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


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

Robert Dreicer, MD: 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.”

Transcript edited for clarity.

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