Second-Line Hormonal Therapy

• Antiandrogen withdrawal (AAWR = anti-androgen withdrawal syndrome)

• Low-dose corticosteriods (examples are hydrocortisone, dexamethasone, prednisone, and triamcinolone).

• Second-Line antiandrogens

• Steriods such as Ketoconazole and  Aminoglutethimide

• Estrogens (DES and Transdermal Estrogen Patches)

• Alternative Therapies

• Other Less Proven Therapies, includes leukine, sandostatin, avodart, nilandron and more.

Definitions

LHRH - luteinizing hormone-releasing hormone, for example Lupron.

GnRH - gonadotropin releasing hormone, another designation for Lupron-like testosterone suppressing drugs.

Introduction

Primary hormonal therapy can be chemical suppression of testosterone via an LH-RH agonist such as Lupron, Zoladex or one of several others that are marketed or via an orchiectomy, which is surgically removing the testicles to suppress testosterone production.  The addition of the antiandrogen adds to this by blocking the androgen receptors on the prostate cancer cells so they cannot respond to the growth stimulation of testosterone or the testosterone precursors coming from the adrenal glands (also see anti-androgen withdrawal below). Sometimes a drug that suppresses the conversion of testosterone to dihydrotestosterone in the prostate cancer cell is also added -- an example of this type of drug are the 5α-reductase inhibitors such as Proscar and the newer drug Advodart(dutasteride.) 

A more general list of LH-RH agonists includes: Lupron(leuprolide acetate), Zoladex(goserelin acetate), buserelin, nafarelin acetate, Viadur (leuprolide acetate implant), Trelstar (triptorelin), and Eligard (leuprolide acetate) and Plenaxis (abarelix).  Plenaxis was withdrawn from the market in 2005 and is only available to patients who were already on the drug.  Not all of these are FDA approved yet or they may never be and all are not available or in general use everywhere. Trelstar has recently been approved by the FDA in a 6 month formulation that will be available in May 2010. This is in addition to the one and 3 month Trelstar. 

A newcomer to first line and possibly second line hormone therapy is degarelix (Firmagon^(R))

a new gonadotropin releasing hormone (GnRH) receptor antagonist, for the treatment of patients with advanced prostate cancer. 

Examples of antiandrogens are Casodex(bicalutamide), Eulexin (flutamide) or Nilandron(nilutamide).  One can try sequencing between these antiandrogens, e.g., Casodex to Nilandron to Flutamide before moving to ketoconazole.

Once primary hormonal therapy has failed, as indicated by a rising PSA or other evidence of disease progression (such as bone metastases) a next option is called secondary hormonal therapies. 

Usually patients remain on an LH-RH agonist, which controls the growth of any androgen responsive prostate cancer cells that are still around.

The treatment sequence usually recommended is as follows:

 

If stopping casodex, it might take 8 weeks before a withdrawal response is seen due to long half-life.  Otherwise, 4 weeks is probably sufficient

Antiandrogen Withdrawal

Stopping the antiandrogen and immediately starting ketoconazole is an option. Clinical trials will usually require stopping antiandrogens.

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Antiandrogen Withdrawal

If taking Casodex(bicalutamide), Eulexin(flutamide) or Nilandron (nilutamide), stopping these, but staying on the LH-RH agonist may precipitate a drop in PSA. This is normally the 1st step if PSA is rising while on complete hormone blockade.  Sometimes, stopping the antiandrogen and immediately starting a secondary hormonal manipulation is also done. 

Withdrawal responses may also be seen with megestrol acetate (Megace), estrogens(e.g., DES), progestational compounds and retinoids1

In the paper by Small et al2, 3 separate studies on AAWR were summarized: 138 total patients, 29(21%) had a PSA decrease ≥ 50% after stopping flutamide -- the individual values were 15%, 29% and 33%.  The median durations of response were 3.5, 3.7+ and 5 months.  Responders had a median time on flutamide of 18-28.3 months and non-responders had shorter median times on flutamide ranging from 12-18.7 months. Men who were on both an LHRH agonist and on flutamide has responses of 22% 18/82, but those who did monotherapy followed by or preceeded by flutamide had responses of 11% (4/36). Responses >2 years is mentioned.

Cancer and Leukemia Group B (CALGB - trial 9583) documented a  randomized, prospective trial of antiandrogen withdrawal alone compared with antiandrogen withdrawal plus high-dose ketoconazole (HDK).3  HDK consisted of ketoconazole, 400 mg p.o. t.i.d. and hydrocortisone, 40 mg p.o. q.d.

The antiandrogen withdrawal-alone arm, had a ≥50% PSA response in only 13% of patients, with an objective response rate of 4%.  AAWR can also provide an objective response as seen by the 4% response rate. There was no difference in survival in early versus later use of HDK.

In yet another study of AAWR, a prospective SWOG (SW Oncology Group) study (SWOG 9426)4 with data from multiple institutions as opposed to primarily single institution studies, enrolled 259 patients.

NA = not available in the abstract.

This abstract was presented in May 2002 at ASCO.  Until the full trial results are published, there isn't a whole lot of information available comparing AA.  The response rate PSA-wise of only 15% is modest at best.

References

1. HI Scher and G JCM Kolvenbag, "The Anti-Androgen Withdrawal Syndrome in Relapsed Prostate Cancer," Eur Urol 1997;31[suppl 2]: 3-7.

2. EJ Small and NJ Vogelzang, "Second-Line Hormonal Therapy for Advanced Prostate Cancer: A shifting Paradigm," Journal of Clinical Oncology, vol. 15, No. 1(January), 1997: pp 382-388.

3. Small E.J., Halabi S., Picus J., et al. "A prospective randomized trial of antiandrogen withdrawal alone or antiandrogen withdrawal in combination with high-dose ketoconazole in androgen independent prostate cancer patients - results of CALGB 9583", ASCO 2001 abstract 695. 

4. A. O Sartor, C Tangen, M Hussain, M Eisenberger, E D Crawford, Anti-androgen withdrawal in prostate cancer: results from SWOG 9426. ASCO 2002 Abstract 785.

Scher and Kelly's paper on flutamide withdrawal in 1993 was followed by the Small et al paper below.

Small E.J., Carroll P.R., "Prostate-specific antigen decline after Casodex withdrawal - evidence for an antiandrogen withdrawal syndrome", Urology, Volume: 43, (1994), pp. 408-410.

The following two references provide excellent overviews of secondary hormonal therapies. W. Oh's, being the most recent and therefore up to date.

WK Oh, "Secondary Hormonal Therapies in the Treatment of Prostate Cancer," Urology 60[Suppl 3A]:87-93, 2002.

Richie JP, Anti-androgens and other hormonal therapies for prostate cancer, Urology 1999 Dec;54(6A Suppl):15-8.

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Low-dose corticosteroids

The paper on low-dose corticosteroids is on its own page. Low-dose corticosteriods can be used as an independent second line hormone therapy.  They are often combined with chemotherapy or with  ketoconazole or Aminoglutethimide(Cytaden).

Triamcinolone is one glucocorticoid to consider and is discussed on its own page also.

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Second Line Anti-androgens

Casodex (Bicalutamide) is a nonsteroidal antiandrogen.  The currently FDA approved dose is 50mg/day and it is usually used in conjunction with an LH-RH agonist.  Some studies are also being done or have been done using Casodex as a monotherapy for a 1st time hormone therapy and doses for this use have generally been 150mg to 200mg/day.  Casodex is an orally administered drug with hot flashes(23%) and nausea(21%) being the most common side effects.

Note: Consider sequencing from Casodex to Nilandron to Flutamide before moving to HDK/HC. Sometimes a response is seen if the dose of Casodex is increased from 50 to 150mg/day.

High Dose Casodex(HDC) - bicalutamide

Low dose casodex = 50mg/day.  High dose casodex = 150 mg/day, although 200mg/day is occasionally prescribed.

High-Dose Casodex for HRPC(androgen-independent prostate cancer) - Summary Table ^1,2,3

^a No prior antiandrogen.

In the study by Kucuk et al², all patients had no prior chemotherapy and no prior antiandrogen. Result-wise they found palliation of pain but no complete or partial responses, but there was the above noted 20% PSA response. Median survival time was 15 months.

The study by Scher et al³ had who were androgen dependent, androgen independent, with or without previous flutamide but the outcomes were reported separately.

Considering just the androgen-independent group, "clinical benefit was observed in patients who had previously progressed on flutamide, independent of the response to flutamide withdrawal. Patients who had progressed on a gonadotropin-releasing hormone (GnRH) analog alone had a low response proportion, whereas those who progressed after two or more hormone therapies did not respond."
 

References

1. Joyce R., Fenton M.A., Rode P., et al. "High dose bicalutamide for androgen independent prostate cancer - effect of prior hormonal therapy", J Urol, Volume: 159, (1998), pp. 149-153.

2. Kucuk O, Fisher E, Moinpour CM, Coleman D, Hussain MH, Sartor AO, Chatta GS, Lowe BA, Eisenberger MA, Crawford ED, Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: a Southwest Oncology Group study (SWOG 9235), Urology 2001 Jul;58(1):53-8.

3. Scher H.I., Liebertz C., Kelly W.K., et al. "Bicalutamide for advanced prostate cancer - the natural versus treated history of disease", J Clin Oncol, Volume: 15, (1997), pp. 2928-2938.

Megestrol acetate

Megestrol acetate is a steroidal antiandrogen with progestational activity. For androgen independent patients, responses are very low with objective responses of only 0-9%(as an antiandrogen) and Dawson et al reported PSA decreases of 8-13% and few objective responses.  Side effects noted were thrombophlebitis and fluid retention.  Oh, notes that based on the above results, megestrol acetate should not be used for HRPC men.

Dawson N.A., Conaway M., Halabi S., et al. "A randomized study comparing standard versus moderately high dose megestrol acetate for patients with advanced prostate carcinoma - cancer and leukemia group B study 9181", Cancer, Volume: 88, (2000), pp. 825-834.

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Steriods - Inhibitors of adrenal androgen production

Testosterone is, for the most part, secreted from the testicles.  However, about 10% can also be produced by the adrenal glands in the form of androgen precursors. Even in hrpc men, there are prostate cancer cells retaining sensitivity to androgens and therefore, reducing the output from the adrenal glands can result in a PSA reduction. See the following pages for more information.

Ketoconazole - both High Dose(HDK) and Low Dose(LDK). The brand name is Nizoral and there is a generic version available. There is also an Intermediate-Dose which is 300mg tid. A table summarizing study results of high dose, low dose and intermediate dose ketoconazole as well as high dose ketoconazole combined with other agents is at ketotable.

Aminoglutethimide (Cytadren). Unfortunately, this drug is no longer available.

Estrogens

Estrogens and anti-estrogens can also play a role as second line hormone therapies.   DES information is detailed at

Estrogens (e.g., DES).

Anti-estrogens, in the form of tamoxifen 200mg/m2 did show some PSA response.  A newer drug, Evista (raloxifene), may have a much greater effect -- it targets the estrogen receptor beta while tamoxifen targets ERalpha. The Cedars-Sinai Prostate Cancer Center has done some clinical trial work with Evista.  Evista is already FDA-approved for treating osteoporosis in women. 

Alternative Therapies

PC Spes - This herbal product is no longer available, having been withdrawn by the manufacturer BotanicLab. The link will take you to some of the information that was available on this preparation. A number of herbal products are now on the market claiming to have the same ingredients as PC-Spes -- presumably without prescription drug contamination as was found with PC-Spes. These include PC Hope, PC Plus, PC Res and, likely, others.

Of course, at some point, PC Spes might return to the market in a contamination free form.  A product being developed by Active Botanicals, Ltd. (UK) is called PCSPES2. See Oncology Reports 2008 for details on a phase I study with 18 HRPC patients. Diarrhea was one of their biggest problems and required a dose adjustment(8 out of the first 10 patients at one month and only 2 out of the last 8 due to an improved dosing schedule). At one month, 7 out of 10 patients had a drop in their PSA doubling time or PSA velocity, which was still apparent in 4 out of 5 patients still on trial at three months and all three patients still on trial at six months. Whether or not they will proceed to a phase II trial is unknown at this time. 

Phase I trial of PC-Spes2 in advanced hormone refractory prostate cancer

Authors: Majid Shabbir, Julie Love, Bruce Montgomery, Oncol Rep. 2008 Mar;19 (3):831-5 18288423 (P,S,E,B). Department of Urology, Frimley Park Hospital, Portsmouth Road, Surrey GU16 7UJ, UK. majidshabbir@hotmail.com.

Howard Hansen 1/3/2003. Updates on 8/4/07 and 8/28/08.

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