ASCO has just released a new set of provisional guidance (a “provisional clinical opinion” or PCO) on the second-line treatment of men with chemotherapy-naive, castration-resistant prostate cancer (CRPC), i.e., men who are progressing on initial androgen deprivation therapy (ADT or “hormone” therapy) but who haven’t had docetaxel-based chemotherapy yet. The full guidance is available in an article by Virgo et al. in the Journal of Clinical Oncology. Brief summaries of the PCO are also available on the MedPage Today and on the Medscape web sites.
What this new guidance tries to do is offer clinicians some help in differentiating between the patients who are “failing seriously” on ADT and need aggressive forms of second-line therapy and those who are failing more slowly and can therefore be managed more carefully over time. The provisional guidance is focused on two subsets of men with prostate cancer:
- Those who are symptomatic, have not received chemotherapy, and have no documentable evidence of metastasis and only biochemical evidence of progression (i.e., men who are M0 CRPC)
- Those who are are aymptomatic or minimally symptomatic, have not received chemotherapy, but have evident, documented metastasis (i.e., men who are M1a CRPC)
The authors set out to provide answers to a series of research questions, and thus came up with a short-list of basic priorities associated with the treatment of chemotherapy-naive CRPC, as follows:
- The fundamental goal in the treatment of all forms of CRPC is palliation of problematic symptoms of prostate cancer, i.e., optimizing the patient’s quality of life by managing symptoms like pain associated with metastasis, while understanding that we still have no forms of care that can reliably extend life for such patients.
- Men with all forms of CRPC should be maintained in a castrate state for as long as this is possible (i.e., their serum T level should be kept as low as possible indefinitely).
- Second-line forms of hormonal therapy, inclusive of drugs like antiandrogens (e.g., bicalutamide/Casodex and enzalutamide/Xtandi) and CYP17 inhibitors (e.g., abiraterone acetate/Zytiga) may be considered for the treatment of men with Mo CRPC who appear to be at high risk for metastasis (i.e., men with with a low PSA doubling time or a high PSA velocity). However, such treatment is not currently recommended as second-line therapy for other patients with CRPC.
- In patients with clear radiographic evidence of metastases and minimal symptoms (M1a CRPC), drugs like enzalutamide or abiraterone acteate + prednisone can and should be offered to patients after the discussion of the potential harms and benefits of such treatment and after the patients’ prefere3nces have been taken into account.
- The use of drugs like radium-223 (Xofigo) and sipuleucel-T (Provenge) are also recognized to be options in the treatment of selected patients.
- There is still no good evidence that can offer guidance about the optimal order of hormonal therapies for CRPC beyond second-line treatment.
- PSA testing every 4 to 6 months is recommended for men with no evident metastases (M0 CRPC) and a slow PSA doubling time or a low PSA velocity.
- PSA testing every 3 months is recommended for men with no evident metastases (M0 CRPC) and a fast PSA doubling time or a high PSA velocity or with evident metastasis (M1 CRPC).
- Routine radiographic restaging can be considered for patients at risk for metastases or who exhibit symptoms or other evidence of disease progression, but is not generally suggested or recommended.
It is notable that the full text of the PCO contains (near the end) an entire section on the cost implications of treatment with the newer forms of second-line therapy for men with chemotherapy-naive CRPC. The PCO states that:
OOP [out-of-pocket] costs, the potential adverse effects of OOP costs (referred to as financial toxicity), and expected quality of life should be discussed with patients during the treatment decision-making process.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: ASCO, castration-resistant, chemotherapy-naïve, CRPC, guidance |
THE "NEW" PROSTATE CANCER INFOLINK 
Definition of CRPC: Testosterone Level and DHT
The paper mentions the question whether the testosterone level component of the definition is currently too high at < 50 ng/ml, with a brief mention that < 32 ng/ml or < 20 ng/ml might be more suitable, but the authors note the absence of Phase III trials to support a change in definition. The authors state that "… how changing the definition would actually affect treatment patterns is unclear. …"
That will surprise a lot of us who are veterans of ADT. For nearly two decades, at least, some oncologists have checked for flaws in delivery of ADT or for unusually rapid clearance of the drug if the patient's T value is not < 20 with a rising PSA, not considering the patient hormone refractory until the T value is < 20 and the PSA is still rising.
And there is this important additional step. There is no mention of DHT (dihydrotestosterone) in the paper. Some oncologists have observed that DHT can be elevated even when T is very low, and that such a pattern can wreck an ADT program if not corrected, letting the cancer continue to be fueled and the PSA to rise. The 5-alpha-reductase inhibitor drugs finasteride and dutasteride are highly effective in reducing the level of DHT.
I have not seen a study of the proportion of patients classed as having CRPC disease who actually simply have experienced flaws in the delivery of the drug, are unusually rapid clearers of the drug, or who have DHT levels that have not been adequately reduced by testosterone suppression.
Dear Jim:
Once again, guidelines are based on high quality data from (usually) randomized clinical trials. There are no such high quality data to substantiate the redefinition of castration as a serum T level of < 30 or < 20 ng/ml. Similarly, there are no such high quality data related to serum levels of DHT. Whether you or I happen to think that these issues are important (and in this case I happen to agree with you), we aren't going to see any change in the definition of castration or the relevance of serum DHT levels until such data are available.
In the case of the assessment of castration levels of serum T, the authors are very careful to point out exactly why the statements they make are based on the older data, and that this is a clear limitation of their study.
Genetic Testing Not Mentioned (An Example of an Epistemological Issue With This Guideline? A Generic Issue With Guidelines?)
As we have read repeatedly on The “New” Prostate Cancer InfoLink, genetic information, especially mutations in key genes, have been associated with drug targeting information, prognosis information, etc. It is noteworthy that genetic information is not addressed in this ASCO Provisional Clinical Opinion guideline document. Searches for the words or acronyms genetic, gene, BRCA, ARV (as in ARV-7), PTEN, and TMPRSS2 were all negative. Yet, such information is relevant to the nature of key specifics that are driving CRPC.
I’m curious why genetic testing was not at least mentioned. The reason may be that this document is primarily driven by phase III randomized clinical trial data, and perhaps such data may simply not have been the focus of major prospective phase III RCTs. Indeed, the introduction states the objective of offering “a rapid response to emerging data in clinical oncology … after publication or presentation of potentially practice-changing data from major studies.” [combined two adjacent sentences]
This may pose an epistemological problem for genetic information, which I believe is not patentable, which could make funding of a large, long, major randomized trial a challenge. While “lower quality of evidence” studies and understanding mechanisms of action may establish the value of certain genetic information, that information may be too specialized to support an “expert consensus”, which is apparently the alternate acceptance route to the main phase III RCT route for these ASCO Provisional Clinical Opinion guidelines. In other words, could it be that the guideline panel is wearing traditional blinders that cause it to be “looking for love in all the wrong places,” as well as in many of the right places, but not right for genetic information.
Dear Jim:
Just because you can’t patent a gene, doesn’t mean that you can’t patent a drug to treat a man or a woman or a child with a specific genetic abnormality. In fact several drugs have already been patented precisely for the treatment of such sets or subsets of patients, and a number of such drugs have been approved by the FDA (going back years) on exactly this basis. The earliest I can remember was imatinib (Gleevec) for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia. However, no one has managed to do this for a specific subset of prostate cancer patients … yet.
Your positing of a hypothetical epistemological problem is inaccurate. The only question is whether, in fact, anyone is going to be able to show a definable clinical benefit for patients who have a specific genetic abnormality. If this really works, it could probably be proven with a well-constructed Phase II trial. This is what Tokai had initially been trying to do in the relatively recent trials of galeterone for the treatment of men with the AR-V7 mutation … but the trial failed (see here).
Since, at present, we have no good data from well-constructed, randomized trials to show that a specific genetic subset of patients with prostate cancer will respond well to a specifically targeted drug, there is very limited value in genetic testing in the treatment of prostate cancer outside of a clinical trials scenario. And there are no data to even support discussion of this idea in a PCO like this.