PSMA ADC in treatment of mCRPC post-chemo and post-abiraterone and/or enzalutamide

Data from an open-label Phase II trial of PSMA ADC — a fully human IgG1 antibody conjugated to monomethyl auristatin E (MMAE) — suggests that this agent has activity in treatment of metastatic, castration-resistant prostate cancer (mCRPC) patients who have already progressed on abiraterone acetate and/or enzalutamide.

However, whether PSMA ADC would prove to have clinically significant efficacy with an acceptable level of safety in such patients, if tested in a much larger, randomized, Phase III clinical trial, is hard to tell from the data to be presented by Petrylak et al. at the upcoming annual meeting of the American Urological Association (see abstract MP82-09 in the Prostate Cancer: Advanced II session).

Petrylak et al. report data from men (in a 119-patient Phase II trial) who had all received at least one taxane-containing chemotherapy treatment regimen (e.g., with docetaxel or cabazitaxel); 95 percent of these patients had also received and progressed on abiraterone acetate and/or enzalutamide. The patients were all then treated with either 2.5 or 2.3 mg/kg of intraveneous PSMA ADC every 3 weeks for up to 8 cycles of therapy.

Various positive signs of clinical activity were evident in the study results, including declines in PSA levels, decreases in circulating tumor cell (CTC) counts, and radiologic responses. However, there was no evidence of complete radiologic responses. In addition, there were significant numbers of adverse events of grade 3 and higher (including neutropenia, fatigue, anemia, and neuropathy).  Three patients actually died of sepsis.

Thus, even though PSMA ADC had some degree of activity in patients with mCRPC who had failed multiple prior forms of treatment, and the 2.3 mg/kg dose was better tolerated than the 2.5 ng/ml dose, it is hard to envisage this agent inducing a meaningful overall survival benefit in a randomized, Phase III clinical trial.

6 Responses

  1. In my view, the Sitemaster’s posting regarding Progenic’s PSMA ADC is more negative than it ought to be. Let me point out at the outset that I have a conflict of interest in commenting on this posting as I am involved in developing a competing PSMA-targeted ADC so, if anything, my conflict might make me biased against the product that is being reported on. Yet, that is not my view.

    It may firstly be worth pointing out to readers that an ADC (antibody-drug conjugate) is a form of targeted therapy designed to deliver a cell killing [cytotoxic] agent specifically to tumor cells but not to normal tissues. This is a very active area of drug development in cancer being pursued by numerous biotechs and pharmas. In the last few years the FDA has approved two such agents, one in Hodgkin’s lymphoma and the second in breast cancer. In those respective fields, the agents are considered transformational products that provide substantial patient benefit.

    While I share the Sitemaster’s concern regarding the three patient deaths due to sepsis, I would take issue with three other statements.

    Firstly, the seeming criticism that “there was no evidence of complete radiologic responses.” While that is almost certainly a factually true statement, the reality is that I don’t know of any agent that produces “complete radiologic responses” in prostate cancer patients in the clinical setting under study. Not mentioned in the Sitemaster’s report is that the agent did result in a respectable partial response (PR) rate. One could actually argue that the PR rate is impressive but I’m not going to go there since that is based on only 31 patients and not a lot of detail is provided in the abstract.

    The Sitemaster also comments that “there were a significant number of adverse event of grade 3 and higher.” Again, a correct statement, but let’s not lose sight of the fact that all of the patients studied had already failed abiraterone and/or enzalutamide and 70% had also failed docetaxel (+/- cabzitaxel). So, these are patients with few to no options, with the majority of them having a median anticipated survival measured in months, not years.

    Lastly, the comment that concerns me the most is the final, editorial comment “… it is hard to envisage this agent inducing a meaningful overall survival benefit in a randomized, Phase III clinical trial.” Certainly, people are entitled to express their opinions, but I don’t think this is a fair or helpful statement. After all, there are examples of current FDA-approved agents in prostate cancer (i.e., they demonstrated improved survival in Phase III trials) that showed significantly less anti-tumor activity in their Phase II trials than Progenics’ PSMA ADC. Neither Provenge nor Xofigo demonstrated any measurable responses whatsoever (not even PRs) nor any significant PSA declines, yet they ultimately were able to demonstrate improved survival. Furthermore, expressing such a negative predictive view does a potential disservice to patients who may be dissuaded from entering a trial of this agent and to drug developers who deserve a fair opportunity to prove whether their agent works or not. It’s hard enough to develop effective anti-cancer agents, let’s not make it unnecessarily harder.

  2. And Dr. Bander is entirely entitled to his opinion too!

  3. Why is that it is not likely for this agent to add survival to such a patient group? What makes you so confident? This is a patient group that is at the end of the road; clearly any agent that reduces PSA and offers improvements on radiological scans deserves to be offered to patients as an option.

    Often on this blog, the Sitemaster deploys undue faith in Phase III trials and their fetish of overall survival benefit, to miss the forest from the trees: agents that improve patient’s lives in any substantive form (even if stabilizing disease for some months) might be much more meaningful to such people and their families, than the know-it-all methodology of Phase III trials calling some medicinal molecule that offers a 3.3 month survival at a that costs $100,000 per year, “meaningful”.

    The honest way to respond would have been simply to report on the report, and let your readers make up their minds.

  4. Thank you Sitemaster and Dr. Bander for discussing this investigational agent.

    Regarding the likelihood of an overall survival benefit, on Tuesday Dr. Ravi A. Madan of the genitourinary group at the NCI spoke to our UsTOO group on immunotherapy. He made the point that immune drugs may be extending survival by decreasing growth rates, though without the often short-term favorable impact on the tumors themselves. Perhaps something similar could be happening here.

    I was impressed by this finding in the abstract for this very late stage group of patients: “In all treated pts, PSA declines of ≥30% and ≥50% were 30% and 14%, respectively (n=113); CTC counts showed a decline of ≥50% in 78% of pts and conversion from ≥5 to <5 cells/7.5 ml blood in 47% (n=77) at any time during the study.” When you add 30% plus 14%, you have 44% with an encouraging PSA response.

  5. Dear Jim:

    Just a point of clarification … The 14% of patients who had a 50% decline in their PSA levels in this trial is a subset of the 30% who had a 30% decline. You can’t add these together to get 44% of patients showing a decrease in their PSA.

  6. Dear Reader-4:

    I have no problem at all with the idea that drugs that improve quality of life for late-stage cancer patients (late-stage prostate cancer patients specifically included) should be approved and made available to such patients — even if they don’t improve survival. Indeed mitoxantrone, strontium-89 (Metastron), and samarium-153 lexidronam (Quadramet) were all approved prior to 1998 for the treatment of metastatic prostate cancer because they had precisely such effects.

    Since the approval of samarium-153, no other drug has ever been proven to have such an effect in metastatic, castration-resistant prostate cancer (mCRPC) unless it also extended survival. For a drug that has no significant survival benefit to be approved for such a use, it needs to demonstrate a benefit to quality of life. There are no evident data in the trial results reported by Petrylak et al. that suggest such an effect. In contrast, there are multiple sets of data suggesting reduction in quality of life, starting with the three deaths and including multiple types of Grade 3/4 adverse effects.

    I am not the person who decides what will and won’t get approved for the treatment of patients, or what trials will need to be done to gain such approval for specific drugs. That is the responsibility of the U.S. Food & Drug Administration and other regulatory authorities around the world, working in collaboration with individual drug developers and companies. However, those regulatory authorities are extremely clear about their requirement for approval of all new drugs: the clinical benefit to patients must, on average, clearly be greater than the risks associated with treatment.

    I would also note that I don’t actually place “undue faith” in “the know-it-all methodology of Phase III trials” at all. But when the FDA and other regulatory authorities (like EMEA in Europe) require such trials, and the pre-approved, primary clinical endpoint of such trials is an increase in survival (as it has been for almost every new drug tested for the treatment of men with mCRPC in the past 10+ years), then that is what a new drug is highly likely to have to demonstrate (unless the developer very clearly sets out to achieve a different primary endpoint — such as reduction in bone pain). The FDA has never approved any drug for the treatment of prostate cancer because that drug reduced PSA levels or because it induced partial radiographic responses. Why? Because no correlation has ever been demonstrated between such results and either survival or patient quality of life.

    It is possible that the combination of CTCs and levels of lactate dehydrogenase (LDH) may be accepted by regulatory authorities as a surrogate endpoint for survival at some point in the near future (see this report from a few weeks ago). That would make it a lot easier to carry out important trials of new drugs in very late-stage prostate cancer. However, the only other primary endpoints accepted by the FDA in men with advanced prostate cancer in recent years have been radiographic progression-free survival (for abiraterone acetate [Zytiga] in mCRPC) and prevention of bone loss and skeletal-related events like fractures (for drugs like zoledronic acid [Zometa] and denosumab [Xgeva] when used in men being treated with any form of androgen deprivation therapy).

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