inhibitors work exactly?
We are inducing a state of synthetic lethality. That is the technical term, and synthetic lethality means that the PARP inhibitors are only going to be beneficial when there is an underlying homologous recombination alteration. When a patient is born with an HRR gene alteration, or if their tumor harbors an HRR gene alteration, those cancer cells are not able to repair double‑strand DNA damage. Those cancer cells can then rely upon single‑strand DNA repair to fix their DNA damage, and PARP, PARP1 more specifically, which is the target of PARP inhibitors. When that protein is inhibited, we are also crippling single‑strand DNA repair. So the consequence for that cancer cell is overwhelming, catastrophic DNA damage, which is caused by double‑strand DNA damage from the underlying mutation and then single‑strand damage by the PARP1 inhibition, so that cell accumulates so much DNA damage that it cannot survive and it commits apoptosis.
Dr. Agarwal: That is such a fantastic, simple explanation of how PARP inhibitors work in these patients who have these mutations. That is a nice segue to the testing. You did mention that it is hard to remember which PARP inhibitors are approved for which mutations.
Fortunately, if we use any clear certified test nowadays, we often get reports in a very simplified fashion. Those companies are doing a fantastic job of telling which PARP inhibitors are approved. It is the testing which is more important. We need to remind ourselves that we need to order germline testing and somatic tissue testing to get that information first. It is unfortunate that until very recently, only 30% of our patients with advanced prostate cancer got tested by NGS testing, and even less so for germline testing. We will come to that in a moment.
However, talking about the prevalence of these mutations, We have seen reports 25% to 30% of patients with advanced prostate cancer, and later they are in the journey with prostate cancer, these mutations seem to get more prevalent. What are your thoughts on this?
Dr. Antonarakis: Let us give our audience some statistics so that they understand the general prevalence and expectation when they order an NGS test. If you have a patient with metastatic prostate cancer – and by the way, this includes PSMA‑positive, detected‑only cases as well. Those are still metastatic in our current thinking.
If you order a germline test on that patient, which is typically done through a saliva sample or a blood sample, where we do the germline testing from sequencing the white blood cells, we will expect to find approximately 10% to 12% of all metastatic prostate cancer patients with a germline genetic mutation in HRR genes, one or more of them. The most common one is BRCA2, but if you add them all up, it is about 12%. That is about one in eight men in your clinic. On a long clinic day, Neeraj, you might see 16 patients; two of those 16 are going to have a germline mutation. That is not so rare.
Then let us answer the question about prevalence in tumor somatic NGS sequencing. In this case, it is even higher. We estimate that approximately 25%, maybe up to 30% of all metastatic APMR biopsies will have a homologous recombination mutation. As you mentioned, over the course of time, especially with the treatment of androgen‑directed therapies, chemotherapies, and radioligands, we may have a slightly increased prevalence. The prevalence will never go to 50%, but it may be closer to 30 or 35%. Even up to one third of patients in the later stages of prostate cancer will have one of these gene mutations.
Dr. Agarwal: Talking about the testing, how do you order these tests when you see these patients? What phase of their prostate cancer? First time when you see a patient with advanced prostate cancer or later, do you wait for them to develop APMR disease? What is your practice?
Dr. Antonarakis: In my practice, I think with a metastatic patient, germline testing should be highly recommended at the first visit if it is not done by somebody else. This is consistent with virtually all of the oncological and urological guidelines, including guidelines outside of the United States.
This can be done, as I mentioned, with a saliva sample or a blood sample, and the NGS companies are making it easy for us. Sometimes they are sending kits to the patient’s home: saliva kits, or some of these companies are even offering mobile phlebotomy, where they will go to the patient’s home and collect the blood sample in the patient’s own environment. That is the easy one. I think that germline testing should be recommended at the first medical oncology visit for metastatic disease if it is not done before. The important thing about germline testing, you only need to do it once. The germline genome is not going to change, because that is the genome that you were born with, so once and done, as I like to say. With respect to the somatic piece, this is where it gets a little bit more nuanced. I still do think that all metastatic prostate cancer patients, including androgen pathway modulation‑naive or sensitive, should undergo testing.
We now have the AMPLITUDE and TALAPRO‑3 studies, which offer benefit to patients with PARP inhibition in the first‑line, metastatic APMN setting. Also, we have the approval of capivasertib, an AKT inhibitor in the metastatic APMN setting with a PTEN loss by immunohistochemistry, which is not exactly NGS, but it is another molecular marker, so I think it should be done for all the metastatic APMN patients.
The tissue is the challenging part. If the patient has had a prostate biopsy recently in the last one to three years, oftentimes I will try to utilize that for simplicity because that tissue has already been collected, but oftentimes that prostate biopsy might be too old, or you may attempt NGS and not have a result from it – unevaluable. In those cases, my typical next step would be a metastatic biopsy, preferably not of a bone. If it is a lymph node, liver, or lung, that is preferable. If this is not safe or feasible, then a circulating tumor DNA test is my third resort, but the circulating tumor DNA test will not be evaluable unless that patient has a fairly high PSA level. If you have a PSA of 0.5, we will typically not detect circulating tumor DNA.
Dr. Agarwal: That is why it is so important to send out the tissue testing when we see the patients for the first time, because the tissue is fresh, and it is more likely that tissue is preserved by the local pathology labs, rather than waiting for three or four years when we may lose the quantity or quality of the tissue, which many consider the gold standard for testing for many of these mutations.
Also, we know that patients who have these mutations, they have poor prognosis. Multiple studies, both real‑world and trial-based patient data sets have shown that patients do not do well with standard‑of‑care therapies when they harbor these mutations in the HRR genes, and that makes it so much more important that they get to have access to these drugs known as PARP inhibitors, mostly oral pills. It can change their lives dramatically in many instances.
That brings me to the monotherapy data. We know PARP inhibitor olaparib has been approved since 2020 based on the PROfound trial. Although it was including ATM, BRCA2, and BRCA1 cohorts, that was a primary cohort. Then there was another cohort which had other 12 genes, as you mentioned, but we did see overall survival benefit with monotherapy olaparib in patients who had been failed by ARPIs, and many of them had received chemotherapy with docetaxel.
Then we have rucaparib, which showed PFS benefit in patients with BRCA1 and BRCA2 mutations in metastatic APMR setting. What is your use of these monotherapy drugs? What is the most likely scenario before we move to the combination therapies in earlier setting?
Dr. Antonarakis: Monotherapy is still utilized, but less so, since we now have the combinations. In patients that are at third‑ or fourth‑line metastatic APMR disease who have a BRCA mutation or some other mutations, we still use them. However, I would like to encourage our audience, Neeraj, to capitalize on the opportunity to use PARP inhibitor plus ARPI combinations as much as possible, especially in the early APMR setting. We are going to talk about TALAPRO‑2 and the PROpel study, but even more recently, we are beginning to use these in APMN setting as well, based on AMPLITUDE and TALAPRO‑3.
Dr. Agarwal: Talking about the combinations, I like to bring audience attention to the fact that, earlier we move, they become more effective. The efficacy get amplified, like we have seen with other drugs, which had moved from APMR setting to APMS or APMN setting. We consistently see a trend of increasing magnitude of benefit with these medications, and same applies to PARP inhibitors. For example, the combination of talazoparib plus enzalutamide in first‑line mCRPC setting, or now mAPMR setting, was associated with an absolute 14‑month improvement in overall survival benefit when talazoparib was combined with enzalutamide, compared to enzalutamide, which is a very effective control arm.
Then we move these agents to first‑line setting, and we consistently see benefit. Could you tell us more about the data from the AMPLITUDE trial, which just reported, and the combination is approved for patients with BRCA2 mutations? And then we can talk about the TALAPRO‑3 trial results.
Dr. Antonarakis: A series of trials have taught us that, especially in the setting of an HRR mutation, the synergy between ARPI agent, such as enzalutamide or abiraterone, plus a PARP inhibitor appears to be quite compelling. This has led, as you mentioned, Neeraj, to the two pivotal studies in the metastatic androgen pathway modulation‑naive or sensitive disease. One of those currently has FDA approval, AMPLITUDE, and the second one, which you led, Neeraj, TALAPRO‑3, will hopefully very soon have an FDA approval.
Let us talk about AMPLITUDE. AMPLITUDE was for metastatic androgen pathway modulation‑naive or sensitive patients. The trial involved multiple HRR genes. However, this is the important part for the audience: the FDA approval of the combination of niraparib plus abiraterone in the metastatic APMN setting is only for BRCA2 exclusively, even though the AMPLITUDE trial testing the ADT‑abiraterone‑niraparib triplet showed some consistent benefits in rPFS for other genes. Despite this, the FDA reasoned that the greatest magnitude of benefit was in the BRCA2 subset, and the approval is only for those patients. At the current time, if you have a BRCA1 mutant patient, you may try to prescribe niraparib and abiraterone if you wish, but this will be considered an off‑label use, and this is not consistent with the FDA label for that combination.
On the other hand, we are hopeful that the TALAPRO‑3 trial will lead to FDA approval of the talazoparib plus enzalutamide combination with ADT in the metastatic APMN/S patients. I am hoping, Neeraj, based on a larger magnitude of benefit compared to the control arm, which was ADT ARPI alone. I am hoping that the FDA approval for talazoparib enzalutamide combined with ADT will be more than just BRCA2, just like we saw in the TALAPRO‑2 trial, where the panel included a 12‑gene list.
Dr. Agarwal: Just to summarize, in the late mCRPC or mAPMR setting, we have olaparib and rucaparib approved as monotherapies. In the first‑line mAPMR setting, we have abiraterone‑based combinations: abiraterone with olaparib and niraparib, and then enzalutamide with talazoparib approved. In the mHSPC or now called as mAPMN or mAPMS setting, we have abiraterone plus niraparib combination approved for patients with BRCA2 mutation, and we have the TALAPRO‑3 study, which showed benefit in gene subgroups or subsets beyond BRCA1 and BRCA2.
I will briefly elaborate on TALAPRO‑3 trial. This is a large trial, like many other phase III trials in newly diagnosed metastatic prostate cancer setting, where patients were randomized to ADT plus enzalutamide plus/minus talazoparib. Radiographic progression‑free survival was the primary endpoint, 50% reduction in risk of radiographic progression or death by adding talazoparib to enzalutamide. Despite the fact that enzalutamide control arm did extremely well, about four years of radiographic PFS, and to build on that solid control with a hazard ratio of 0.5. As I said, 50% reduction is really remarkable.
I was really impressed by the efficacy beyond BRCA1 and BRCA2. If you look at BRCA1 and BRCA2 mutation, about 60% reduction in risk of progression or death, but in non‑BRCA1/BRCA2 patients who had other mutations, there was about 40% reduction in risk of progression or death. Strikingly, we saw benefit in ATM mutation‑positive patients, with about a 60% reduction in risk of progression or death. CDK12 mutation‑positive patients who have more aggressive disease – in our practice, they also seem to tremendously benefit. Of course, PALB2 is known to be a sensitizing mutation. We saw a benefit across the board, and I think that really makes us very hopeful that talazoparib plus enzalutamide combination gets approved in the near future, so we have that option for our patients.
Talking about the side effects, Emmanuel, what side effects do you mostly worry about for PARP inhibitors in general? If I want to ask you in one line, how do you manage side effects? How do you do that?
Dr. Antonarakis: Let us finish our conversation by talking about toxicity, which is important. Neeraj, I am going to cheat a little bit, and I am going to answer that briefly. Then I am going to ask you a question, because you have had so much experience.
In my opinion, anemia is a major one, nausea, anorexia. Some people do lose weight because their appetite is suppressed. We see some constipation in some patients. There are some other cell lines that can be suppressed. Thrombocytopenia and neutropenia, although I have never seen a neutropenic fever myself. Then some of them may cause ALT/AST increases; some of them may cause creatinine increases.
What I would like to ask you, Neeraj, because I know that you have so much experience on this, and our audience would benefit from your knowledge. Please take us into a deep dive on anemia, which, especially with talazoparib/enzalutamide, is quite prevalent, and how does one anticipate, mitigate, or treat this if it happens?
Dr. Agarwal: The bottom line is we should start everyone at the standard doses. I have got phone calls from my colleagues in the community whether we should decrease the dose upfront. The answer is no, because most patients are able to tolerate the drug eventually. We should only reduce the dose when we have to.
Regarding nausea and vomiting GI side effects, which are more common with olaparib, I send them with anti‑nausea prescriptions. I do not even wait for them to get nausea and tell them to preempt nausea. With grade 1 nausea, slight nausea, they should start taking the pills, and with severe cases I reduce the dose, and they do extremely well.
Regarding anemia, which was quite common in TALAPRO‑3 trial, grade 3/4 anemia was present in 50% of patients; the most notable finding was most of those anemia happened in first three or four months. Once the dose was reduced, which was mandated by the protocol, patients were able to tolerate talazoparib very well. That is exemplified by same duration of talazoparib therapy, about three years in patients who developed grade 3/4 anemia versus who did not develop grade 3/4 anemia.
What I do in my practice is I start them on standard dose of enzalutamide plus talazoparib. I monitor their hemoglobin every month or sometimes every 15 days locally. They do not even have to come to the clinic. If I see them on track to develop grade 3/4 anemia, meaning the hemoglobin is going down – and we all are used to dealing with chemotherapies and a lot of toxic drugs in our clinics. We can anticipate who is going to develop grade 3/4 anemia. I do not wait for them to develop grade 3/4 anemia. I reduce the dose of talazoparib from 0.5 to 0.35 mg, and that is the key.
Before I start them on talazoparib or any PARP inhibitor, I make sure that they do not have predisposition for anemia. Vitamin B12 level, iron level, folate level, especially those patients who are vegetarian or vegan, they may be vitamin B12 deficient. I make sure they are not deficient and start them at full dose, monitor the hemoglobin every month locally, with the results being faxed to us, and if I see hemoglobin going down, I reduce the dose of talazoparib without waiting for them to develop grade 3/4 anemia, and that is the bottom line.
Dr. Antonarakis: What a wonderful explanation, and your experience with these drugs definitely shows with this answer. Hopefully our audience gained some knowledge about the mechanism of action, indications for genetic testing, germline and somatic, the four FDA‑approved PARP inhibitors each with a unique clinical space and, very importantly, side effect management, so we can maintain these patients on these drugs as long as possible so that they benefit the most.
Dr. Agarwal: Key is to test these patients, our patients, when we see them for the first time. Every single guideline endorses testing with germline and tumor NGS testing. Thank you very much, Emmanuel. It was such a pleasure to spend time with you and learn from you.
Dr. Antonarakis: It is always a pleasure. Thanks very much, Neeraj.