Paul Zito, MD LSU Hematology Oncology Fellow, PGY4 9/14/18 Prostate Cancer Paul Zito, MD LSU Hematology Oncology Fellow, PGY4 9/14/18

Most common in incidence, third most common in death for men.

Incidence. Death Rates Overall, the prostate cancer death rate has been decreasing by about 2-3% per year since 1990s.

Overall → SEER Statistics

8:1 ratio of incidence to mortality. A disease of aging. 8:1 ratio of incidence to mortality. Majority of die of unrelated causes.

Risk Factors Age. Nearly 70% of men > 80 yo have occult prostate cancer. Race/ethnicity: Blacks > White > Hispanic > Asian Family History (5-10% cases). If age < 55 at diagnosis or multiple relatives, risk is higher. More than 30 single nucleotide polymorphisms (SNPs) identified. BRCA (especially BRCA 2) and Lynch syndrome increase risk. One or more relatives with breast, ovarian, pancreatic - Suggests BRCA Colorectal, endometrial gastric, ovarian, pancreatic, small bowel, urothelial, kidney, bile duct suggests Lynch Bratt et al. JNCI 2016. ASCO SEP Fifth Edition

Peripheral zone is palpable by digital rectal examination (DRE).

Prostate Cancer Characteristic Metastatic Involvement Bone dominant sclerotic metastases Skeletal related events: bone pain, spinal cord compression, pathological fractures, need for surgery or radiation. Hypercalcemia is NOT generally associated with it. Nodal disease Possible obstruction (GI, GU). Visceral: lung, liver Brain Leptomeningeal (base of skull) more common. Intra-parenchymal is rare.

Stage/Prognosis defined by TNM, PSA, Gleason T1c is most common since PSA was approved.

Adding the first and second most common patterns seen in a prostate biopsy gives the Gleason score (e.g. Gleason 3+3 = 6, or Gleason 4+3 = 7).

Gleason Scores vs. Groups D’Amico et al. JAMA 1998. Epstein et al. Eur Urol 2016. Groups (vs. scores) may help to better risk assess and guide prognosis and treatment discussions. NCCN guidelines for treatment looks at Risk Groups which factors in Tumor, Gleason Score, Grade Group and PSA - Very Low risk to Very high then Regional and Metastatic.

Initial Prostate Ca Dx

Risk Stratification

Low Risk Group Treatment

High Risk Group Treatment

Androgen Deprivation Therapy Chemical Castration Surgical castration equally effective as ADT, less preferred by patients “Anti-androgens”

Need baseline dexa scan Need baseline dexa scan. Cardiovascular morbidity (metabolic syndrome, diabetes, HLD, atherosclerosis).

In practice, TNM is more relevant for urologists, used for staging of localized disease. “Disease States” are more useful after relapse of localized disease or for metastatic disease when considering treatment. 2016 MD Anderson Board Review

Regional Risk Group

MD Anderson Board Review 2016

Newly Diagnosed Localized Disease Managed by urologists; truly another lecture. Treatment based on risk stratification based on TNM, Gleason, PSA. Treatment depends on risk assessment and patient factors; options include: Active surveillance: involves serial biopsies. For low risk patients with low likelihood to succumb to disease, but who can benefit from curative treatment if they progress. Observation: For low risk patients and/or those with short life expectancy; if progression would consider palliative ADT. Radical Prostatectomy + Pelvic LND. If LN +, then ADT +/- EBRT, or observation. Radiation (EBRT +/- brachytherapy) +/- ADT. Advantage of surveillance/observation is avoiding QOL- altering side effects of a therapy that the patient may not have even needed. Gleason 6 (or less), PSA <10, monitor

Initial Management After Therapy

Newly Diagnosed Localized Disease Radical prostatectomy/PLND with positive LNs → benefit from immediate (vs. delayed) ADT + Abiraterone + Steroid. Category 1 NCCN recommendation. Based on significant improvement in OS (HR 1.84; p = 0.04), PFS (HR 3.42; p < .0001).1 Radiation treatment, intermediate risk disease: addition of concurrent ADT for 4-6 months (6 months if PSA velocity > 2 ng/mL/yr) is beneficial based on multiple studies.2 Radiation treatment, high risk disease: benefit from concurrent/adjuvant ADT for at least 2 years. Category 1 NCCN recommendation. Based on significant improvement in OS when compared with only 2 months of ADT (81.0% v 70.7%, P =.044).3 Addition of anti-androgen to ADT in this setting requires further study. Messing et al. Lancet Oncol. 2006. ASCO-SEP, fifth edition. Hanks et al. JCO 2003.

Non-metastatic, biochemical relapse Refers to PSA persistence or recurrence by 2ng/mL above nadir. Treatment vs. observation depends on PSA velocity and PSA-DT (doubling time > 10 mos, consider observation). If progression is s/p prostatectomy → EBRT +/- ADT vs. observation. Data is not as great and mostly retrospective. If progression is s/p EBRT +/- ADT → intermittent ADT vs. observation Assuming not a candidate for local therapies like cryosurgery, brachytherapy. Intermittent ADT found to be non-inferior and better tolerated than continuous.1 Crook et al. NEJM 2012.

ADT for PSA without Metastasis Influenced by PSA velocity Good 15 yr prognosis which is approximated by absolute PSA, PSA-DT, Initial Stage, Grade and PSA at time of definitive therapy Earlier ADT may be better than delayed ADT but treatment should be individualized Some patients candidates for salvage after PSA recurrence, eg. Radiation after failed RT, or RP or Cryosurgery after failed radiation. Consider intermittent ADT. A Phase 3 trial that compared intermittent to continuous ADT showed intermittent was not inferior with respect to survival and QOL better in intermittent arm. Prostate Ca deaths offset by Non-prostate deaths. Gleason 8-10 had higher median overall survival in continuous arm, 14 months longer.

Metastatic, hormone-naïve Addition of anti-androgen in this setting is to prevent LHRH-flare with overt metastases (at least 7 day overlap). Otherwise, combined therapy provides modest to no benefit over castration alone in this setting. NCCN Guidelines

ADT for Metastatic Disease ADT Gold Standard Intermittent to Continuous no difference in survival Close monitoring of PSA and imaging during intermittent, may need to switch to continuous LHRH agonist or antagonist and bilateral orchiectomy are equally effective Androgen receptor activation and autocrine/paracrine androgen synthesis are potential mechanisms of recurrence of Prostate Ca during ADT. In patients with minimal symptoms consider administration of secondary hormone therapy including addition of or switching to different antiandrogen.

CHAARTED Trial 2015 High volume disease: visceral metastases and/or four or more bone metastases. No prednisone was used.

STAMPEDE Trial 2016 Failure-Free and Overall Survival curves. ADT (standard of care, SOC) alone or with docetaxel Time from randomisation (months) Time from randomisation (months) Addition of 6 cycles of docetaxel increased median OS from 67 to 77 months (HR 0.76; p= 0.003). (No survival benefit with addition of zolendronic acid). Did not stratify high vs. low volume, but confirmed role of docetaxel. England follows this study (gives to all patients regardless of volume of disease). Problem: could earlier use of docetaxel decrease efficacy of rechallenge in CRPC? Maybe.* *Lavaud et al. ASCO 2016, #5080

Castration Resistant Prostate Cancer (CRPC) Serial rising PSAs (non-metastatic) or progressive disease on scans (metastatic), despite castrate levels of testosterone (< 20-50 ng/mL). Mechanisms include: Androgen receptor overexpression/amplification or mutations (splice variants). Ligand-independent activation (e.g. de-novo synthesis of intra- tumoral androgens). Alternative ligands (e.g. adrenal androgens). Thus, castrate levels of testosterone should be maintained with continued ADT or orchiectomy. ASCO SEP, Fifth edition.

Non-Metastatic CRPC Continue ADT maintain Testosterone < 50ng/dl. Consider observation if PSA-DT > 10 months. No phase 3 trials, no “standard of care” If PSA-DT < 10 months Addition of antiandrogen (e.g. Apalutamide, Enzalutamide). Trial of antiandrogen withdrawal (based on observation that overtime these agents can contribute to prostate cancer progression). Responses are often short-lived (median 2-4 months) before further progression. ASCO-SEP, Fifth Edition NCCN Guidelines

M0 Castrate Resistant

Metastatic CRPC MD Anderson Board Review 2016

Systemic Therapy for M1

MSI and Pembrolizumab in Solid Tumors The approval was based on data from 149 patients with MSI-H or dMMR cancers enrolled across 5 single-arm clinical trials. Ninety patients had colorectal cancer (CRC) and the remaining 59 patients had 1 of 14 other tumor types. The objective response rate (ORR) with pembrolizumab was 39.6% (95% CI, 31.7-47.9), including 11 (7.4%) complete responses (CRs) and 48 (32.2%) partial responses (PRs). The ORR was 36% in patients with CRC and 46% in patients with other tumor types. The median duration of response was not yet reached (range, 1.6+ months to 22.7+ months). Among patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 months.

Subsequent Therapy M1 no Visceral Mets

Subsequent Therapy for M1 with Visceral Mets

Metastatic CRPC Immunotherapy with Sipuleucel-T (2010) Autologous cellular vaccine. Antigen is prostate acid phosphatase (PAP) bound to granulocyte-macrophage CSF as an immune response enhancer. Once every 2 weeks for 3 infusions. Median survival 25.8 vs. 21.7 mos with placebo (HR 0.78; p = 0.03). For use only with asymptomatic and early metastatic CRPC without visceral involvement. Despite OS advantage, no impact on PSA or radiographic response, so use early until patient is ultimately in need of another agent. Kantoff et al. NEJM 2010.

Metastatic CRPC Abiraterone – Approved 2011 Abiraterone and ketoconazole are CYP17 inhibitors → inhibit androgen synthesis in testicular, adrenal, and prostate tissue. Needs glucocorticoid (prednisone) replacement. Abiraterone 10x more potent than ketoconazole. May cause hyper- aldosteronism (HTN, fluid retention, hypokalemia).

Metastatic CRPC Abiraterone Pre-Docetaxel: rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; Abiraterone improved OS - median: 35.3 vs 30.1 mo; but did not reach the prespecified statistical efficacy boundary Rathkopf et al. Eur Urol 2014. Post-Docetaxel: 14.8 months vs. 10.9 months - OSMedian OS 14.8 mos with abiraterone vs. 1.9 mos with placebo (HR 0.65; p < 0.001).De Bono et al. NEJM 2011.

Metastatic CRPC Enzalutamide – Approved 2012 Highly potent androgen receptor antagonist, without stimulating the receptor like first-generation antiandrogens may.

Metastatic CRPC Enzalutamide Post-Docetaxel Scher et al. NEJM 2012. Pre-Docetaxel Beer et al. NEJM 2014. OS was 18.4 months versus 13.6 months

So far, no information on how to sequence abiraterone vs So far, no information on how to sequence abiraterone vs. enzalutamide for mCRPC. At this point choice may be driven by side effects and the fact that enzalutamide was the only one tested on patients with liver metastases. Unclear if there is cross-resistance (and therefore benefit of switching from one to the other). Prospective studies are needed. MD Anderson Board Review 2016

Metastatic CRPC MD Anderson Board Review 2016

Metastatic CRPC Docetaxel - 2004 Standard of care first-line chemotherapy, after showing 18.9 mos median OS versus 16.5 mos with mitoxantrone, with HR for death 0.76; p = 0.009.1 Often deferred until symptomatic or rapidly progressing. No current evidence on its efficacy after rechallenge (if formerly used for hormone-naïve disease). 1. Tannock et al. NEJM 2004.

Metastatic CRPC MD Anderson Board Review 2016

Metastatic CRPC Radium 223 – Approved 2013 Alpha particle-emitting calcium mimetic. Naturally targets growth factor-producing osteoblasts that otherwise support prostate cancer. Improved median OS: 14.9 vs. 11.3 mos compared to placebo (HR 0.70; p < 0.001). Indication: mCRPC- symptomatic bone metastases, no visceral mets (regardless of docetaxel status as patients had received, were not eligible, or declined docetaxel). Administration: 1 minute infusion Q4wk x 6 doses. Requires minimal radiation protection during handling/treatment. Safety: 2% myelosuppression, low grade diarrhea. No restrictions on contact with other people. Short diameter of penetration (compared to beta- emitters), so safer. Excretion: intestinal. PSA may not decrease and impact on bone scan unknown. Parker et al. NEJM 2013.

MD Anderson Board Review

Metastatic CRPC MD Anderson Board Review 2016

Costs Sipuleucel-T treatment consists of three infusions at approximately two-week intervals for one month. The cost for a complete course of treatment of three infusions is $93,000, which includes the cost of administration. For the extended survival period of 4.1 months with sipuleucel-T, the average monthly expenditure is $22,683 per month of added median survival. Docetaxel, the drug of choice for metastatic, hormone-refractory prostate cancer, is administered every three weeks for a total of 10 cycles. The cost of one cycle of docetaxel approaches $4,000, or a total of $14,000-> 40,000 for all 10 cycles.19(Depending on source) The median extended survival period for prostate cancer patients receiving docetaxel is 2.4 months, or an average cost of $16,667 per month of added survival. Radium- 223 - 6 cycles of treatment cost $69,000. - 3.6 months OS advantage around $20,000 per month Enzalutamide costs approximately $60,000 for 8 months of treatment; OS = around 5 months benefit or $12,000 per month

Metastatic CRPC Cabazitaxel – Approved 2010 Semi-synthetic taxoid derivative. Indication: mCRPC previously treated with docetaxel. Consider G-CSF. De Bono et al. Lancet 2010.

Bone Metastases and Skeletal Related Events Significant improvement in skeletal related events with denosumab over zolendronic acid. No effect on survival. Per MD Anderson Review, “not dramatically better”, and use of either is acceptable. May choose based on side effect profile. Both require dental clearance and Vit D/Ca supplement. Fizazi et al. Lancet 2011

MD Anderson Board Review 2016

Asian J Urol. 2017 Jan; 4(1): 37–43 Cost-effectiveness analysis of treatments for metastatic castration resistant prostate cancer Matthew E. Pollard,a Alan J. Moskowitz,b Michael A. Diefenbach,c and Simon J. Hallc,∗