In this issue: > Radionuclide treatment for mCRPC

> Resource use in metastatic prostate cancer

> Time to testosterone rebound and comorbidity in prostate cancer

> Bone health in men receiving ADT

> Guideline: anticancer therapy in metastatic non-castrate prostate cancer

> QoL during treatment with chemo-hormonal therapy

> Blood glucose, glycaemic control and prostate cancer risk

> Costs of screening for prostate cancer

> Focal irreversible electroporation for localised prostate cancer

> Docetaxel vs surveillance after radical prostatectomy

ADT = androgen deprivation therapy; aHR = adjusted hazard ratio;BMD = bone mineral density; CI = confidence interval;CT = computed tomography; CVM = cardiovascular-specific mortality;GP = general practitioner; HIFU = high-intensity focused ultrasound;HR = hazard ratio; mCRPC = metastatic castration-resistant prostate cancer;MDM = multidisciplinary meeting; PCSM = prostate cancer-specific mortality;PET = positron emission tomography; PSA = prostate-specific antigen;PSMA = prostate-specific membrane antigen; QoL = quality of life;SEER = Surveillance, Epidemiology, and End Results-Medicare.

Abbreviations used in this issue:

Issue 19 - 2018Making Education Easy

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Welcome to issue 19 of Prostate Cancer Research Review. An Australian phase 2 trial has demonstrated the potential for effective radionuclide treatment in patients with metastatic castration-resistant prostate cancer, prompting further investigation in future trials. Following on the findings of a Surveillance, Epidemiology, and End Results-Medicare (SEER) database analysis reveal that increased resource use in men with metastatic prostate cancer does not result in improved survival or quality of care at the end of life. Other studies reviewed in this issue focus on the topics of time to testosterone rebound and comorbidity in prostate cancer, bone health in men receiving androgen-deprivation therapy (ADT), anticancer therapy in metastatic non-castrate prostate cancer, quality of life (QoL) during treatment with chemo-hormonal therapy, blood glucose, glycaemic control and prostate cancer risk, costs of screening for prostate cancer, focal irreversible electroporation for localised prostate cancer and docetaxel versus surveillance after radical prostatectomy.

I hope you find the research in this issue useful to you in your practice and I look forward to your comments and feedback.

Kind Regards,

Associate Professor Nathan Lawrentschuknathan.lawrentschuk@researchreview.com.au

[177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 studyAuthors: Hofman MS et al.

Summary: This single-arm, single-centre, phase 2 trial examined the use of [177Lu]-prostate-specific membrane antigen (PSMA)-617 (4 cycles, 6 week intervals; mean dose 7.5 GBq per cycle) in 30 men with metastatic castration-resistant prostate cancer who had progressed after treatment including docetaxel, cabazitaxel, abiraterone acetate and enzalutamide. Over a 3-month follow-up, 17 (57%) patients (95% CI 37-75) experienced a PSA decline of ≥50%; 14 (82%) of 17 patients with measurable disease had an objective response in nodal or visceral disease. Clinically meaningful reductions in pain severity and interference scores occurred at all time points and 37% of patients reported a ≥10-point improvement in global health score by the second treatment cycle. The most common treatment-related adverse events were grade 1 dry mouth (87%), grade 1 and 2 transient nausea (50%), and grade 1 and 2 fatigue in 50%. Grade 3 or 4 thrombocytopenia possibly attributable to [177Lu]-PSMA-617 occurred in four patients.

Comment: An excellent trial performed out of Melbourne, Australia no less. Not surprising given the uptake of PSMA PET-CT in our region and this type of radionuclide therapy (theranostics) is a natural extension. Theranostics get to the cancer with a specific agent or molecule (in this case PSMA), attach something to that molecule that kills at close range (in this case the radioactive agent lutetium). You can, of course, image prior to and after for efficacy measurement along with measuring PSA. Of course the risk with treatments such as this is the assumption it will be effective in all patients, nothing could be further from the truth. Indeed careful patient selection and imaging helped to achieve optimal results in this trial. All we can hope is that this treatment does lead to prolonged survival. More trials opening soon.

Reference: Lancet Oncol. 2018;19(6):825-33Abstract

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Independent commentary by Associate Professor Nathan Lawrentschuk.Nathan has appointments at the University of Melbourne, Department of Surgery as an Associate Professor and consultant uro-oncologist, the Department of Surgical Oncology at Peter MacCallum Cancer Centre and the Olivia Newton-John Cancer Research Institute, Austin Hospital as a senior clinical researcher. He has written over 300 peer-reviewed full journal article publications and 10 book chapters and reviews for over 30 scientific journals. Nathan is the BJUI USANZ supplement Editor and is on the editorial board of Nature Reviews Urology. He is also the Vice-Chairman of WUOF (World Urologic Oncology Foundation).

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Improving bone health in men with prostate cancer receiving androgen deprivation therapy: Results of a randomized phase 2 trialAuthors: Alibhai SMH et al.

Summary: This single centre, parallel-group, randomised controlled phase 2 trial compared education-based care models (bone health pamphlet and brief recommendations for family physician [BHP+FP]; pamphlet and support from a bone health care coordinator [BHP+BHCC]; usual care) to improve bone health care in 119 prostate cancer patients receiving ADT. More men receiving the BHP+BHCC underwent a bone mineral density (BMD; primary endpoint) test within 6 months than usual-care group recipients (78% vs 36%; p < 0.001) and BMD testing was also increased in BHP+FP recipients (58% vs 36%; p = 0.047). There was an increase in the proportion of patients using calcium and vitamin D only in BHP+FP recipients (p = 0.039).

Comment: An interesting study that backs up the usefulness of Men’s Endocrine Clinics but also engaging with GPs. The latter is more palatable in less serviced areas and the overall process can involve nurses who actually achieved most in this randomised trial. Educating and having at least some resources is important and with different models we can all probably do a better job with bone health of patients.

Reference: Cancer 2018;124:1132-40Abstract

Optimizing anticancer therapy in metastatic non-castrate prostate cancer: American Society of Clinical Oncology Clinical Practice GuidelineAuthors: Morris MJ et al.

Summary: The American Society of Clinical Oncology have developed clinical practice guidelines for patients with metastatic prostate cancer untreated by testosterone-lowering agents based on three prospective randomised studies using docetaxel plus ADT (GETUG-AFU 15, STAMPEDE, CHAARTED) and two studies (LATITUDE and STAMPEDE) using abiraterone plus ADT; all trials assessed effects on overall survival (OS). The STAMPEDE trial (n = 2962) favoured the addition of docetaxel to ADT (HR 0.78; 95% CI 0.66-0.93) as did the CHAARTED trial (n = 790; HR 0.73; 95% CI 0.59-0.89), but the GETUG-AFU 15 trial was negative. Adding abiraterone (with prednisone or prednisolone) to ADT was favoured in both the STAMPEDE (n = 1199; HR 0.62; 95% CI 0.51-0.76) and CHAARTED (n = 1917; HR 0.63; 95% CI 0.52-0.76) trials. The guidelines recommend the use of ADT plus docetaxel or abiraterone in newly diagnosed metastatic non-castrate prostate cancer patients, with the greatest benefit in de novo high-volume metastatic disease (CHAARTED). Similar survival benefits with abiraterone acetate occur in high-risk patients (LATITUDE) and in metastatic populations (STAMPEDE).

Comment: When the trials do not quite agree lets go to guidelines. But what if they appear like a velvet sledgehammer? Then we must continue to look and absorb what blows we can. As they state “the strongest evidence of benefit with docetaxel is in men with de novo high-volume (CHAARTED criteria) metastatic disease.” Yet we still have arguments in our MDMs and more than likely the younger the patient the more aggressive. It’s a pity all the men who have had their cancer treated following such guidelines (that really came into effect well before publication) are not followed, then we would actually know the answer! That’s without the vexing situation of conventional imaging versus PSMA PET-CT…

Reference: J Clin Oncol. 2018;36(15):1521-39Abstract

Increased resource use in men with metastatic prostate cancer does not result in improved survival or quality of care at the end of lifeAuthors: Golan R et al.

Summary: This analysis of data from the SEER database from 2004 to 2012 (n = 3026), assessed factors and outcomes associated with increased imaging and serum PSA measurement in men with metastatic prostate cancer. In total, 791 (26%) patients were defined as extreme users (PSA testing more than once per month, or cross-sectional imaging or bone scan more often than every 2 months over a 6-month period) and were more commonly young, white/non-Hispanic, married, higher earning, and more educated (all p < 0.001). Extreme use was not associated with better quality of end-of-life care. Yearly post-diagnosis health care costs were 36.4% higher among extreme users (95% CI 27.4-45.3; p < 0.001).

Comment: This is an interesting observational paper and sits well with our primed logic of the “worried well” using more health resources. Is this just an extension of that concept? Importantly one may blandly conclude that “less is more” in advanced prostate cancer, which goes against our mandate of aggressive treatment where fit enough and possible. The throwaway line of “monitoring for disease progression… should be reserved for those in whom findings will change management” is interesting. This has only become worse with rising PSA levels leading to PSMA PET-CT scans and lesions… and treatment. Conceivably we may be spending even more money in Australia for little benefit – food for thought.

Reference: Cancer 2018;124(10):2212-9Abstract

Impact of time to testosterone rebound and comorbidity on the risk of cause-specific mortality in men with unfavorable-risk prostate cancerAuthors: McDuff SGR et al.

Summary: This randomised controlled study examined the effect of testosterone rebound after radiotherapy with or without 6 months of ADT on risk of prostate cancer-specific mortality (PCSM)) in 206 men with unfavourable-risk prostate cancer. Over a median follow-up of 18.2 years, 30 (18.6%) patients had died of prostate cancer, 39 (24.2%) died of cardiovascular disease, and 92 (57.1%) had died of other causes. As time to testosterone rebound increased, PCSM decreased in those with no or minimal comorbidity (aHR 0.53, 95% 95% CI 0.34-0.84; p = 0.007) and in those with moderate-to-severe comorbidity (aHR 0.37; 95% CI 0.14-0.99; p = 0.048). However, increasing time to testosterone rebound increased the risk of CVM in those with moderate-to-severe comorbidity (aHR 1.87; 95% CI 1.40-2.49; p < 0.001]), but not no or minimal comorbidity (aHR 0.86; 95% CI 0.57-1.29). In men with moderate-to-severe comorbidity and high-risk prostate cancer, achieving a time to testosterone rebound approaching 18 months may minimise CVM risk without increasing PCSM risk.

Comment: More than ever the importance of ordering a serum testosterone with PSA has been emphasised. Interest has focused recently on serum testosterone and achieving the lowest level possible for men on ADT with gains made in survival if the testosterone is absolutely maximally suppressed (<1.7 nmol/L or 50 ng/dL). This type of data feeds against the notion of intermittent ADT to some degree and possibly keeping men on ADT longer in some circumstances, but being aware that ADT itself contributes to CVM. How to balance it all? Against this background this study is of interest focusing on time to testosterone rebound and recurrence after combination radiation and ADT. The message is that in select men at risk of cardiovascular disease, intermittent ADT may be better. So now comorbidity is important, not just in whom we treat but how we treat them.

Reference: Cancer 2018;124:1391-9Abstract

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Research Reviews are prepared with an independent commentary from relevant specialists. To become a reviewer please email geoff@researchreview.com.au.Research Review Australia Pty Ltd is an independent Australian publisher. Research Review receives funding from a variety of sources including Government depts., health product companies, insurers and other organisations with an interest in health. Journal content is created independently of sponsor companies with assistance from leading local specialists. Privacy Policy: Research Review will record your email details on a secure database and will not release them to anyone without your prior approval. Research Review and you have the right to inspect, update or delete your details at any time. Disclaimer: This publication is not intended as a replacement for regular medical education but to assist in the process. The reviews are a summarised interpretation of the published study and reflect the opinion of the writer rather than those of the research group or scientific journal. It is suggested readers review the full trial data before forming a final conclusion on its merits. Research Review publications are intended for Australian health professionals.

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Costs of screening for prostate cancer: Evidence from the Finnish Randomised Study of Screening for Prostate Cancer after 20-year follow-up using register dataAuthors: Booth N et al.

Summary: A second analysis of data from the Finnish Randomised Study of Screening for Prostate Cancer cohort focused on the publicly funded healthcare costs associated with organised prostate cancer screening using individual-level data on prescription medications and inpatient and outpatient care for 80,149 men. Mean prostate cancer-related costs were 10% lower in the screening arm over a 20-year observation period, mean all-cause healthcare costs were also lower in the screening arm, but not significantly different between arms. Mean all-cause healthcare costs were approximately 10% higher for men dying from prostate cancer but the difference between arms was not significant.

Comment: Interesting that in a well-conducted 20-year trial on prostate cancer screening we can still have so few answers. All we can state is there may be some minor cost benefit to screening. That is it. Do not hold your breath for more. Well, at least screening is not more expensive, as that would certainly draw the attention of those predisposed to negativity when it comes to making decisions about any aspect of prostate cancer screening or treatment.

Reference: Eur J Cancer. 2018;93:108-18Abstract

Focal irreversible electroporation as primary treatment for localized prostate cancerAuthors: van den Bos W et al.

Summary: This study examined safety, QoL and short-term oncological outcomes of primary focal irreversible electroporation (IRE) in 63 patients with organ-confined clinically-significant prostate cancer (high-volume disease with Gleason sum score 6 [International Society of Urological Pathology (ISUP) grade 1] or any Gleason sum score of 7 [ISUP grades 2-3]). Over 6 months, QoL questionnaires suggested a small decrease in sexual QoL (median score 66 vs 54; p < 0.001), but no change from baseline levels in physical, mental, bowel or urinary QoL domains. A 70% decline in PSA (1.8 ng/mL) was observed at 6-12 months. Narrow safety margins (p = 0.047) and system errors (p = 0.010) were potential early risk factors for in-field oncological failure. Follow-up biopsies indicated in-field oncological control was 84% and whole-gland oncological control was 76%, and this was increased to 97% and 87% when narrow safety margins and system errors were excluded.

Comment: Focal therapy will simply not go away. Choose your method: hot, cold, radiation, ultrasound (HIFU) or focal IRE aka the “nanoknife”. Some may well have a place with low-volume intermediate-risk cancer. As always case selection is the key and with MRI, transperineal biopsy and perhaps even PSMA PET-CT we may be able to best select the patients for this treatment. The idea is really turning patients with low-volume disease into active surveillance patients, steering them away from radical treatment. This paper shows IRE to be another player, but perhaps the advantage over HIFU (in other studies where radical prostatectomy has followed the treatment) is that the IRE may actually kill all the cancer cells. Like all methods and techniques, longer follow-up data is required and if no bridges are burned in carefully selected patients it may be the way forward in selected men.

References: BJU Int. 2018;121(5):716-24Abstract

Docetaxel versus surveillance after radical prostatectomy for high-risk prostate cancer: Results from the prospective randomised, open-label phase 3 Scandinavian Prostate Cancer Group 12 trialAuthors: Ahlgren GM et al.

Summary: This multinational, open-label, randomised, phase 3 trial assessed the impact of six cycles of docetaxel 75 mg/m2 every 3 weeks versus surveillance on biochemical disease-free survival in 459 patients after radical prostatectomy for high-risk (pT2 margin positive or pT3a Gleason score ≥4+3; pT3b; lymph node positive disease Gleason score ≥3+4) prostate cancer. During a median 56.8 months of follow up, the PSA progression ≥0.5 ng/mL (primary endpoint) was reached by 190 (41.8%) patients; progression risk at 5 years was 41% (docetaxel 45%, surveillance 38%). The restricted mean survival time to endpoint did not differ between docetaxel and surveillance recipients (43 vs 46 months; difference 3.2 months; 95% CI 6.7 to -1.5). 116 serious adverse events occurred with docetaxel versus 41 with surveillance.

Comment: I’m pretty sure we participated in a similar trial over a decade ago – the studies were negative then and still are now. The role of adjuvant treatments in men undergoing radical prostatectomy remains as elusive as ever, and without such treatments in our armoury we will have to simply await trials, and more than likely better drugs.

Reference: Eur Urol. 2018;73(6):870-76Abstract

Quality of life during treatment with chemohormonal therapy: Analysis of E3805 chemohormonal androgen ablation randomized trial in prostate cancerAuthors: Morgans AK et al.Summary: This study assessed QoL in metastatic hormone-sensitive prostate cancer patients receiving ADT plus docetaxel (n = 397) versus ADT alone (n = 393). Recipients of ADT plus docetaxel had a decline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores at 3 months (p < 0.001), but no difference between baseline and 12 months. ADT plus docetaxel recipients had lower FACT-P scores than ADT alone recipients at 3 months (p = 0.02), but higher scores at 12 months (p = 0.04). However these differences did not exceed a minimal-clinically-important difference at any time point. ADT plus docetaxel recipients also had lower Functional Assessment of Chronic Illness Therapy-Fatigue scores at 3 months than ADT alone recipients (p < 0.001). Both arms had worse FACT-Taxane scores (p < 0.001) over time versus baseline. Brief Pain Inventory scores did not differ between treatment arms.

Comment: Efficacy has always been the key, but with newer agents in the field, attention has rightly switched to QoL issues. This study is reassuring in that combination ADT and docetaxel appears to be well tolerated and effects in the longer term are not there, doubly good as we have patients still alive to tell us that! So expect more QoL studies and battles as to who has the best QoL, with efficacy being about equivalent and then the third battle of funding and cost will be upon us.

Reference: J Clin Oncol. 2018;36(11):1088-95Abstract

Fasting blood glucose, glycaemic control and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate CancerAuthors: Murtola TJ et al.Summary: The Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC) cohort provided data for an analysis of the risk of prostate cancer in 17,860 men classified as normoglycaemic, prediabetic or diabetic. Over a median follow-up of 14.7 years, 1663 prostate cancer cases were diagnosed. Men with diabetic blood glucose levels had an elevated prostate cancer risk (HR 1.52; 95% CI 1.31-1.75) versus normoglycaemic men. This increased risk occurred across all tumour grades and persisted for a decade, but the risk association was removed by use of anti-diabetic agents.

Comment: We all know diabetes is bad and causes many diseases - let us now add prostate cancer to that list. Of course the study did not control for all confounders, but this finding should make us even more likely to use our endocrine colleagues in men with diabetes and perhaps prompt us to remind their general practitioner or others the importance of looking further into that “borderline blood sugar” they have had. Perhaps we should incorporate a glucose measure into our monitoring?

Reference: Br J Cancer. 2018;118(9):1248-54Abstract