Role of GnRH agonists in Cancer Prostate.pptx

Role of GnRH in Ca. Prostate

1. DR. KALYANARAM KONE ROLE OF GnRH ANALOGUES IN CARCINOMA PROSTATE

2. cancer of the prostate = center of catastrophe Pro = state

3. In 1853, J. Adams, a surgeon at The London Hospital, described the first case of prostate cancer, which he discovered by histological examination . Adams noted in his report that this condition was “a very rare disease” * Adams J. The case of scirrhous of the prostate gland with corresponding affliction of the lymphatic glands in the lumbar region and in the pelvis. Lancet. 1853;1:393

4. In the United States, it is the most commonly diagnosed cancer in men, with 180,000 new cases and about 31,000 deaths occurring annually Prostate is the second leading site of cancer among males in large Indian cities like Delhi, Kolkatta , Pune and Thiruvananthapuram, third leading site of cancer in cities like Bangalore and Mumbai and it is among the top ten leading sites of cancers in the rest of the population based cancer registries (PBCRs) of India. The PBCRs at Bangalore (Annual Percentage Change: 3.4%), Chennai (4.2%), Delhi (3.3%), Mumbai (0.9%) and Kamrup Urban District (11.6%) recorded a statistically significant increasing trend in incidence rates over time.

5. Indian J Urol. 2016 Apr-Jun; 32(2): 103–108. Demography and disease characteristics of prostate cancer in India Krishnamoorthy Hariharan and Venugopal Padmanabha

6. PROBLEM 1 The deep-rooted fear about cancer drives the decision-making process, rather than scientific evidence

7. PROBLEM 2

8. What is the ideal treatment ?

9. TREATMENT MODALITIES- ANYTHING IS CORRECT Medical therapy Surgical therapy Radiation Cryotherapy

10. “It is said that if you know your enemies and know yourself, you will not be imperiled in a hundred battles; if you do not know your enemies but do know yourself, you will win one and lose one; if you do not know your enemies nor yourself, you will be imperiled in every single battle.” —Sun Tzu

11. “To attack a cancer cell specifically, one needed to begin by identifying its biological behavior, its genetic makeup, and its unique vulnerabilities”. The search for magic bullets needed to begin with an understanding of cancer’s magical targets.

12. Vulnerability Persistence of Androgens and AR signaling key to Prostate cancer progression AR the most important therapeutic target (both hormone sensitive and in castration resistant disease)

13. MAGIC BULLET 1 ( Orchidectomy ) prostate carcinoma: compare castration It had been known for at least a century that prostatic epithelium undergoes atrophy after castration (Hunter, 1840). The breakthough in Huggin’s hypothesis was the recognition that benign prostatic epithelium and prostate carcinoma were biochemically analogous and they would respond in a similar fashion to androgen ablation either by Castration or Estrogen therapy Negative results of castration in two men with prostate cancer reported by Young (1936). But in a series of 21 consecutive patients with locally advanced or metastatic prostate cancer who underwent surgical castration at the University of Chicago - “A noticeable improvement occurred in the clinical status of all but three patients” with weight gain, resolution of anemia, and improvement in pain. (Huggins et al, 1941).

14. MAGIC BULLET 2 (Estrogens) The first central inhibition of the axis exploited the potent negative feedback of estrogen on luteinizing hormone (LH) secretion it is now known that estradiol is a 1000- fold more potent at suppressing LH and follicle- stimulating hormone (FSH) secretion by the pituitary compared with testosterone ( Swerdloff and Walsh, 1973). Among the various estrogenic compounds Diethylstilbestrol (DES) has been most widely studied and used (1-5 Mg/day). Other one - Fosfestrol tetrasodium ( Honvan ) 360-480 mg tid . Maintenance: 120-240 mg tid ; may gradually reduce to 240 mg daily.

15. TYPICAL PATIENT (Till 80s) – LATE DETECTION PRESENTED WITH METASTATIC DISEASE ADT WAS THE GOLD STANDARD CREATED A NEW DISEASE- CRPC

16. Huggins was awarded the Nobel Prize in Physiology in 1966. He admitted “Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease”

17. Magic Bullet 1- Permanent castration and disfigurement Magic Bullet 2- Reversible castration but Cardiovascular complications and DVT SEARCH CONTINUED ……… .

18. Magic Bullet 3 – LHRH Agonists The first isolation of luteinizing hormone–releasing hormone (LH-RH) by Schally and colleagues (1971) required the hypothalami of 165,000 pigs to obtain 800 μg of the 10 amino acid peptide. Discovery of the structure of LHRH in 1971 by Schally and his colleagues stimulated the synthesis of highly potent analogs of LHRH with the objective of treating infertility. In 1977, Schally received the Nobel Prize in Physiology and Medicine for this exciting work

19. Even more unexpected was the finding that of all the species studied, man was the most sensitive to the inhibitory action of LHRH agonists on testicular androgen biosynthesis and that medical castration could be easily achieved with LHRH agonists in adult men. Contrary to the usual pattern in medical discoveries, the castration effect of LHRH agonists was first observed in men and not in experimental animals where castration is difficult or sometimes impossible to achieve with daily administration of LHRH agonists .

20. Initially, the clinical utility of these agents was hampered by their short half-lives, requiring daily injections to maintain suppression of the hypothalamic- pituitary axis. The generation of long-acting depot preparations, lasting several months, has established LH-RH agonists as the dominant treatment in hormone therapy for prostate cancer.

21. The clinical utility of the current LH-RH agonists is based on the creation of analogues of native LH-RH by amino acid substitutions, particularly position 6 in the peptide, increasing their potency and half-lives

22. In a review of 24 trials, involving more than 6600 patients, survival after therapy with an LH-RH agonist was equivalent to that of orchidectomy ( Seidenfeld et al, 2000).

23. The initial exposure to more potent agonists of LH-RH results in a flare of LH and testosterone levels (Waxman et al, 1985). This phenomenon is seen with all available LH-RH preparations and can result in a severe, life- threatening exacerbation of symptoms. They are, associated with up to a 10-fold increase in LH, may last for 10 to 20 days ( Weckerman and Harzmann , 2004).

24. T he coadministration of an antiandrogen functionally blocks the increased levels of testosterone ( Labrie et al, 1987; Kuhn et al, 1989; Schultz and Senge , 1990). Although it had been argued that the administration of the antiandrogen should precede the administration of the LH-RH agonist by a week, others have found no differences in PSA levels with the simultaneous administration of both agents (Tsushima et al, 2001). Given the predictable length of the are phenomenon, antiandrogen co-administration is required for only 21 to 28 days.

25. Potential of reversibility Enable use of intermittent ADT Avoid the physical and psychological discomfort associated with orchiectomy Lower risk of cardiotoxicity than diethylstilbestrol , and result in equivalent oncologic efficacy when compared to Orchidectomy Benefits of GnRH Agonists

26. The commonly used GnRH analogues Triptorelin Leuprolide Goserelin Available since decades Efficacy –proven in various clinical studies and routine clinical practice Status- recommended by various clinical guidelines Comparison- studied, but not extensively GnRH agonists

27. Triptorelin: A Unique GnRH Agonist

28. Patients had histologically confirmed advanced PCa (stage C or D) Inclusion Criteria Serum testosterone concentration of > 1440 ng/L A Karnofsky performance index of >40; Expected survival of ≥ 12 months; No other malignancy (except dermatological) for 5 years. Endpoints Primary End Point: percentage of patients with castration at 29 days and at 2-9 months of treatment. Secondary endpoint: LH levels, bone pain, PSA levels, QOL, testosterone pharmacodynamics, survival, and safety variables Triptorelin pamoate microgranules 3.75 mg, I/M every 28 days for 9 injections (n=140) Leuprolide acetate microspheres 7.5 mg,I /M every 28 days for 9 injections (n=144) Triptorelin vs Leuprolide Heyns CF, et al. BJU Int. 2003;92(3):226-31.

29. Results Maintenance of castration level Heyns CF, et al. BJU Int. 2003;92(3):226-31. The maintenance of castration in men treated with Triptorelin pamoate 3.75 mg (green line, open circles ) or leuprolide acetate 7.5 mg (red line, open squares) for 9 months (Kaplan-Meier survival analysis)

30. The 9-month survival rate was significantly higher in triptorelin group *P=0.033 Results Survival Benefit with Triptorelin Heyns CF, et al. BJU Int. 2003;92(3):226-31.

31. Any adverse event 93.6 95.1 Intensity (% of patients) Mild 83.6 84.7 Moderate 60.7 70.1 Severe 24.3 34.7 Most frequent (% of patients) Hot flushes 58.6 54.2 Skeletal pain 21.4 16.7 Headache 13.6 18.8 Constipation 15.0 15.3 Triptorelin 3.75 mg (n = 140) (N = 144) Leuprolide 7.5 mg Heyns CF, et al. BJU Int. 2003;92(3):226-31. Safety Results

32. Patients ≥ 18 years ; diagnosis of advanced PCa & a candidate for t/t with triptorelin IM or leuprolide SC Multicenter, randomized, cross-over, open-label study Aim- To assess patients’ and health care providers’ ratings of injection site tolerability associated with leuprolide or triptorelin administration Single injection of triptorelin 22.5 mg I/M in either buttock (n=58) Leuprolide 45 mg S/C in upper- or mid-abdominal area (n=49) Single injection of triptorelin 22.5 mg I/M in either buttock Leuprolide 45 mg S/C in upper- or mid-abdominal area Shore ND, et al.   Urol Nurs . 2013;33(5):236-44, 248. Comparison of tolerability and AEs

33. Leuprolide Significantly more anxiety prior to injection and about future injections Triptorelin Less bothersome bruising and swelling and significantly greater overall injection experience (p=0.0009) Both patients’ and clinician’s had greater satisfaction with triptorelin IM vs leuprolide SC Shore ND, et al.   Urol Nurs . 2013;33(5):236-44, 248.

34. The NICE Evidence Review Group Considered Ferring’s submission for degarelix vs other therapeutic alternatives for the treatment of advanced hormone- dependent prostate cancer (HDPC) in August 2013 Reviewed , critiqued and conducted their own evaluation and comparison of the clinical and economic benefits compared with the existing therapeutic options for advanced PC LHRH analogs were compared at the highest scientific level by NICE Uttley L et al. Degarelix for treating advanced hormone-dependent prostate cancer: A single technology appraisal. ScHARR , University of Sheffield. 2013 ).

35. MTC (Mixed Treatment Comparisons ): The essential tool for indirect comparisons , employed in the NICE appraisal A generalization of pairwise meta-analysis to account for indirect comparison Guidelines from HTA bodies for use in appraisal and in clinical recommendation Use of both direct and indirect comparions Indirect evidence Direct evidence Uttley L et al. Degarelix for treating advanced hormone-dependent prostate cancer: A single technology appraisal. ScHARR , University of Sheffield. 2013 ).

36. They looked at comparative randomized clinical trials MTC 1 st step : An exhaustive selection of clinical studies Trial – Duration Intervention Comparator CS21 Klotz et al. 2008 – 12 months Degarelix Leuprorelin monthly 7.5mg ( with or without Bicalutamide) CS28 Anderson et al., 2013 – 3 months Degarelix Goserelin 3.6 mg ( with bicalutamide ) CS30 Mason et al, 2013 – 3 months Degarelix Goserelin 3.6 mg ( with bicalutamide ) CS31 Axcrona et al., 2012 – 3 months Degarelix Goserelin 3.6 mg ( with bicalutamide ) Iversen et al., 1998 – 4 years Bicalutamide Goserelin 3.6 mg Heyns et al., 2003 – 9 months Triptorelin Leuprorelin 7.5 mg Uttley L et al. Degarelix for treating advanced hormone-dependent prostate cancer: A single technology appraisal. ScHARR , University of Sheffield. 2013 ).

37. MTC 2 nd step : A network of therapeutic options and related trials Degarelix Leuprorelin Triptorelin Bicalutamide Goserelin Indirect evidence Direct evidence Uttley L et al. Degarelix for treating advanced hormone-dependent prostate cancer: A single technology appraisal. ScHARR , University of Sheffield. 2013 ).

38. ERG consideration Different study durations and therefore diferent time points across included studies Heterogeneity in baselin characteristics between studies Low number of deaths in the selected studies Methodological approach Standardisation in the study duration (use of hazard ratios vs odd ratios) Bayesian statistics to address heterogeneity between studies MTC 3 rd step : Accounting for the heterogeneity between the different trials Uttley L et al. Degarelix for treating advanced hormone-dependent prostate cancer: A single technology appraisal. ScHARR , University of Sheffield. 2013 ).

39. Triptorelin was associated with a lower mortality risk than goserelin , leuprorelin , degarelix (and bicalutamide ) All LHRH analogs are not equivalent NICE Evidence Review Group findings Numerical difference Significant difference Favours the 1 st treatment Favours the 2 nd treatment Uttley L et al. Degarelix for treating advanced hormone-dependent prostate cancer: A single technology appraisal. ScHARR , University of Sheffield. 2013 ).

40. Triptorelin pamoate induced castration at a slower rate, but it maintained castration as effectively as leuprolide No evidence of deleterious effects of slow induction of castration Survival rate at 9-month significantly higher with Triptorelin Triptorelin 3.75 mg has a better tolerability profile , less moderate and severe side effects Conclusion Heyns CF, et al. BJU Int. 2003;92(3):226-31.

41. OTHER MEDICINES (ADT) Anti androgens Steroidal- Cyproterone Non-steroidal- Flutamide , Bicalutamide LHRH Antagonists Degarelix Inhibition of Androgen synthesis Aminoglutethimide , Ketoconazole

42. Currently approved for mCRPC only. Abiraterone acetate Abiraterone acetate (AA) is a CYP17 inhibitor (a combination of 17 hydrolase and 17-20 lyase inhibition). By blocking CYP17, AA significantly decreases the intracellular testosterone level by suppressing its synthesis at the adrenal level and inside the cancer cells ( intracrine mechanism). This compound must be used together with prednisone/prednisolone (2 x 5 mg) to prevent drug-induced hyperaldosteronism. Enzalutamide Enzalutamide is a novel anti-androgen with a higher affinity than bicalutamide for the AR receptor. While non- steroidal anti-androgens still allow transfer of ARs to the nucleus, enzalutamide also blocks AR transfer and therefore suppresses any possible agonist-like activity.

43. LHRH Antagonists The LH-RH antagonists bind immediately and competitively to the LH-RH receptors in the pituitary, reducing LH concentrations by 84% within 24 hours of administration ( Weckerman et al, 2004). The direct antagonistic activity eliminates the LH and testosterone flare, which is the major therapeutic advantage of these agents: there is no need for antiandrogen co-administration. Hormonally naive patients with impending spinal cord compression or severe bone pain for whom surgical castration is not appropriate may uniquely benefit from this class of agents A new LH-RH antagonist, degarelix , (240/80 or 240/160 mg Monthly) has completed phase 2 and phase 3 studies in prostate cancer ( Gittelman et al, 2008; Klotzet al, 2008). Unlike with abarelix there were no systemic allergic reactions with degarelix . In the phase 3 study, degarelix was compared with leuprolide: at 1 year of treatment degarelix was not inferior to leuprolide, and, based on this result, it has been approved for use in the United States.

44. Complications Osteoporosis Serum testosterone and estradiol levels were much lower on men receiving LH-RH agonists compared with those on non- steroidal antiandrogen therapy; accordingly, markers of bone turnover were significantly higher in men taking LH-RH agonists compared with those on nonsteroidal antiandrogen therapy, suggesting the nonsteroidal antiandrogens may help maintain BMD. Treatment of osteoporosis begins with recognition. BMD of the hip, as measured by dual-energy x-ray absorptiometry, should be considered on all men who are anticipated to be on long-term ADT (Bae and Stein, 2004; Diamond et al, 2004). Smoking cessation, weight-bearing exercise, and vitamin D and calcium supplementation can help improve BMD. Daily supplementation of calcium and vitamin D is recommended by the National Institutes of Health at doses of 1200 to 1500 mg/day and 400 IU/day, respectively. Bisphosphonates (Alendronate 70 mg weekly, Zoledronic acid 4 mg monthly injections) Transdermal estradiol

45. 2. Hot Flashes Described as a subjective feeling of warmth in the upper torso and head followed by objective perspiration, hot ashes are not life threatening but are among the most common side effects of androgen ablation, affecting between 50% and 80% of patients Megestrol acetate (20 mg, twice per day) ---- 5 mg twice daily MPA (20 mg a day) Cyproterone acetate start at 50 mg/day and be titrated to 300 mg/day. Estrogenic compounds, such as low-dose DES (1 mg a day) and transdermal estradiol, appear to be the most effective treatment, with up to 90% partial or complete resolution of symptoms - painful gynecomastia and thromboembolic effects have limited the utility of this approach Clonidine, a centrally acting α agonist ( Arkamine 0.2-0.4 mg per day or patch once a week) Antidepressant agents - particularly the SSRI - Venlafaxine ( Sentosa 12.5 mg, twice daily) Antiseizure agent gabapentin 300 mg twice or thrice a day Ergotamine, belladonna and phenobarbitol (EBP)

46. 3. Sexual Dysfunction (Erectile Dysfunction and Loss of Libido) My dear old friend, where have you gone?
 You used to be so tall.
 All my life, I've known you well,
 And now you seem so small.
 What happened to those glory years,
 When we were both so free?
 You used to dominate my life,
 Now, all you do is pee!

47. Loss of sexual functioning is not inevitable, however, with up to 20% of men on ADT able to maintain some sexual activity Libido is more severely compromised, with approximately 5% of men maintaining a high level of sexual interest with ADT Medical treatments, such as oral phosphodiesterase type 5 inhibitors, or local treatments, such as intracavernosal injections of alprostadil , can still be effective in selected patients If there is any fairness in the negative effects of ADT on sexual function it is the decline in both libido and erectile functioning

48. 4. Cognitive Function There is a strong suggestion that ADT is linked to subtle but significant cognitive declines in men with prostate cancer (Nelson et al, 2008). The declines were associated with tasks requiring complex information processing (Green et al, 2004). A short course of ADT (36 weeks) increased depression and anxiety scores on formal neuropsychologic evaluations (Almeida et al, 2004); Major depressive disorder was prevalent in 12.8% of men on ADT, 8 times greater than the national rate and 32 times the rate of men older than 65 years of age ( Pirl et al, 2002). Finally, psychologic distress accounted for approximately one third of declines in fatigue severity scale in men undergoing ADT (Stone et al, 2000).

49. 5. Changes in Body Habitus A loss of muscle mass and increase in percent fat body mass are common in men undergoing ADT, and these changes are most pronounced with the initiation of ADT (van Londen et al, 2008). After 1 year of ADT the mean overall weight increases from 1.8% to 3.8%, which translates into about 5 lb for a 200-lb man ADT is associated with an increase in appetite and a low testosterone level is associated with increased insulin levels and abdominal girth ( Seidell et al, 1990). Regular vigorous exercise may help patients limit the accumulation of fat and even prevent prostate cancer progression. Men older than the age of 65 who engaged in vigorous exercise more than 3 hours per week had a 70% reduction in prostate-cancer specific death ( Giovannucci et al, 2005).

50. 6. Diabetes and Metabolic Syndrome Given the changes in body habitus, it is not surprising that metabolic syndrome, a clustering of specific cardiovascular disease risk factors related to insulin resistance, is present in more than 50% of men undergoing long-term ADT (Braga- Basaria et al, 2006). Unlike classic metabolic syndrome, however, characterized by visceral fat accumulation, ADT preferentially increased subcutaneous fat. In a small but carefully controlled prospective study, ADT signicantly decreased insulin sensitivity in men with prostate cancer (Smith et al, 2006). These findings were supported by a larger observational study (73,196 men with prostate cancer) in which there was a significant risk of developing diabetes with ADT (Keating et al, 2006).

51. 7. Cardiovascular Morbidity and Mortality Given the generally adverse effects of ADT on body habitus, glucose metabolism, and lipid profiles, it is not surprising that studies have found that ADT is associated with increased cardio-vascular morbidity and mortality. The effects appear to be most pronounced in men with lower-risk prostate cancer treated with ADT. In a large (22,816 subjects), population-based registry, newly diagnosed prostate cancer patients who received ADT for at least 1 year had a 20% higher risk of cardiovascular morbidity compared with similar men who did not receive ADT ( Saigal et al, 2007). In men older than the age of 65 undergoing radical prostatectomy who also received ADT, the cumulative incidence of cardiovascular death was 5.5% over 5 years compared with 2.0% in those not receiving ADT (Tsai et al, 2007). On the other hand, in men with locally advanced prostate cancer treated with radiation therapy and ADT there was not an increase in cardiovascular mortality compared with men receiving radiation therapy alone ( Efstathiou et al, 2008).

52. 8. Gynecomastia Gynecomastia, an increase in breast tissue, and mastodynia , or breast tenderness, may occur together or independently. Estrogenic compounds, such as DES, induce gynecomastia in 40% of patients (Smith, 1996). Likewise, the peripheral conversion of testosterone to estradiol associated with the antiandrogens induces gynecomastia at high rates: 66.3% of men taking 150 mg bicalutamide developed gynecomastia and 72.7% developed mastodynia . Prophylactic radiation therapy (10 Gy ) has been used to prevent or reduce painful gynecomastia. Radiation has no benefit once gynecomastia has begun. Liposuction and subcutaneous mastectomy have been used to treat established gynecomastia ( Higano , 2003). The selective estrogen receptor modulator tamoxifen has been used to treat mastodynia ( Serels and Melmann , 1998).

53. 9. Anaemia The anemia associated with ADT is normochromic, normocytic, and very common: 90% of men receiving combined androgen blockade experienced declines in hemoglobin concentration of at least 10% (Strum et al, 1997). Declines in hemoglobin begin within 1 month of ADT initiation (Strum et al, 1997) and continue for 24 months (Choo et al, 2005). Compensatory mechanisms limit the symptomatic effects of anemia to a small subset (13%) of men (Strum et al, 1997). The etiology of anemia is thought to be secondary to lack of testosterone stimulation of erythroid precursors and a decrease in erythropoietin production. In an animal model, however, erythropoietin levels increased after ADT ( Voegeli et al, 2005). Whatever the etiology, clinically, patients respond to recombinant human erythropoietin. The anemia is reversible after stopping ADT but may take up to a year (Strum et al, 1997).

54. Poor man’s Alternatives Low dose DES - 1mg/day - it has never been conclusively demonstrated that DES at 1 mg/day is not as effective and as safe as LHRH analogs. In at least two studies, this dose of DES appeared equivalent to castration. When compared to 5 mg of DES, LHRH analogs have a more favorable cardiovascular safety profile with a reduced risk of deep vein thrombosis and congestive heart failure. LHRH analogs are associated with hot flashes and may lead to osteoporosis over several years. Potential benefits of estrogen include hot flashes and osteoporosis, as well as preservation of some libido. * Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr . 1988:165-170. *Robinson MR. EORTC protocol 30805: a phase III trial comparing orchidectomy versus orchidectomy and cyproterone acetate and low dose stilboestrol in the management of metastatic carcinoma of the prostate. Prog Clin Biol Res . 1988;260:101-110

55. 2. Ketoconazole - 400 mg thrice a day An orally active, broad-spectrum azole antifungal agent, ketoconazole interferes with two cytochrome P450–dependent pathways: by inhibiting 14-methylation the conversion lanosterol to cholesterol is blocked, and it also blocks 17,20-desmolase, impacting on the conversion of C21 to C19 steroids. The effects were rapid, with testosterone levels dropping to the castrate level within 4 hours of administration in some cases (Trachtenberg et al, 1983); the effects were also immediately reversible, indicating dosing must be continuous to maintain low testosterone levels (400 mg every 8 hours).

56. TYPICAL PATIENTS (After 80s) EARLY DETECTION The ultimate conclusion of numerous studies is that although androgen ablation provides significant palliative therapy for most patients, it is never curative. These results are consistent with the fact that prostate cancers are composed of a heterogeneous collection of androgen-dependent and -independent cells. Androgen-ablative therapy, no matter how completely or early it is given, does not eliminate the androgen-independent cell type.

57. The realization that androgen ablation is never curative has led to two alternative approaches to the treatment of prostate cancer. The first has been an attempt to develop better treatments for systemic disease. The second has been to successfully develop methods to aggressively screen (DRE, PSA) and to improve surgical techniques for cancers that are still confined to the prostate and so are potentially treatable by definitive local therapy with minimal complications. So, as we have entered the twenty-first century, the characteristics of the typical prostate cancer patients have changed dramatically. At present, most patients are diagnosed in their sixties with localized — not metastatic disease.

58. INDICATIONS OF ADT CRPC Early (T1,T2) - Adjunct to RRP and Radiation Metastatic disease – Early vs Late Continuous vs Intermittent Single agent vs MAB Locally advanced - Early vs Late Continuous vs Intermittent Single agent vs MAB

59. Combined Androgen Blockade The concept of adding an antiandrogen to surgical castration or LH-RH agonists is based on the idea that, after the elimination of testicular androgens through surgical or medical castration, adrenal androgens still contribute to prostate cancer progression In concept, the approach is sensible and some clinical trials showed prolonged survival in patients treated with combined androgen blockade with advanced prostate cancer compared with standard ADT (Crawford et al, 1989; Dijkman et al, 1997; Denis et al, 1998). Buton extensive scrutiny in a meta-analysis of 27 prospective, randomized, international clinical trials of the combination of an antiandrogen with either castration or an LH-RH agonist the collective result was clinically insignificant (Prostate Cancer Trialists ’ Collaborative Group, 2000).

60. Timing of ADT “ADT can’t hurt, so why not use it early.” First, the natural history of prostate cancer progression, even in the hormonally intact individual, is protracted Second, despite dramatic clinical responses, men undergoing ADT will either die of a non–prostate cancer cause (estimated at 20% based on the combined androgen blockade meta-analysis) or will eventually demonstrate evidence of castration-resistant disease and die of prostate cancer. Third, ADT is not an innocuous therapy: beyond the quality of life side effects discussed earlier, in a global sense men on ADT age more rapidly; the natural extension of more rapid aging is earlier death

61. The questions about the timing of ADT are not new. In 1973 the results of a large (more than 1900 men) study performed by the then Veterans Administration of early versus late hormonal therapy were reported ( Byar , 1973). In men with metastatic disease, death from prostate cancer occurred in 48% of men treated early versus 47% of men treated late. In men with locally advanced disease, death from prostate cancer occurred in 14% of men treated early versus 17% of patients treated late. The lack of a survival benefit in men treated early coupled with the known side effects of therapy support the recommendations that hormonal therapy should be instituted in men with symptomatic disease.

62. Intermittent Androgen-Deprivation Therapy The rationale for intermittent ADT is based on two complementary ideas. First, in preclinical animal models (Shionogi breast cancer tumor, LNCaP prostate cancer tumor) exposure to androgen deprivation on a intermittent, rather than continuous, basis lengthened the time to the emergence of androgen- refractory cancer growth ( Akakura et al, 1993; Sato et al, 1996). Because androgen-refractory prostate cancer is synonymous with lethal prostate cancer, any manipulation of the hormonal milieu that can delay progression into this state would be welcomed. Second, many patients (and their physicians) have increasingly questioned the real benefit of continuous ADT, given the profound and often debilitating side effects associated with its use. With readily reversible ADT, recovery of normal testosterone levels should occur when androgen ablation is stopped. In theory, the quality of life side effects of ADT on intermittent treatment should be some fraction of those side effects when ADT is used continuously.

63. Intermittent hormonal therapy consists of an initial active androgen suppression period, usually between 6 and 9 months, followed by a corresponding length of time where no active therapy is undertaken. Patients are then followed at regular intervals off therapy, and when laboratory values meet threshold criteria for reactivation of disease, active androgen suppression is reinitiated until maximal effect is again observed. Each period of active treatment followed by treatment cessation is referred to as one cycle of treatment. Ordinarily, patients who respond to an initial cycle will be observed to respond by objective criteria to a second initiation of androgen suppression

64. Most of the reported phase II clinical trials have utilized approximately 8 months of androgen blockade followed by a period of no treatment when serial PSA is followed. Treatment is usually restarted after the PSA crosses a threshold of approximately 10 ng/ mL. There are some anecdotal observations in the reported trials that the inability of a patient to reach normal levels of PSA with initiation of therapy could be considered a poor prognostic indicator.

65. SWOG 9346, a multicenter randomized trial Intermittent versus Continuous Androgen Deprivation in Prostate Cancer N Engl J Med 2013; 368:1314-1325 Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority , suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life.

66. CONSENSUS STATEMENTS IAD is based on intermittent castration. Therefore, only drugs leading to castration are suitable. LHRH antagonist might be a valid alternative to an agonist. The induction cycle cannot be longer than 9 months, otherwise testosterone recovery is unlikely. ADT should be stopped only if patients have fulfilled all of the following criteria: -  well-informed and compliant patient; -  no clinical progression; -  clear PSA response, empirically defined as a PSA < 4 ng/mL in metastatic disease. Strict follow-up is mandatory, with clinical examination every 3-6 months. The more advanced the disease, the closer the follow-up should be. The same laboratory should be used to measure PSA. Treatment is resumed when the patient progresses clinically, or has a PSA rising above a predetermined (empirically set) threshold: usually 10-20 ng/mL in metastatic patients. The same treatment is used for at least 3-6 months. Subsequent cycles of treatment are based on the same principles until the first sign of castration resistance become apparent. The group of patients who will benefit most from IAD still has to be defined but the most important factor seems to be the patient’s response to the first cycle of IAD, e.g. the PSA level response. IAD might be an option in patients with metastatic disease after a standardised induction period.

67. CRPC Almost without exception those no longer responding to ADT (androgen-refractory) remain on ADT. In 87% of patients with androgen-refractory prostate cancer, the administration of exogenous androgen results in symptomatic tumor flare (Fowler and Whitmore, 1982). Therefore the term androgen independent is not completely precise: such a cancer is no longer dependent on androgen (and thus may be considered independent), but since it remains responsive to androgen it is not wholly independent of the influence of androgen

68. EARLY DISEASE

69. Immediate versus Delayed ADT in Clinically Localized Disease Eur Urol. 2009 Oct;56(4):609-16. The role of primary androgen deprivation therapy in localized prostate cancer. Wong YN1, Freedland SJ, Egleston B, Vapiwala N, Uzzo R, Armstrong This large, population-based study suggests that ADT did not improve survival in men with localized prostate cancer, but it suggests that ADT may instead result in worse outcomes compared with observation. Patients and physicians should be cognizant of the potential long-term side effects of ADT in a patient population for which expectant observation is an acceptable treatment strategy.

70. JAMA. 2008 Jul 9;300(2):173-81. Survival following primary androgen deprivation therapy among men with localized prostate cancer. Lu-Yao GL1, Albertsen PC, Moore DF, Shih W, Lin Y, DiPaola RS, Yao SL. CONCLUSION: Primary androgen deprivation therapy is not associated with improved survival among the majority of elderly men with localized prostate cancer when compared with conservative management

71. Graff JN, Mori M, Li H, Garzotto M, Penson D, Potosky AL, Beer TM Title: Predictors of overall and cancer-free survival of patients with localized prostate cancer treated with primary androgen suppression therapy: results from the prostate cancer outcomes study. Journal: J Urol 177(4):1307-12 Date: 2007 Apr In a community-based cohort study (Prostate Cancer Outcomes Study), men with localized prostate cancer treated with primary ADT within 1 year of diagnosis had a 91% cancer-specific survival but only a 66% overall survival at 5 years (Graff et al, 2007).

72. In the bicalutamide Early Prostate Cancer (EPC) program, men were randomized to bicalutamide 150 mg or placebo in addition to standard for care (See et al, 2003). End points of these trials include overall survival, progression-free survival, and tolerability. In the subset of men with clinically localized disease the overall survival was significantly worse in those undergoing ADT with 150 mg bicalutamide compared with placebo ( Iversen , 2004). Among the 2285 patients under watchful waiting, 71% had cT1–cT2 disease, whereas the remaining patients had locally advanced disease. In both cases, at a median follow-up of 7.4 yr , overall survival (OS) was not improved in men receiving bicalutamide compared with placebo

73. Men with localized, low-risk prostate cancer should not be treated with ADT without first being informed of the risks. Avoidance of prostate cancer progression and death may come at the expense of a higher overall death rate. These data support the hypothesis that the more rapid aging associated with ADT will bring men with low-risk prostate cancer more quickly to their deaths.

74. Combination: ADT + Radical Prostatectomy In nonrandomized clinical trials of ADT before radical prostatectomy the effects on the surgical specimen were dramatic. Positive surgical margin rates fell from nearly 50% in hormonal intact patients to 15% in ADT patients (Lee et al, 1997). Glands with no evidence of malignancy (P0) were not uncommon. Randomized prospective studies of 3 months of ADT following by radical retropubic prostatectomy were compared with radical retropubic prostatectomy alone ( Witjes et al, 1997; Soloway et al, 2002; Klotz et al, 2003). In both short (15 month mean follow-up) and longer (4 to 7 years) follow-up there was no significant difference in PSA progression between the groups. The lack of improved biochemical recurrence in these three, randomized, prospective trials using 3 months of neoadjuvant ADT before RRP argues strongly that this combination is not indicated in the treatment of prostate cancer.

75. Combination: ADT + Radiation Therapy Unlike the lack of long-term improved cancer-specific progression with the combination of ADT and radical prostatectomy, there have been several phase 3 clinical trials that have shown a benefit with the combination of ADT and external-beam radiation therapy in overall survival, cancer-specific survival, or freedom from disease progression. The benefit appears to be in men with locally advanced disease and/or those with high-grade, high-risk disease.

76. For RT plus ADT compared with RT alone In patients with low-risk PCa (cT1–cT2a, Gleason score 2–6, PSA <10 ng/ml), the combination of RT and ADT is comparable to RT alone (LE 1b) and thus should be discouraged. Patients with intermediate-risk disease (cT2b, Gleason score 7, PSA 10.1–20.0 ng/ml) may benefit from combined hormonal treatment for 4–6 mo (LE 1b). Patients with high-risk (cT2c or Gleason score 8–10, or PSA >20 ng/ml) and locally advanced disease are likely to benefit from combined hormonal treatment for 24–36 mo (LE 1a). The role of ADT in patients undergoing high-dose RT (>76 Gy ) and the most appropriate extent of the radiation field require further study.

77. Management of local/loco-regional disease Watchful waiting with delayed hormone therapy is an option for men with low-risk disease. Watchful waiting with delayed hormone therapy is an option for men with localised or locally advanced disease who are not suitable for, or unwilling to have, radical treatment [I, A]. Active surveillance is an option for men with low-risk disease [II, A]. Radical prostatectomy or radiotherapy (external beam or brachytherapy) are options for men with low- or intermediate-risk disease [I, B]. Options for patients with high-risk or locally advanced prostate cancer include external beam RT plus hormone treatment [I, B] or radical prostatectomy plus pelvic lymphadenectomy [III, B]. Primary ADT alone is not recommended as standard initial treatment of non-metastatic disease [III, B].

78. Neoadjuvant and adjuvant hormone treatment Neoadjuvant and concurrent ADT for 4–6 months are recommended for men receiving radical RT for high-risk disease, and should be considered for men with intermediate-risk disease [I, A]. Adjuvant ADT, for 2–3 years, is recommended for men receiving neoadjuvant hormonal therapy and radical RT, who are at high risk of prostate cancer mortality [I, A].

79. Post-operative radiotherapy / ADT Immediate post-operative radiotherapy after RP is not routinely recommended. Patients with positive surgical margins or extra-capsular extension after RP, with undetectable serum PSA, should be informed about the pros and cons of adjuvant RT [I, A]. Patients with evidence of multiple lymph node metastases after surgery may benefit from early androgen deprivation (LE 1b); however, the best schedule and approach (continuous or intermittent ADT) remain undefined. The role of antiandrogen monotherapy is unknown in this case, and routine use is not indicated.

80. Treatment of relapse after radical therapy Following RP, patients should have their serum PSA level monitored. Salvage RT to the prostate bed is recommended in the event of PSA failure. Salvage RT should start early (e.g. PSA <0.5 ng/ml) [III, B]. Biopsy of the prostate after RT should only be carried out in men with prostate cancer who are being considered for salvage local therapy Early ADT is not routinely recommended for men with biochemical relapse unless they have symptomatic local disease, or proven metastases, or a PSA doubling time <3 months [IV, B]. Intermittent ADT is recommended for men with biochemical relapse after radical RT starting ADT [I, B].

81. Management of advanced/metastatic disease Continuous ADT is recommended as first-line treatment of metastatic, hormone-naïve disease [I, A]. • Men starting ADT should be informed that regular exercise reduces fatigue and improves quality of life [30] [I, A]. • ADT plus docetaxel is recommended as first-line treatment of metastatic, hormone-naïve disease in men fit enough for chemotherapy [1, A]. Patients with evidence of neuro-endocrine change in their prostate cancer should receive chemotherapy in addition to ADT

82. METASTATIC AND LOCALLY ADVANCED DISAESE

83. Lymph Node Metastatic Prostate Cancer at Radical Prostatectomy A randomized prospective study of immediate ADT compared with delayed ADT was performed in men with histologic evidence of metastatic prostate cancer in regional lymph nodes after radical prostatectomy by the Eastern Cooperative Oncology Group (ECOG). At the time of the initial report, at 7.1 years of median follow-up, overall survival significantly ( P < .02) favored the immediate ADT group compared with the delayed ADT group: in the immediate ADT group, only 3 of the 7 deaths were due to prostate cancer compared with 16 of the 18 cancer specific deaths in the delayed ADT group (Messing et al, 1999). In an updated report, median overall survival was significantly longer in the immediate ADT compared with the delayed ADT group, 13.9 versus 11.3 years, respectively (Messing et al, 2003, 2004). Eight of 18 men in the immediate ADT group died of prostate cancer compared with 25 of 28 in the delayed ADT group. Nevertheless, based on this randomized, prospective trial, there appears to be a benefit to immediate ADT in those with histologic evidence of lymph node metastases at the time of radical prostatectomy.

84. In node-positive disease with radical prostatectomy there is a significant survival advantage favoring immediate ADT, with a 2.6-year difference in median overall survival.

85. Locally advanced disease- RT vs RT+ADT Bolla etal RTOG Protocol Granfors et al

86. Lymph node-positive disease without primary treatment A European Organization for the Research and Treatment of Cancer (EORTC) trial of immediate versus delayed ADT in pN1-3M0 patients without local treatment of the primary tumor was performed in 302 patients, of which 115 were randomized to delayed ADT and 119 to immediate ADT ( Schröder et al, 2004). At a median follow-up of 13 years, the median overall survival on immediate ADT was 7.6 years (95% CI, 6.3 to 8.3 years) versus 6.1 years (95% CI, 5.7 to 7.3 years) in the delayed ADT group. The 10-year cumulative incidence of death from prostate cancer was 55.6% in the delayed ADT group versus 52.1% in the immediate ADT group ( Schröder et al, 2009). Based on these data, 20.8 patients would need to be treated with immediate ADT to spare one life at 5 years and 28.6 would need to be treated to spare one life at 10 years.

87. In node-positive disease without primary treatment there is no significant advantage to immediate ADT, although on balance there is a 1.5-year median survival advantage.

88. Immediate vs Delayed ADT in Locally Advanced, Asymptomatic Metastatic Disease or Disease Not Suitable to Local Treatment A trial of immediate versus delayed ADT in men with locally advanced or asymptomatic metastatic prostate cancer was conducted by the Medical Research Council (MRC) Prostate Cancer Working Group Investigators Group (1997). A total of 934 men were included (500 M0, 261 M1, and 173 Mx ), with 469 randomized to immediate ADT and 465 randomized to delayed ADT. As originally reported there was a significant survival advantage in the M0 group; on longer follow-up the overall survival advantage is not significant (Kirk, 2004). Overall, men in the delayed ADT arm died significantly more often from prostate cancer and had significantly more symptoms related to disease progression. Based on these data the benefits of immediate ADT would seem to support its use.

89. Cochrane Database Syst Rev. 2002;(1):CD003506. Early versus deferred androgen suppression in the treatment of advanced prostatic cancer.- Nair B1, Wilt T, MacDonald R, Rutks I. ”Early androgen suppression may provide a small but statistically significant improvement in overall survival at 10 years.”

90. In locally advanced, asymptomatic metastatic and clinically present but undefined prostate cancer treated in a community setting with limited disease monitoring, immediate ADT results in significantly better prostate cancer–specific survival but not better overall survival.

91. Timing of androgen-deprivation therapy- TROG STUDY Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised , multicentre , non-blinded, phase 3 trial Prof Gillian M Duchesne, MD Published: 04 May 2016, Lancet Background - Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy. Interpretation - Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options

92. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer ProtecT Study Group* N Engl J Med 2016; 375:1415-1424 October 13, 2016 CONCLUSIONS At a median of 10 years, prostate-cancer–specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring.

93. Prognostic factors 80% drop in PSA within 1 month Nadir PSA level Pre treatment Testosterone level

94. A rise in PSA level, which is evidence of the emergence of castration- resistant disease, preceded bone metastatic progression by several months, with a mean lead time of 7.3 months (Cooper et al, 1990; Miller et al, 1992). The odds ratio for progressing to castration-resistant progression within 24 months of starting ADT was almost 15 times higher for patients who did not achieve an undetectable PSA level (Benaim et al, 2002a) For each unit increase in Gleason score, the cumulative hazard of castration-resistant progression was nearly 70%

95. Consistently predictive variables (by both univariate and multivariate analysis) of survival in this state include performance status; serum lactate dehydrogenase (LDH), serum alkaline phosphatase, and hemoglobin levels; and PSA response to secondary therapy A 50% decline in PSA value in response to chemotherapy was one of the most significant variables predicting survival. A nomogram, based on a larger groups of patients, the presence of visceral disease, Gleason score, performance status, baseline PSA value, LDH and alkaline phosphatase levels, and hemoglobin level were useful in modeling prognosis ( Smalez et al, 2002; Halabi et al, 2003).

96. ECONOMIC CONSIDERATIONS In a study of 96 men undergoing ADT for prostate cancer over a 10-year period the cost of LH-RH agonists ranged from greater than 10.7 to 3.2 times the cost of bilateral orchiectomy and the cost of combined androgen blockade was 17.3 to 20.9 times greater ( Mariani et al, 2001). Clearly the cost of ADT, as currently being delivered, is extraordinary. In two studies that offered orchiectomy versus medical therapy for ADT, 70% of patients chose medical therapy ( Iversen et al, 1998). Avoiding the largely psychologic quality of life issues unique to orchiectomy (disfigurement, permanence) comes at an expense that would seem disproportionate to the risk, and yet society has chosen to accept this expense.

97. Interesting snippets The published statistics on prostate cancer show that single men are diagnosed much less frequently than married men. On the other hand, married men diagnosed with prostate cancer live longer than single men with the disease. The conclusion that can be drawn from this is that men should stay single, but should get married if diagnosed with prostate cancer.

98. Prostate cancer in Dogs Prostate cancer has been reported to occur more commonly in neutered than intact male dogs in several case series. Neutered males had a significantly increased risk for each form of cancer. Neutered males had an odds ratio of 3.56 (3.02-4.21) for urinary bladder TCC, 8.00 (5.60-11.42) for prostate TCC, 2.12 (1.80-2.49) for prostate adenocarcinoma, 3.86 (3.13-4.16) for prostate carcinoma, and 2.84 (2.57-3.14) for all prostate cancers. Relative risks were highly similar when cases were limited to those with a histologically confirmed diagnosis. * Prostate. 2007 Aug 1;67(11):1174-81. A population study of neutering status as a risk factor for canine prostate cancer. Bryan JN1, Keeler MR, Henry CJ, Bryan ME, Hahn AW, Caldwell CW.

99. Bipolar Androgen therapy (BAT) Prostate . 2016 Sep;76(13):1218-26. doi : 10.1002/pros.23209. Epub 2016 Jun Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer : Results From the Phase II BATMAN Study . Schweizer MT1, Wang H2, Luber B2, Nadal R2, Spitz A2, Rosen DM2, Cao H2, Antonarakis ES2, Eisenberger MA2, Carducci MA2, Paller C2, Denmeade SR2 Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT. BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections. Conclusions- BAT demonstrated preliminary efficacy in men with HS PC following 6-month of ADT. BAT may improve QoL in men treated with ADT.