Robert Dreicer, MD

: I am often asked to sort of speculate where [I think] therapeutic management of mCRPC [metastatic castration-resistant prostate cancer] is going, and I think put simply it’s going to get complicated. It’s already complicated. It’s a very heterogeneous disease; we all understand that, because of the leftward earlier movement of the therapies we used for mCRPC, there are gaps. There are a number of drugs in the pipeline and there are a number of drugs that may see regulatory approval early in 2022, including lutetium177-PSMA-617. There are also PARP [poly adenosine diphosphate-ribose polymerase]/ARI [alpha reductase inhibitor] combinations for which level 1 evidence is forthcoming. We know that certain patients with DDR [DNA damage response and repair] mutations need to be targeted differently at least today, but the potential for “BRCA-ness,” or increasing synthetic lethality with a combination of a PARP and an ARI, may open up a very interesting time frame. There are other PSMA [prostate-specific membrane antigen] therapeutics coming, both in terms of radioactive materials including alpha particles, as well as a whole generation of PSMA-targeted immunomodulatory therapies—CAR [chimeric antigen receptor] Ts, biospecifics, etc. I think what we’re going to increasingly see is the segmentation hopefully based on some biomarker to begin to deliver different sequences to specific groups of patients going forward. We’re not there. We need better therapies, and again, at the end of the day, we’re not curing mCRPC, we need to move to a paradigm where that becomes an option for a subset of patients as these therapies come online.

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Robert Dreicer, MD, describes the future of metastatic castration-resistant prostate cancer.

Emerging Therapies for Metastatic Castration-Resistant Prostate Cancer

: Among the drugs that are in trials now, there is a drug that I have been asked about as I have a relationship with the ongoing phase 3 [trial] and that’s sabizabulin, which is an oral cytoskeletal disruptor. It probably disrupts the cytoskeleton in a number of different mechanisms. It’s not taxane; it’s not a taxane-like drug, although it has similar targets. This oral agent has been in phase 1/2 trials. We have data from a phase 1B study that was led by Dr Mark Markowski of Johns Hopkins Hospital [Baltimore, MD] and this data was presented at ASCO [American Society of Clinical Oncology annual meeting] last year and no doubt will likely be updated at coming meetings. What we know about this agent is it’s an oral agent and it’s relatively well tolerated. Its toxicities tend to be GI [gastrointestinal], nausea, and some diarrhea but at the dose being studied in phase 3, it is a relatively well-tolerated therapy. What we've seen so far in this phase 1B study, which was about 30 patients with mCRPC [metastatic castration-resistant prostate cancer] that had progressed on at least 1 ARI [alpha reductase inhibitor] is that there's some evidence of antitumor activity that’s manifested both in seeing some soft tissue responses, some PSA [prostate-specific antigen] declines, and a couple of these patients have been on a drug for a long period of time, more than a year, approaching 2 years. My perspective on this agent is that there’s activity, it strikes me as almost a static agent, again that’s me speaking, that’s not data that we have yet, but in terms of the ability to have a drug on-board and have the ability to alter the natural history. We’re not seeing a dramatic resolution of disease, but we are seeing people who are able to tolerate this agent for prolonged periods of time and have antitumor activity. It’s an interesting compound because of the data seen to date. There is an ongoing phase 3 trial to test this drug further.

Sabizabulin is in a phase 3 trial entitled VERACITY, and this is a relatively small phase 3 trial that is randomizing patients to receive sabizabulin vs the alternative ARI. Eligibility, mCRPC patients who’ve progressed on an ARI, only minimal taxane prior exposure was allowed, so standard therapy in the castrate-sensitive or metastatic CRPC setting is not allowed, so this is really an early study of ARI progressing patients. The primary end point in this trial; radiographic progression-free survival. The eligibility is otherwise relatively straightforward, encompassing the issue of prior treatment. This study is open at a number of sites both in the U.S. and in Europe, and hopefully, it’s going to accrue relatively rapidly and give us an understanding of the utility of sabizabulin in mCRPC.

If sabizabulin happens to demonstrate activity, meaning meeting its primary end point of radiographic progression-free survival, and would eventually receive regulatory approval, this is a drug that you could also perceive to be used relatively early on in the disease course. It’s being tested in patients who have not been particularly heavily treated, these are ARI progressors, and so these patients are not uncommon. It appears to be a relatively well-tolerated drug, given the fact that there are a number of patients in the early phase 1 studies that have tolerated the drug for long periods of time with disease control. You could see this agent being used exactly in the clinical setting in which it’s being tested, as a drug that may provide long-term disease control with a relatively good quality of life. Now, obviously, we’re not there yet. We need to see. We need to finish phase 3, get the data, and then assess the safety, but this is a drug that you could see being used relatively early in the disease course among a number of clinicians—medical oncologists, urologists— who manage advanced disease and that population of clinicians.

A prostate cancer expert explains the potential advantages of sabizabulin, a new treatment for metastatic castration-resistant prostate cancer currently in a phase III clinical trial.

Sabizabulin for Metastatic Castration-Resistant Prostate Cancer

: I’m often asked what is a reasonable second-line therapy for patients with mCRPC [metastatic castration-resistant prostate cancer], and when I think about that question, of course, the first issue is what’s the clinical status of the patient and are they symptomatic or not? What prior therapies did they receive, not only in the mCRPC setting, but did they receive ADT [androgen deprivation therapy] intensification in the castrate-sensitive setting? Lines of therapy actually don’t help me very much, because again a patient getting a second-line in mCRPC may actually be getting a third or even a fourth-line of therapy based on prior treatment. Maybe a non-metastatic castrate-sensitive disease. Maybe in castrate-sensitive metastatic prostate cancer. I tend to think about it more as what and where. Where is the patient? What prior therapies have been administered? If somebody says to me, “Hey, this patient has seen a taxane maybe in the castrate-sensitive metastatic setting and received an ARI [androgen receptor inhibitor], and now has overt disease progression and is symptomatic.” My answer may be very different, perhaps cabazitaxel [Jevtana]. I may also ask the question, “What’s the patient genomic status?” If somebody says to me this patient has a BRCA1 [BReast CAncer gene 1] mutation based on germline, I may then say, “A patient who’s seen an ARI or an ARI and a taxane would be a very good candidate for olaparib [Lynparza], and if a taxane has also been given, or rucaparib [Rubraca] because that’s level 1 evidence supported.” Again, the sequence and the number of prior therapies as opposed to an arbitrary line of treatment is important. There are still a lot of unmet needs in this setting. There are new drugs that may be approved here. There is a myriad of new compounds being studied in this setting. We have a dearth of therapies available, as we’ve moved some of these treatments earlier into the castrate-sensitive metastatic setting.

Not infrequently am I asked about how to approach patients whose biology seems to be very different. For example, a patient who may have received abiraterone [Zytiga] as ADT intensification for castrate-sensitive disease and now has slow PSA [prostate-specific antigen] progression is completely asymptomatic and maybe there’s a nodal disease. That’s a patient where I might think about sipuleucel-T [Provenge] or a clinical trial, or even potentially the alternative ARI if the abiraterone response had been very prolonged. The alternative to that is a patient who perhaps has extensive disease both bone and nodal disease, high volume or high-risk presentation with a de novo presentation, has a very short response to ADT intensification perhaps with a drug like abiraterone. I’m very likely to use a taxane in that clinical setting because I need to get some antitumor activity rapidly. I’m not likely to use a therapy like sipuleucel-T or the alternative ARI because I really need to see antitumor activity. Again, there are differences in biology and one has to think about how you might use therapies in sequence based on the clinical status of the patient.

Infrequently, I’m asked about the patient who has said, “Look Doc, I don’t want chemotherapy and might there be other options in the mCRPC setting?” In all honesty, I must tell you that there are very few symptomatic patients, and again, with the use of taxane-based chemotherapy in the mCRPC setting, I think there’s some nuance there. Again, although these drugs were developed, both docetaxel and cabazitaxel in this setting, we know that there is level 1 evidence and we see a modest improvement in survival. But I think that many clinicians who treat a lot of prostate cancer tend to use taxanes in the mCRPC setting when patients are symptomatic because of its rapid ability to improve disease-related symptoms like pain and decreased appetite, weight loss, fatigue, etc. I think part of it is to also recognize the taxanes; both docetaxel and cabazitaxel are actually relatively well-tolerated therapies. So I think it’s important not to lose the utility of a therapy just because of some historical concern or somebody just sort of blankly saying, “I don’t want to have chemotherapy.” That said, there are obviously alternative nonchemotherapeutic options. There are clinical trials and radium-223 for the appropriate patient with a bone-only disease that doesn’t have significant disease-related symptoms. Sometimes the patient who’s had the alternative ARI, who’s had a very long response may benefit from a clinical trial of the alternative drug, and there are a host of agents in the pipeline for investigation. There are still options, although limited options, and again I want to emphasize that taxanes typically are pretty well tolerated. We don’t want to take away from the patient who may benefit from these therapies just simply because they initially say, “Hey, I don’t want chemotherapy.”

Robert Dreicer, MD, discusses the available second-line therapy options and unmet needs in metastatic castration-resistant prostate cancer.

Second-Line Therapy Options in Metastatic Castration-Resistant Prostate Cancer

Metastatic castration-resistant prostate cancer as a sort of a disease state has evolved pretty dramatically over the last couple of years, and we’re really poised to make additional changes. Among the most important issues is actually what happens in the castrate-sensitive metastatic setting. When people talk about a sequence of therapies, the first thing you have to figure out is, what happened when they were castrate-sensitive metastatic? We know that there is level 1 evidence, really practice-changing evidence, that ADT, androgen deprivation therapy, intensification with drugs like abiraterone [Zytiga], or apalutamide [Erleada], or enzalutamide [Xtandi], or docetaxel is the standard of care. We also know that its adoption rate still has a ways to go. When somebody says to me, “What’s a standard sequence for a patient with mCRPC [metastatic castration-resistant prostate cancer]?” There is no standard answer. You have to understand where we were in terms of what the patient’s received, what’s the clinical setting that the patient is currently in, is the patient symptomatic, or is this a PSA [prostate-specific antigen] only mCRPC progression? Are you a user of sipuleucel-T [Provenge] or not? Do you have investigation studies available? Did the patient receive an androgen receptor inhibitor? Abi [abiraterone], or enza [enzalutamide], or apa [apalutamide], in the castrate-sensitive setting? Because that will dictate changes and other changes are coming. We anticipate perhaps early in 2022, FDA [Food and Drug Administration] approval of an agent lutetium-177- PSMA [prostate-specific membrane antigen]-617 adding yet another drug to the mCRPC setting. There’s also evidence that likely will be presented over the next couple of months, which might suggest that patients benefit in the mCRPC setting by adding an ARI [androgen receptor inhibitor], drugs like abiraterone, or perhaps enzalutamide to a PARP inhibitor. There are a lot of changes, and you really have to sort of pay attention, but I think the key is the context of where the patient is by the time they arrive at mCRPC.

When people ask the question, what are frontline therapies for patients with mCRPC? Again, one of the things that I take into consideration before I answer the question is, where is the patient in terms of prior therapies? Were they a de novo presentation with metastatic disease and were they intensified with drugs like docetaxel or an ARI? Were they evolved from prior local therapy to metastatic disease and received androgen deprivation therapy only? What’s the context of where they are in terms of mCRPC? For example, is it a patient who got intensified with abiraterone, and now has a slowly rising PSA in a castrate setting, completely asymptomatic? Versus a patient who again maybe had ADT primarily, and now has not only biochemical progression but has new bone metastases and is symptomatic. How we approach these 2 different patients would be very different. There is limited sequence level 1 evidence to tell us that you must do X, Y, and Z, and part of it is because of not only the heterogeneity of the disease itself but increasingly the kinds of therapies that these patients may have seen prior. And that also may include genomic data. What is the BRCA [BReast CAncer gene] or ATM [ataxia telangiectasia mutated] status of a patient? Are there DDR [DNA-damage response] mutations?There’s no simple answer, but there is a way of thinking about the clinical spectrum that you have to start with to identify what might be the optimal therapy for an individual patient.

Robert Dreicer, MD, provides an overview of the first-line therapy options available in metastatic castration-resistant prostate cancer and the recent advances in detection, diagnosis, and treatment.

Robert Dreicer, MD

Articles

Emerging Therapies for Metastatic Castration-Resistant Prostate Cancer

Sabizabulin for Metastatic Castration-Resistant Prostate Cancer

Second-Line Therapy Options in Metastatic Castration-Resistant Prostate Cancer

First-Line Therapy Options in Metastatic Castration-Resistant Prostate Cancer