What’s in the future pipeline for treatment of mCRPC?

Over the past year we have provided readers with extensive information about some of the new forms of therapy such as abiraterone acetate, MDV3100, TAK-700, and others that have shown great promise and are already in Phase III clinical trials for post-chemotherapy and chemotherapy-naive, metastatic, castration-resistant prostate cancer (mCRPC). However, there is a lot going on beyond the late-stage research into these widely publicized products, and a recently published review by Antonarakis and Carducci offers good insight into some of the farther reaches of the ongoing clinical trials.

It isn’t possible here to provide a concise summary of all the different investigational agents that Antonarakis and Carducci discuss in their article in Clinical Genitourinary Cancer. Rather, in what follows, we have tried to offer just a flavor of some of the more interesting areas of ongoing clinical research. Some readers may wish to obtain their own copy of the actual article from their local medical library (or spend $30.00 to download the entire article from the journal’s web site)

The authors begin by noting that, although the angiogenesis inhibitor bevacizumab (Avastin) showed no survival benefit when combined with docetaxel + prednisone in a recent Phase III clinical trial, it would be wrong to think that this has eliminated it as a potentially valuable agent in the management of late stage prostate cancer. Bevacizumab may still have potential when used in combination with other newer agents, and we may well hear of new trials in the future that combine bevacizumab with such drugs.

Other types of anti-angiogenic agents currently in clinical trials for the management of mCRPC include drugs like sorafenib, sunitinib, valatinib, aflibercept, and lenalidomide. It may take a while to work out how these drugs could best be used to delay the progression of prostate cancer, and the value of sunitinib and aflibercept is already doubtful, but it would be surprising if none of the anti-angiogenic agent ever showed any type of significant benefit. The question is more likely to be whether the benefit will outweigh the recognized adverse events of these agents. As we reported yesterday, tasquinimod is an anti-angiogenic agent that has already shown potential and will soon be entering Phase III trials.

A second class of drugs are the so-called PI3K/Akt/mTOR pathway inhibitors. These include mTOR inhibitors like everolimus, temsirolimus, and ridaforolimus and the relatively new Akt inhibitor MK2206. As yet, none of these drugs has entered Phase III clinical trials for mCRPC.

Another category of drugs are those that affect apoptosis (induction of programmed cancer cell death), of which the best known is probably custirsen (formerly known as as OGX-011). Custirsen is currently in Phase III clinical trials in combination with docetaxel and prednisone. Other drugs that fall into this class include AT-101, LY2181308, and YM155, all of which are currently in Phase II clinical trials.

After that we start to get into newer type of agents that are probably not as widely heard of so far. Here are some examples:

  • IGF pathway inhibitors such as cixtumumab and figitumumab (both in Phase II trials)
  • Src kinase inhibitors such as dasatinib, sarasatinib, and KX2-391 (of which dasatinib is already in Phase III clinical trials)
  • The so-called “hedgehog” inhibitors vismodegib and itraconazole (both in Phase II clinical trials)
  • Epigenetic agents like panobinostat and azacitidine (also in Phase II trials)
  • PARP inhibitors like olaprib and ABT-888 (again in Phase II trials)

Then there are other drugs that aren’t mentioned by Antonarakis and Carducci — drugs that we have commented on previously like cabozatinib (XL184), vorinistat, EZN-4176, OGX-427, apoptone (HE323), and a whole bunch more.

A decade ago you could count the truly promising drugs in Phase II and Phase III clinical trials for mCRPC on your fingers. In those 10 years, we have discovered a whole swath of new opportunities to affect the progression of the more advanced forms of prostate cancer. Obviously, not all of these drugs will succeed. Indeed many will “fall by the wayside.” However, the potential for better and more active agents for men with metastatic and/or castration-resistant forms of prostate cancer is extraordinary by comparison with where we were a decade ago. There is a great deal to look forward to … and good reason to have a positive outlook toward the clinical application of these new opportunities.

5 Responses

  1. What about the Medivation poster. Nearly double the PFS compared to abiraterone. Strong stuff.

  2. MDV3100 is already in two Phase III clinical trials. The first of these trials will potentially report data some time late this year or early in 2012 (more likely).

    One cannot reasonably make any judgment about the potential effectiveness of MDV3100 based on progression-free survival from an open-label trial and compare it to the overall survival data for abiraterone from a randomized, double-blind, placebo-controlled trial. The data presented by Higano et al. in the poster on MDV3100 at the recent Genitourinary Cancers Symposium confirm data presented in The Lancet back in April 2010 (see this link), and those data had first been reported at the annual meeting of ASCO in 2009. We’re just going to have to wait and see what the AFFIRM trial results show us (for post-docetaxel patients). The PREVAIL study (for chemotherapy-naive patients) is still open for enrollment. I would not expect results from that study before 2013.

  3. All true.
    The benefit of any treatment in the hormone axis is greatest earlier in the course of the disease. The poster and media release last week included the pre-chemo numbers for the first time which, by the PSAWG1 standard, has progression-free survival time measured in YEARS. I have never seen such a report in CRPC. The anxiety of time, and trial completion, is a battle.

  4. Dear John:

    It is true that progression-free survival times measured in years for men with CRPC have never been reported before (that I am aware of), but we really don’t know how meaningful these data are because (also as far as I am aware) it has never been measured before in a large group of pre-chemo patients who have failed at least two prior types of hormonal therapy.

  5. Appreciate the gathering of these several trials to this site for easy reference when patients are asking about new drugs in the pipeline.

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