Metastatic prostate carcinoma. Lee Say Bob July 2017

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Cornelia Cecilia Wilkins
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1 Metastatic prostate carcinoma Lee Say Bob July 2017

2 Scenario A 58 year old gentleman presents with PSA 200 ng/ml with hard prostate and bone mets. LUTS but upper tracts are normal with normal RP. history of CVD with a cardiac stent inserted 2 years ago and is on Aspirin. Discuss management options: Antiandrogen vs LHRH analog vs LHRH antagonist

3 Hormonal therapy Androgen deprivation (ADT) can be achieved by suppressing the secretion of testicular androgens Medical castration Surgical castration inhibiting the action of circulating androgens at the level of their receptor. Complete androgen blockade (CAB)

4 LHRH agonists Long-acting LHRH agonists are currently the main forms of ADT. Delivered as depot injections on a 1-, 2-, 3-, 6-monthly, or yearly basis. After the first injection induce a transient rise in LH and FSH leading to the testosterone surge or flare-up phenomenon, which starts 2 to 3 days after administration and lasts for 1w.

5 LHRH agonists MOA: Stimulation of LHRH receptors in the pituitary produces an initial increase in LH and FSH, which causes an initial increase in testosterone. Further LHRH agonism suppresses LH and FSH secretion, resulting in a decrease in testosterone. Eg: Leuprolide (Lupron, Eligard) Histrelin (Vantas) Goserelin (Zoladex) Triptorelin (Trelstar) A castration level - within 2 to 4 weeks.

6 Flare-up phenomenon The flare-up phenomenon might lead to detrimental clinical effects (the clinical flare) such as increased bone pain acute BOO obstructive renal failure spinal cord compression cardiovascular death due to hypercoagulation status. Pts at risk are usually those with high-volume symptomatic bony disease

7 Prevention of flare-up Concomitant therapy with an anti-androgen decreases the incidence of clinical flare, but does not completely remove the risk. Prevention of flare-up is important in symptomatic patients or when a clinical flare might lead to severe complications. Anti-androgen therapy is usually continued for 4 weeks.

8 LHRH antagonists Bind to LHRH receptors, leading to a rapid decrease in LH, FSH and testosterone levels without any flare. The practical shortcoming of these compounds is the lack of a long-acting depot formulation with only monthly formulations being available.

9 LHRH antagonists Degarelix is an LHRH antagonist 240 mg in the first month Followed by monthly injections of 80 mg Castrate level at day 3. Its definitive superiority over the LHRH analogues remains to be proven. AST, ALT and GGT increased in 10% of pts. Injection site irritation (40%) vs LHRH agonists (3%).

10 Morbidity from Medical or Surgical Castration S/e from castration increases with the duration of tx Changes in body habitus (gynecomastia, testicular atrophy, loss of muscle mass, weight gain, increased subcut fat) Adverse lipid profile Diabetes (insulin resistance) CVD Anaemia (normocytic) Fatigue Osteoporosis Periodontal disease Sexual dysfunction Infertility Hot flashes Cognitive deficits

11 Anti-androgens Classified accd to their chemical structure as: steroidal cyproterone acetate (CPA) megestrol acetate medroxyprogesterone acetate non-steroidal/pure nilutamide flutamide bicalutamide

12 Anti-androgens MOA: Compete with androgens at the receptor level. This is the sole action of non-steroidal antiandrogens and leads to an unchanged or slightly elevated testosterone level. Steroidal antiandrogens have progestational properties leading to central inhibition by crossing the BBB.

13 Non-steroidal anti-androgens Non-steroidal anti-androgen monotherapy does not suppress testosterone secretion and it is claimed that libido, overall physical performance and bone mineral density (BMD) are frequently preserved. Non-androgen pharmacological s/e differ between agents, with bicalutamide showing a more favourable safety and tolerability profile than flutamide and nilutamide. Potential liver toxicity (occasionally fatal), requiring regular monitoring of pts liver enzymes.

14 CAB Monotherapy IAD vs Continuous ADT Immediate vs delayed ADT Hormonal tx combined with chemo

15 Combination therapies (CAB) The largest RCT in 1,286 M1b pts found no difference between surgical castration with or w/o flutamide. However, results with other anti-androgens or castration modalities have differed and SRs have shown that CAB using a non-steroidal anti-androgen (NSAA) appears to provide a small survival advantage (< 5%) vs. monotherapy (surgical castration or LHRH agonists) beyond 5 years of survival but this minimal advantage in a small subset of pts must be balanced against the increased s/e a/w long-term use of NSAAs.

16 Non-steroidal anti-androgen monotherapy Based on a Cochrane SR comparing NSAA monotherapy to castration (either medical or surgical), NSAA was considered to be less effective in terms of OS clinical progression treatment failure and treatment discontinuation due to adverse events. The evidence quality of the studies included in this review was rated as moderate.

17 Intermittent versus continuous androgen deprivation therapy 3 independent reviews and 2 meta-analyses, looked at the clinical efficacy of IAD therapy included 8 RCTs of which only 3 were conducted in pts with exclusively M1 disease. 5 remaining trials included different pt groups, mainly locally advanced and metastatic pts relapsing. SWOG 9346 is the largest trial conducted in M1b patients. Out of 3,040 selected pts, only 1,535 were randomised based on the inclusion criteria set. At best, only 50% of M1b pts might be candidates for IAD, i.e. the best PSA responders.

18 IAD None of the trials addressing M1 pts only showed a survival benefit, but there was a trend favouring continuous treatment for OS and PFS. Trend favouring IAD in terms of QoL, esp regarding tx-related s/e, such as hot flushes. In some cohorts the negative impact on sexual function was less pronounced Other possible long-term benefits of IAD include bone protection and a protective effect against metabolic syndrome.

19 IAD No benefit observed for the endocrine, psychiatric, sexual and neurological s/e based on a detailed analysis from the SWOG 9346 trial. Testosterone recovery was observed in most studies leading to intermittent castration. Must only be considered as an option in a well-informed patient bothered by significant s/e and willing to avoid them.

20 IAD The PSA threshold at which ADT must be stopped or resumed still needs to be defined in prospective studies. Consensus amongst authors on some 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.

22 Immediate versus deferred ADT In symptomatic pts, immediate tx is mandatory. Controversy exists for asymptomatic metastatic pts due to the lack of quality studies. A Cochrane review extracted 4 good-quality RCTs: VACURG I trial VACURG II trial MRC trial ECOG 7887 study All of these studies were conducted in the pre-psa era and included pts with advanced PCa, who had received early vs. deferred ADT, either as primary therapy or as adjuvant therapy after RP. No improvement in OS was observed in the M1a/b population, although early ADT significantly reduced disease progression and assc cx.

23 Hormonal treatment combined with chemotherapy 3 large RCT were conducted. GETUG 15 trial CHAARTED STAMPEDE All trials compared ADT alone as the standard of care with ADT combined with immediate docetaxel (75 mg/sqm, every 3w) (within 3 mths of ADT initiation). The primary objective in all three studies was OS. >> Upfront docetaxel combined with ADT should be considered as a new standard in men presenting with metastases at 1 st presentation, provided they are fit enough to receive the drug

24 EAU 2017

25 EAU 2017

26 Conclusion A 58 year old gentleman presents with PSA 200 ng/ml with hard prostate and bone mets. LUTS but upper tracts are normal with normal RP. history of CVD with a cardiac stent inserted 2 years ago and is on Aspirin. Options LHRH antagonist LHRH agonist + antiandrogen (4 weeks) Bilateral orchidectomy Chemotherapy

27 Summary There is no level 1 evidence for, or against, a specific type of ADT, whether orchiectomy, an LHRH analogue or antagonist, except in patients with impending spinal cord compression for whom either a bilateral orchidectomy, or an LHRH antagonist are the preferred options.

28 Thank You

29 Primary ADT has been the standard of care for over 50 years. There is no level 1 evidence for, or against, a specific type of ADT, whether orchiectomy, an LHRH analogue or antagonist, except in patients with impending spinal cord compression for whom either a bilateral orchidectomy, or an LHRH antagonist are the preferred options.

Initial Hormone Therapy

Initial Hormone Therapy Alan Horwich Institute of Cancer Research and Royal Marsden Hospital, London, UK Alan.Horwich@icr.ac.uk MANAGEMENT OF PROSTATE CANCER Treatment windows Subclinical Localised PSA