Urology, Uro-oncology and Sexology Update

VOLUME 2; ISSUE 3 2023 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE This publication is intended for registered healthcare professionals only.

Replenish Restore Revive Sterile sodium hyaluronate solution Pharmaco Distribution (Pty) Ltd. 3 Sandown Valley Crescent, South Tower, 1st Floor, Sandton, 2196 P.O.Box 786522, Sandton, 2146, South Africa. Tel: +27 11 784 0077. Website: www.pharmaco.co.za References: 1. Cicione A, Cantiello F, Ucciero G, et al. Intravesical treatment with highly-concentrated hyaluronic acid and chondroitin sulphate in patients with recurrent urinary tract infections: Results from a multicentre survey. Can Urol Assoc J. 2014;8(9-10):E721-7 1 BPS/ INTERSTITIAL CYSTITIS For full prescribing information, please refer to package insert S4 CYSTISTAT® Solution (40mg Sodium hyaluronate Each 50 ml of solution contains 40 mg Sodium hyaluronate Reg. No: A40/18.10/0062 Restored GAG layer Bladder muscle Damaged GAG layer Lumen of the bladder GAG layer Irritants (eg. urine) HA

VOLUME 2; ISSUE 3 2023 Editor Prof Shingai Mutambirwa - Urologist MBChB, MMed (Urology) Medunsa Head of Urology - Sefako Makgatho Health Sciences University Chairman - The South African Urological Association Academic committee Chairman - Medical and Scientic Advisory Board of The Prostate Cancer Foundation Editorial Board Dr. Sheynaz Bassa - Clinical and Radiation Oncologist MBChB (Univ of Natal), FC Rad (Onc) SA Head of Department: Radiation Oncology Steve Biko Academic Hospital and The University of Pretoria Dr Jireh Serfontein - Medical Sexologist MBChB (Pret.), Dip HIV Management, MMed Sexual Health (Univ. Sydney) Clinical head: My Sexual Health Pretoria Editorial and Publishing Ofce Maria Philippou Randburg 2194 Enquiries 082 3355 444 Publisher Maria Philippou Andrew Oberholzer Disclaimer All rights reserved. No editorial matter published in Urology, Urooncology and Sexology Update may be reproduced in any form or language without written permission from the publishers. While every effort is made to ensure accurate reproduction, the Prostate Cancer Foundation, the authors, publishers and their employees or agents shall not be responsible or in any way liable for any errors, omissions or inaccuracies in the publication whether arising from negligence or for any consequences arising there from. The inclusion or exclusion of any product does not mean that the Prostate Cancer Foundation, the publisher or the editorial board advocates or rejects its use either generally or in any particular eld or elds. This publication is intended for registered healthcare professionals only. If you received this publication or a link to this publication in error, please do not directly or indirectly use, print, copy, forward, or disclose any part of this publication. Please delete the copy or link to the publication and notify the publisher. UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE CONTENTS 1 Why involve a genetic counsellor in prostate cancer care? Apex Chronicles The Prostate Cancer Foundation's 2023 Suit Up September campaign Radiotherapy in the setting of Oligometastatic Prostate Carcinoma Male sexual dysfunctions: the impact on the partner Interview with Dr Greg Boustead More Daredevils than ever before 2 6 9 10 16 22 25 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE Supported by:

2 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE “I'm sorry, you have prostate cancer” are the words that about 1 in 20 South African men will hear in their lifetime. Hearing these words conrming a cancer diagnosis not only brings forth a ood of emotions but also triggers a cascade of questions from “How did this happen?” to “What caused it?” and “What about my children?” These inquiries are precisely the type of complex issues that a genetic counsellor is uniquely equipped to address. Genetic factors in prostate cancer development While the majority of prostate cancers will arise spontaneously and at random, While the majority of prostate cancers will arise spontaneously and at random, some individuals may carry a genetic mutation (variant) associated with an inherited cancer syndrome. A mutation is a change in the genetic code which causes the gene to be dysfunctional which in turn leads to an increased risk for a certain condition/cancer. Suspicion of an inherited cancer syndrome arises when specic factors come into play, such as metastatic prostate cancer (cancer has spread to other parts of the body), cancers diagnosed at an unusually young age (younger than 55 years for prostate cancer), the presence of multiple affected family members spanning generations, a personal history of multiple primary cancers and certain ancestral backgrounds, most notably Afrikaner and Ashkenazi Jewish populations. Research studies have suggested that about 15% of men who are diagnosed with metastatic and 5 to 7% with early-stage prostate cancer will carry a genetic mutation associated with an inherited cancer syndrome. The likelihood of genetic involvement surges to about 43% for men diagnosed before the age of 55 years. There are several genes believed to be associated with an inherited predisposition to prostate cancer. Genes associated with prostate cancer Hereditary prostate cancer in families with a young age of onset has been attributed to mutations in the HOXB13 gene. Men who carry variants in this gene have an eightfold increased risk of prostate cancer and an approximately tenfold increased risk of earlyonset cancer. Mutations in this gene are not believed to be related to an increased risk for any other types of cancers. Mutations in the BRCA1 and BRCA2 genes have a strong association with familial prostate cancer, with the BRCA2 gene showing the strongest association. Men with a BRCA2 variant are at an eightfold and BRCA1 variant a threefold increased risk. Men with these mutations are also at an increased risk of male breast cancer, melanoma and pancreatic cancer. These genes also confer a high risk for female breast and ovarian cancer. Mutations in these genes are highly prevalent amongst men of Afrikaner and Ashkenazi Jewish ancestry. The Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2 and EPCAM) are believed to slightly increase the risk for prostate cancer. Lynch syndrome is an inherited cancer syndrome which classically leads to an increased risk for colorectal, pancreatic, ovarian, endometrial, upper bowel and urinary tract cancers. The exact associated prostate cancer risk for these genes is uncertain, but the MSH2 and MSH6 genes are Why involve a genetic counsellor in prostate cancer care? Dr Chantelle Scott – Genetic Counsellor BSc Hons Genetics (Stell). MSc Med Genetic Counselling (UCT). PhD Human Genetics (Stell) Whilst studying for a BSc undergraduate degree majoring in both psychology and genetics, Chantelle was introduced to the genetic counselling profession. She realised that the profession would combine her interest in both psychology and genetics. In 2008 she embarked on the journey to become a genetic counsellor, this began with the requirement to complete a BSc honours degree in genetics at Stellenbosch University, followed by a MSc (Med) in Genetic Counselling at the University of Cape Town. This was followed by an internship after which she was registered as a genetic counsellor with the HPCSA. Her passion for research and improving the health care services offered to individuals and their families led her to pursuing a doctoral degree. She was awarded with a PhD in Human Genetics in 2018. She has also worked for a year in the UK as a general and cancer genetic counsellor. Apart from running a private practice Chantelle has been involved in training students and assisting with research projects at various departments at the Faculty of Medicine and Health Sciences at Stellenbosch University, including the division of Urology. She has recently been appointed to the Medical and Scientic Advisory Board of the Prostate Cancer Foundation.

ELIGARD® utilises the unique ATRIGEL® delivery system for controlled release of leuprolide over time1-3 ELIGARD® offers 3 and 6-month dosing options to suit patient needs1-3 Dosing Intervals Approximate Injection Volume Per Dosage Dosage 0.375 ml 3 MONTHS 22.5 mg 0.375 ml 6 MONTHS 45 mg Suspension ELIGARD® is injected into the subcutaneous space. Rapidly Formed Solid Polymers respond to water by precipitating and trapping leuprolide acetate in a solid implant. Controlled Drug Release Over Time Biodegradable polymers degrade by hydrolysis, slowly releasing leuprolide acetate. For full prescribing information refer to the Professional Information (PI) approved by the South African Health Products Regulatory Authority. S4 ELIGARD® Registration number: A39/26/0649. Composition: One syringe contains the ATRIGEL® Delivery System, and the other contains lyophilised leuprolide acetate. The second syringe contains lyophilised leuprolide acetate and is designed to deliver 22,5 mg leuprolide acetate at the time of subcutaneous injection. S4 ELIGARD® Registration number: A39/26/0651. Composition: One syringe contains the ATRIGEL® Delivery System, and the other contains lyophilised leuprolide acetate. The second syringe contains lyophilised leuprolide acetate and is designed to deliver 45 mg leuprolide acetate at the time of subcutaneous injection. Reference: 1. South African Approved Professional Information (PI), 3 March 2023. 2. Schulman C. et al. Expert opinion on 6-monthly luteinizing hormone agonist treatment with the single-sphere depot system for prostate cancer. BJU Int 2007;100(Suppl. 1):1-5 3. ATRIGEL® delivery system [online]; Available from: http://eligardhcp.com/atrigel-delivery. Accessed on 3 October 2023. 4. Crawford DE. et al. Extended release, 6-month formulations of leuprolide acetate for the treatment of advanced prostate cancer: achieving testosterone levels below 20 ng/dl. Expert Opin. Drug Metab. Toxicol. (2015) 11(9):1465-1474. 5. Meani D. et al. Practical differences between luteinizing hormone-releasing hormone agonists in prostate cancer: perspectives across the spectrum of care. Ther Adv Urol 2018, Vol. 10(2) 51–63. Applicant: Key Oncologics (Pty) Ltd. Reg. No. 95/013825/07. 39 11th Avenue, Houghton Estate, Johannesburg, 2198, South Africa. Tel: +27 11 483 0060/5. Email: key@icon.co.za. www.keyoncologics.co.za. To report an adverse event or product complaint please email: safety@keyoncologics.co.za or phone: +27 79 471 1771. 22357T. 10/2023. ELIGARD® is indicated for the palliative treatment of advanced prostate cancer.1 Benefits of Subcutaneous Injections4,5 • Greater number of potential injection sites • A shorter needle designed to reach no further than the subcutaneous space • Smaller drug volumes • Decreased muscle mass is not a concern • Less injection site discomfort compared with intramuscular delivery Areas with sufficient subcutaneous tissue

4 associated with an approximately threefold increased risk of developing prostate cancer. Other genes that are associated with hereditary prostate cancer include CHEK2, NBN, ATM, PALB2, BRIP1, RAD51C, RAD51D and TP53, even though the exact risk gures are uncertain. It is important to note, that to date, not all the prostate cancer-causing genes have been identied. Therefore, if a person has a strong family history and many individuals affected with prostate and/or other cancers, a negative (normal) genetic test cannot exclude a hereditary cancer syndrome. In these families the genetic counsellor will use the family history information to determine the cancer risks and make surveillance recommendations. Motivations for genetic testing in prostate cancer Recent International guidelines have introduced recommendations for the inclusion of genetic testing in the assessment of men diagnosed with prostate cancer. In Box 1, you will nd a summary of the latest guidelines from the National Comprehensive Cancer Network (NCCN) and the European Association of Urology (EAU). If an individual meets the outlined criteria, it is highly probable that the cost associated with genetic testing will be covered by local medical insurers. This typically requires a motivation letter, providing a compelling rationale for the necessity of genetic testing, from their genetic counsellor, urologist and/or oncologist. Understanding a patient's genetic status upon being diagnosed with prostate cancer is of paramount importance as it plays a pivotal role in tailoring the most suitable treatment and management plan. For individuals with genetic prostate cancer, the stakes are higher, as they face a potentially more aggressive form of the disease and decreased survival rates when early detection is missed. Additionally, they have an elevated risk of cancer recurrence, even following curative treatments initiated for early-stage disease, necessitating a proactive approach to management. In the current era of precision medicine, treatment efcacy is increasingly determined by an individual's unique genetic make-up. Notably, several FDAapproved gene-targeted therapies are now available, primarily benetting metastatic prostate cancer patients. These therapies include PARP-inhibitors and immunotherapies. PARP-inhibitors have exhibited promising results, particularly in men who carry mutations in DNA repair genes such as BRCA1, BRCA2, ATM, CHEK2, NBN, PALB2, RAD51C, RAD51D. Conversely, the immunotherapies are designed to target the Lynch syndrome genes. It is important to note that genetic tests to determine therapy encompass both germline and somatic testing. Germline testing is done on a blood or saliva sample and looks at the genetic mutations a person is born with and carry in every cell of your body. Somatic testing examines the cancer cells to identify genetic mutations acquired due to external factors, such as lifestyle and environmental inuences. Importantly, mutations in somatic cells are not inherited and cannot be passed on to subsequent generations. Furthermore, genetic testing yields insights into the risk of developing a second prostate or other types of cancers. An inherited cancer syndrome, contingent upon the specic gene involved, can predispose individuals to various other cancer types. Knowing which other areas of the body are at risk allows the healthcare providers the opportunity to put the most appropriate surveillance plan in place to either prevent or detect cancer at an early manageable stage. For instance, a man with prostate cancer carrying a BRCA2 genetic mutation, also faces an increased risk of breast, melanoma and pancreatic cancer. To address the breast cancer risks he may be advised to conduct monthly self-examinations and undergo annual clinical examinations of the chest area starting from the age of 35 years. Annual full bodyskin examinations by a dermatologist can help mitigate melanoma risk, while additional pancreatic cancer screening is recommended from the age of 50 years if a strong family history of this cancer type is present. Genetic testing holds signicance not only for the individual diagnosed with cancer, but also for their children and other blood-related family members. When a man carries a cancer-causing gene variant, each of his children has a 50% chance of inheriting it. This information is crucial for both his sons and daughters, as these gene variants often include a heightened risk of breast and ovarian cancer. Equipped with this knowledge, the affected individual's children, siblings, and other relatives can implement essential cancer-risk management strategies to safeguard against these malignancies. It's imperative for unaffected family members to have genetic counselling before undergoing genetic testing to ensure that they fully comprehend the implications of the results. Importantly, genetic testing does not impact the insurance policies and premiums of individuals diagnosed with cancer. However, it may lead to certain exclusions and/or increased premiums for unaffected individuals. Therefore, it's advisable for unaffected individuals to secure their life and other insurance policies before undergoing genetic testing. The role of genetic counsellors in prostate cancer care Genetic counsellors are allied health care professionals that are trained in the principles and practices of genetic testing, hereditary cancer assessment and informed decision-making for genetic testing. They assess an individual's personal and family medical history to offer advice on whether genetic testing is appropriate. To promote informed decision-making, they provide information on the risks, limitations and benets of each genetic testing option as genetic testing is not always straightforward. Each genetic test has limitations with regards to the technology that is used and cannot UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE

5 always detect all genetic variations in the genes screened for. In addition, there is also the possibility of detecting a gene variant of uncertain signicance (VUS). A VUS is a rare variation in the genetic code for which too little information is available on how it impacts the function of the gene. These variants can either be normal non-cancer-causing or cancercausing. Further studies are usually needed to classify a VUS. A genetic counsellor assists in variant classication, the accurate interpretation of the genetic test results and guiding the individual through an uncertain result. Genetic counsellors use the genetic test results in combination with the individual's personal and family history to do a personalised cancer risk assessment and offer advice on the most appropriate cancer risk management options. If appropriate, they also coordinate genetic testing and determine the risks for the individual's family members. Receiving a positive genetic test result and/or diagnosis of an inherited cancer syndrome may illicit unwanted emotions and cause anxiety about the future. It may also lead to concerns related to the individual's family. These psychosocial concerns are addressed by genetic counsellors who provide additional avenues of support to promote adaptation to the implications of an inherited cancer syndrome. In summary, genetic testing holds tremendous potential in prostate cancer management. Given its intricacies and far-reaching implications, genetic counselling is an indispensable companion in this journey for the following reasons: • Guided test selection: Genetic counsellors aid in selecting the most appropriate tests tailored to the individual's unique situation. • Precision in interpretation: Genetic test results can be complex, but with a genetic counsellor's expertise, there's a reduced risk of misinterpretation, minimising anxiety or false reassurance. • Tailored cancer management: With their guidance, the most effective and personalised cancer management plan can be crafted, optimising treatment outcomes. This partnership extends beyond the individual to their family members, ensuring that the right surveillance is in place to mitigate the risk of advanced stage prostate cancer and other gene-related cancers. By providing this support, genetic counselling not only enhances peace of mind, but also safeguards the well-being of both the individual and their loved ones. Box 1: International guidelines for prostate cancer genetic testing National Comprehensive Cancer Network (NCCN) Version 4.2023 The following men should be offered genetic testing. Men with: • Metastatic, regional (node positive), very-highrisk localised, or high-risk localised prostate cancer or intermediate risk prostate cancer with intraductal/cribriform histology, regardless of age • One or more rst-, second- or third-degree relatives with breast, colorectal or endometrial cancer younger than 50 years and/or male breast, ovarian, pancreatic at any age. • One rst-, second- or third-degree relatives with metastatic, regional, very-high risk, or high-risk prostate cancer at any age • One or more rst-degree relative with prostate cancer at age 60 years or younger • Two or more rst-, second- or third-degree relatives with breast or prostate cancer at any age • Three or more rst- or second-degree relatives with Lynch syndrome cancers, especially if diagnosed younger than the age of 50 years • A known family history of familial risk mutation (pathogenic/likely pathogenic variants) • Ashkenazi Jewish ancestry • Personal history of breast, pancreatic, colorectal, gastric, melanoma, upper tract urothelial, glioblastoma, biliary tract and small intestinal cancer European Association of Urology (EAU) 2023: Germline genetic testing should be considered in men with: • Personal or family history of prostate cancer or other types arising from DNA repair gene mutations • Metastatic prostate cancer • High-risk prostate cancer and a family members diagnosed with prostate cancer at age younger than 60 years • Multiple family members diagnosed with clinically prostate cancer at age younger than 60 years or a family member who died from prostate cancer • A family history of high-risk germline mutations or a family history of multiple cancers on the same side of the family Bibliography 1. Giri, VN, Morgan, TM, Morris, DS. et al. Genetic testing in prostate cancer management: Considerations informing primary care. CA Cancer J Clin. 2022. https://doi.org/10.3322/caac.21720. 2. Mottet, N et al. EAU guidelines: Prostate cancer. EAU. https://uroweb.org/guideline/prostatecancer. 3. National Comprehensive Cancer Network. Clinical Guidelines in Oncology (NCCN Guidelines ): Prostate Cancer. Version 4.2023. ® NCCN https://www.nccn.org/ guidelines/guidelinesdetail?category=1&id=1459. 4. Russo, J, Giri VN. Germline testing and genetic counselling in prostate cancer. Nat Rev Urol. 2022 Jun;19(6):331-343. doi: 10.1038/s41585-022-00580-7. Epub 2022 Apr 21. PMID: 35449224; PMCID: PMC9022414. 5. South African National Cancer Registry data of 2020. https://www.nicd.ac.za/centres/national-cancerregistry/cancer-statistics/. 6. Tuffaha, H, Edmunds, K, Fairbairn, D et al. Guidelines for genetic testing in prostate cancer: a scoping review. Prostate Cancer Prostatic Dis. 2023. https://doi.org/10.1038/s41391-023-00676-0. 7. Vietri MT, D'Elia G, Caliendo G, Resse M, Casamassimi A, Passariello L, Albanese L, Ciof M, Molinari AM. Hereditary Prostate Cancer: Genes Related, Target Therapy and Prevention. Int J Mol Sci. 2021 Apr 4;22(7):3753. doi: 10.3390/ijms22073753. PMID: 33916521; PMCID: PMC8038462 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE

6 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE The inaugural Apex (Advancing prostate cancer excellence) meeting was held in Lisbon, Portugal between 8-9 September 2023. Hosted by Bayer, the meeting was a convergence of leading prostate cancer researchers in one room to share their knowledge and expertise. The therapeutic strategies for prostate cancer have expanded rapidly - from testosterone suppression (ADT) and mitoxantrone two decades ago, to a current pool of twelve therapies (and counting) that have demonstrated an increase life expectancy. These include systemic therapies and androgen receptor pathway inhibitors (ARPI). Prostate Specic Antigen (PSA), humorously referred to as “patient/physician specic anxiety”, remains a sensitive measure of disease activity. The appropriate means to monitor disease response in the metastatic setting is uncertain. Should this be based on biochemical progression, or should it include biochemical and clinical progression bearing in mind there is often a small window of opportunity to initiate newer therapies while the patient remains in an optimal performance status. There is often a 6-month lag between biochemical progression and radiological progression while 25% of patients will demonstrate radiological progression before PSA progression. Small cell differentiation may occur during the disease process. A high serum LDH, the presence of lytic lesions, relatively low PSA in the setting of visceral disease are factors that should raise suspicion of histological transformation. While PSMA PET or targeted imaging is often used to stage patients, one needs to be bear in mind that contrast CT scan is complimentary to identify non-PET avid disease. This is important in patients with progressive disease and those planned for later lines of therapy. However, PSMA PET remains more sensitive in detection of metastatic disease as seen in the proPSMA study (J Nucl Med 2020). MRI has an established role for biopsy guidance and staging of localised disease as was conrmed in the PROMIS study (Lancet 2017). Systemic therapy is being initiated sooner, following the proven efcacy in nonmetastatic castration resistance disease as well as recent trials demonstrating a benet in high-risk disease. Nomograms in addition to risk classication can assist with the selection of appropriate therapies. The Katan nomograms and CAPRA risk model are important tools in treatment selection. Pathology Improvements in pathological assessment have been important in identifying high risk patients that will benet from earlier, longer systemic therapies in addition to local treatment. Biochemical failure is more often evident in tumours demonstrating a large cribriform pattern and intraductal carcinoma. Somatic gene testing including ® tools such as Decipher®, Oncotype Dx® and Prolaris are important in selecting the correct patients for adjuvant radiotherapy post radical prostatectomy. Castration resistant non metastatic prostate cancer (nmCRPC) nmCRPC is diagnosed by a rising PSA without any evidence of disease. The PSA doubling time (PSADT) is predictive of the risk of distant metastases and often manifests within 18 months if left untreated. One should bear in mind that contrast CT scan and bone imaging was used to exclude metastatic disease in clinical trials. Apex Chronicles Dr Sheynaz Bassa is the Head of Radiation Oncology at The University of Pretoria and Steve Biko Academic Hospital. She studied medicine at The University of Natal Medical School and graduated Summa Cum Laude in 1998. She went onto to specialise in clinical and radiation oncology at The University of Witwatersrand and completed her studies in 2006. She is a full member of the South African Society of Radiation and Clinical Oncology and the European Society of Radiotherapy and Oncology. She is also a member of the Prostate Cancer Foundation's Medical and Scientic Advisory Board. She has numerous publications to her name and has assisted with the compilation of a number of diagnostic and treatment guidelines. Dr Sheynaz Bassa Clinical and Radiation Oncologist MBCHB Univ. of Natal. FC Rad Onc (SA) University of Witwatersrand

DDAVP® Tablet 0.1 mg 0.2 mg TO BE DISCONTINUED Minirin® Melt 60 mcg (to be launched soon) 120 mcg 240 mcg S4 MINIRIN® Melt 120 μg (sublingual tablet) Each unit contains 120 μg desmopressin acetate (120 μg free base) Registration No.: A42/18.2/0346. S4 MINIRIN® Melt 240 μg (sublingual tablet) Each unit contains 240 μg desmopressin acetate (240 μg free base) Registration No.: A42/18.2/0347. S4 MINIRIN® Melt 60 μg (sublingual tablet) Each unit contains 60 μg desmopressin acetate (60 μg free base) Registration No.: A42/18.2/0345. S4 DDAVP® Tablet 0,1 mg. Each tablet contains desmopressin acetate 0,1 mg. Reg No.: A29/18.2/0429. S4 DDAVP® Tablet 0,2 mg. Each tablet contains desmopressin acetate 0,2 mg. Reg No.: A34/18.2/0402. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION: FERRING (Pty.) Ltd. Route 21 Corporate Park, 6 Regency Drive, Irene Ext 30. Pretoria, South Africa. Tel: +27 12 345 6358 Fax: +27 12 345 1156. www.ferring.co.za. DDAVP, MINIRIN MELT, FERRING, and the FERRING logo are registered trademarks of Ferring B.V. For full prescribing information please refer to the package insert approved by the medicines regulatory authority. For medical enquiries or to report any adverse events, please send an email to safety.mailbox3@ferring.com. https://bit.ly/3hUP4km. ZA-MN-2300005 Effective date: July 2023. Switch to Minirin® Melt - The PREFERRED FORMULATION for the MAJORITY OF PATIENTS1,2 IMPROVED RESPONSE and COMPLIANCE compared to tablet2 Can be taken without water3 SIMILARLY PRICED to DDAVP tablets®4 Minirin® Melt is indicated for: 1. Management of Central Diabetes Insipidus3 2. The symptomatic short term (4-8 weeks) treatment of primary nocturnal enuresis in children older than 5 years who have normal ability to concentrate urine3 References: 1. Lottmann H, et al. A randomised comparison of oral desmopressin lyophilisate (MELT) and tablet formulations in children and adolescents with primary nocturnal enuresis Journal compilation. Int J Clin Pract. September 2007,61(9):1454-1460. 2. Juul KV, et al. Desmopressin melt improves response and compliance compared with tablet in treatment of primary monosymptomatic nocturnal enuresis. Eur J Pediatr. 2013;172:1235-1242. 3. MINIRIN® Melt Registered Package Insert, dated 06 March 2014. 4. Database of Medicine Prices 14 June 2023. Switch from DDAVP® tablet to Minirin® Melt TODAY How to switch from tablets to Melt formulation:2 DDAVP® 0.2 mg is equal to Minirin® Melt 120 mcg 2x DDAVP® 0.2 mg is equal to Minirin® Melt 240 mcg

8 PSMA PET does not alter ongoing systemic therapy in this patient cohort and is not advocated by many experts. The goal standard of systemic therapy is an improvement of overall survival, but other factors should be considered especially in the nmCRPC group of patients who remain asymptomatic from disease. Drug-drug interactions, side effects of therapy and quality of life are important issues that one should consider when selecting appropriate therapy in nmCRPC. Darolutamide was found to delay the onset of metastatic disease from 18 months to 40 months. In addition, there were fewer neurological side effects, treatment discontinuations or severe adverse events (ARAMIS NEJM 2019). Management of High-risk disease Local therapies include external beam radiotherapy (EBRT), EBRT and brachytherapy or surgery (radical prostatectomy and radical lymph node dissection). Patient and disease related factors are important in selecting appropriate treatment. The inclusion of the regional nodes in radiotherapy elds has always been contentious. The POP-RT study has conrmed that nodal EBRT was superior in terms of disease-free survival but not overall survival (Murthy, JCO 2021). Clinical trials with SBRT boost to the prostate and prophylactic hypofractionated RT (5Gy x 5 fractions) to pelvic nodes are currently under way and will provide a resource friendly alternative for busy radiotherapy centres. The Canadian PCS IV has conrmed that there is no benet with extended adjuvant ADT in high-risk prostate cancer (18 months vs 36 months). There have been no gains with the inclusion of systemic therapy (neoadjuvant or adjuvant) to surgery for highrisk disease. Two years of adjuvant abiraterone +- enzalutamide conferred a metastases free survival benet in patients with high-risk disease. However, 15% of patients did not receive radiotherapy, a signicant number did not receive pelvic nodal RT and grade 3 toxicity was increased. This option may be suitable for patients with PSMA signicant disease, but this remains investigational. There are several ongoing studies looking at the addition of adjuvant ARPI in high-risk prostate cancer including DASL-HiCAP where darolutamide will be added to ADT following RT for denitive or salvage RT in high-risk disease. Biochemical recurrence (BCR) Both the PRESTO and EMBARK (J Urol 2023) demonstrated a benet in metastases free survival with the use of ARPI in high risk BCR patients. Radium 223 The use of Radium 223 (Ra-233) has declined despite overall survival data dating back to 2013. It should be introduced early on during the disease and, in the setting of bone only metastases. It should not inuence the use of Lutetium-177 (LU-177) therapy during later lines of therapy. This is evident from the LARU study presented at ESMO in 2022. Bone marrow toxicity and response rates were not altered by prior Ra-223 use even when docetaxel was sequenced between these two strategies. Treatment sequencing Treatment selection is guided by: 1. The timing of metastatic disease: de novo or metachronous metastatic disease 2. Prior therapies in the case of metachronous disease 3. Patient risk prole and preference 4. Access to care 5. Volume of disease (CHAARTED) or high-risk disease (LATITUDE). This is always a matter for discussion. Patients often defer to ARPI therapies in view of the convenience of oral therapies and acceptable side effect prole. The use of ARPI following prior ARPI therapy is not clinically meaningful with enzalutamide followed by abiraterone (and vice versa) offering a modest 3month PFS. The results of the CARD study demonstrated that cabazitaxel produces clinically meaningful benet when offered after prior ARPI or docetaxel therapy as compared to a switch in ARPI therapies. This included benets in PFS and OS. Ra-223 is appropriate for bone only disease while LU177 is active in both bone and soft tissue disease provided the disease is PSMA avid. The mean SUV may be predictive of LU-177 response, but this remains investigational. Most experts concurred that PSMA PET was only utilised if LU-177 was being considered for treatment. Most experts utilise conventional imaging (CT scan and bone scan) to monitor disease progression. Conclusion The future of metastatic prostate cancer is promising. As one expert indicated, it is a chess game anticipating the tumour behaviour, initiating an appropriate therapy for the clinical scenario, and consistently staying ahead to optimise sequencing and to gain durable responses. Nonetheless, tumour biology is a predeterminant of treatment outcomes and much of the future research lies in this area. CHAARTED ≥4 bone metastases including >=1 outside the vertebral column or pelvis +/or visceral metastases LATITUDE ≥2 high risk features of ≥3 bone metastases Visceral metastases ≥ISUP Grade 4 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE

9 Thanks to Everyone Who Supported The Prostate Cancer Foundation's Suit Up September Campaign to Help Raise Awareness About Prostate Cancer Free State University's Radiation Oncology and Uroloy Departments Dr Evelyn Moshokoa and team September is prostate cancer awareness month and every year The Prostate Cancer Foundation asks people to Suit Up for just one day to help us raise awareness about prostate cancer. Suit Up September badges are sold for R50 to help raise funds for the Prostate Cancer Foundation's activities and projects. The Team from The Panorama Centre for Surgical Oncology in Cape Town Tygerberg Uro-Oncology MDT Our patient affairs board vicechairman Thulani Sibisi suiting up at Bara Thanks to Bionike and Dischem for providing the Suit Up Saturday prizes Suit Up Saturday Dr Dino Chetty Dr Ingo de Mûelenaere Bionike prizes for Suit Up Saturday This year's Suit Up September campaign coincided with the South African Congress of Oncology (SACO) which was held in Cape Town from 1 to 3 September. A suit Up Saturday competition was held with prizes provide by Bionike. UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE

10 UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE Prostate cancer is among the most common cancers in males worldwide. The spectrum of prostate cancers range from localised low and high risk tumours to metastatic hormone sensitive and hormone resistant disease. Radiation therapy is an important treatment modality in the management of prostate carcinoma and its role has evolved in the setting of oligometastatic disease. Oligometastatic prostate cancer (OMPC) can be dened as cancer with a limited number of metastases, typically fewer than 5 lesions. These patients have a better prognosis than patients with extensive 4 metastatic disease. The concept of oligometastatic disease was rst proposed by Sam Hellman and Ralph Weichselbaum at the American Society of Clinical Oncology (ASCO) over 20 years ago. It is derived from the Greek word “oligo” meaning “few.” The concept involves controlling a primary tumor completely or controlling a single or limited number of metastatic lesions with local therapy, which can result in a cure. Oligometastatic disease is an intermediate biological state with a unique clinical picture within the spectrum of advanced disease, which has a favourable phenotype that is ideal 3 for an intensive approach. The relatively slow proliferation rate of prostate cancer is reected in a low α/β ratio between 1 and 4. Because the α/β ratio for prostate cancer is similar to or lower than the surrounding tissues responsible for most of the toxicity reported with radiation, radiation treatment elds and schedules using extremely hypofractionated regimens and stereotactic radiotherapy result in good cancer control rates [1] without increased risk of late toxicity. Stereotactic body radiotherapy (SBRT) is a form of real or near-realtime image guidance radiation therapy that uses high doses of radiation delivered in a precise and targeted method to the tumour, in a very limited number of fractions with low toxicity and excellent tolerance. DR NIRASHA CHIRANJAN Radiotherapy in the setting of Oligometastatic Prostate Carcinoma "I have lived through the effects of cancer on close family and friends. This rst-hand experience inspired me to pursue my studies in Oncology. Having walked this road, I am determined to give my patients the care they need, and so rightfully deserve. I remain steadfast in my dedication to my patients, their families and have long ago resolved to make this walk with them - my life's work." – Dr Nirasha Chiranjan. Dr Chiranjan completed her MBchB at the University of Cape Town in 2006. Following two years of internship at McCord's Hospital in Durban, Dr Chiranjan completed a year of community service at Evander Hospital in Mpumalanga. In 2010, she joined the Radiation Oncology Department at the Charlotte Maxeke Johannesburg Academic Hospital. Dr Chiranjan was successfully admitted as a Fellow of the College of Radiation Oncologists in early 2014 and joined DMO in August of the same year, where she is now a senior partner. She consults at the Ahmed Kathrada Cancer Institute, Sandton Oncology and the West Rand Oncology Centre and is part of a team of eight Oncologists that consult at the DMO locations. Being available to the patient is of importance to us. Our Oncologists are available daily to our patients, throughout their treatment programme, and beyond for follow up care and are rostered on call, 24/7 - all year. Dr Chiranjan treats a broad range of malignancies, with special interest in prostate, breast, gynaecological, head and neck, and central nervous system areas. She is an active participant in several multi-disciplinary forums related to cancer treatment and also has a keen interest in screening processes. Example of a stereotactic body radiation therapy (SBRT) planning on a metastatic bone lesion

12 De novo (synchronous) oligometastatic disease represents patients found to have metastatic disease at the time of initial diagnosis. Oligorecurrent (metachronous) disease are patients initially treated with denitive therapy to cure their malignancy who subsequently develop limited metastatic disease recurrence. The use of close PSA monitoring after primary treatment together with active incorporation of more sensitive and specic molecular imaging modalities such as PSMA-PET for local and systemic staging, has emerged as a crucial approach for early detection of oligorecurrence. Finally, oligoprogressive disease represents patients with known metastatic disease who exhibit few isolated areas of progression in a background of otherwise stable disease. This oligometastatic state may be an apparent turning point between stillcontrollable regional disease that might be managed with local intervention, and diffuse disease for which systemic therapies are the mainstay. Oligorecurrent prostate cancer is now the preferred term for designating such relapses after primary curative-intent 2 treatments. Metastasis-directed therapy for oligometastatic disease Although promising, additional data from prospective studies are required to determine the role of metastasis-directed therapy (MDT) for males with oligometastatic disease, especially how it should be integrated with androgen deprivation therapy (ADT) and novel agents like androgen receptor pathway inhibitors. Decisions regarding treatment must be individualized, taking into account a wide range of factors (eg, site of metastasis, disease-free interval, patient age, PSA kinetics, patient comorbidities etc). After prior denitive therapy, patients will occasionally present with metachronous oligometastatic disease, which most of the time is diagnosed using positron emission tomography (PET CT) with more sensitive prostate-specic radiotracers. The following data are available regarding the benet of metastasis-directed therapy for males with oligometastatic prostate cancer: • In an early phase II trial (STOMP), 62 asymptomatic patients with a biochemical recurrence after primary denitive treatment, one to three metastases on conventional (not PET-based) imaging, and a serum testosterone >50 ng/mL were randomly assigned to observation alone or to metastasis-directed therapy . In the latest analysis, presented at the 2020 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, the time to initiation of ADT based on progression of symptoms, progression to more than three metastases, or progression of known lesions was signicantly longer in patients who received initial metastasis-directed therapy (ve-year ADT-free survival 34 versus 8 percent, HR 0.57, 95% CI 0.380.84), although ve-year overall survival was 8 similarly high in both groups (85 percent) Systemic Therapy Oligometastasis Oligorecurrence MDT to all disease MDT to recurrent disease MDT to progressive disease MDT to symptomatic disease Oligiprogression Widely Matastatic Disease PET CT imaging shows right sacroiliac bone metastasis corresponding to the small focus of increased radiotracer uptake. (B) Metastasis-directed stereotactic body radiotherapy was administered at 40 Gy in 5 fractions; isodoses of 95%, 90%, 50%, and 30% (yellow, green, light blue, and violet lines, respectively) indicate the small irradiated volume (isodose of 95%) and the rapid fall of dose outside the target (isodose of 30%). (C) PET CT imaging showing no radiotracer uptake to the right sacroiliac bone metastasis after irradiation UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE

13 • Additional information is available from two uncontrolled phase II trials, both of which used prostate-specic PET scanning: • In one trial 72 patients with a rising PSA after denitive local therapy and negative conventional imaging, who all then underwent prostate-specic membrane antigen (PSMA)- PET/CT to detect and localize oligometastatic disease . Overall, 38 were found to have a PSMAdetected oligometastatic recurrence that was thought amenable to metastasis-directed therapy, 92 percent of which were nodal only, the remainder skeletal. At a median follow-up of 15.9 months, 22 percent of the 37 patients who were treated with SBRT (n = 27) or surgery (n = 10) normalized their PSA. Median time to PSA progression (freedom from ADT) was 17.7 months. • The OLIGOPELVIS GETUG P076 trial studied highdose salvage radiotherapy plus short-term androgen deprivation therapy in 67 patients with isolated oligometastatic pelvic node relapse detected by PET CT after treatment for localized disease. 35 had previously received prostate radiotherapy. After a median follow-up of 49 months, median biochemical relapse-free survival was 25.9 months, 58 percent remained progression free at 9-10 three years. The benets of stereotactic body RT (SBRT) for treatment of oligometastatic disease can be illustrated by the following reports: • The phase II Observation versus Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer trial (The ORIOLE Phase 2 Randomized Clinical Trial) randomly assigned 54 males with recurrent, hormone-sensitive, oligometastatic prostate cancer (three or fewer lesions as determined by conventional imaging) to observation and no further treatment for six months or to SBRT to the metastatic sites outside of the prostate that were detected by conventional imaging. Six months after randomization, progression (dened as a PSA increase, radiographic progression on conventional imaging, or symptomatic decline) was observed in 19 percent of those undergoing SBRT versus 61 percent of the control group. The patients randomized to SBRT all underwent PET CT using highly sensitive, prostate cancerspecic PSMA-based radionuclides at baseline and at six months. • In another randomized phase II study (SABRCOMET) of 99 patients with cancer of a variety of primary tumors (16 with prostate cancer) and up to ve metastatic lesions to any site (65 had bone metastases), when compared with palliative care alone (which included standard-fractionation RT with or without systemic chemotherapy), the use of SBRT for treatment of oligometastatic disease was associated with a signicant improvement in ve-year overall survival (42 versus 18 percent, p = 0.006) • A meta-analysis of 23 observational studies of SBRT for oligometastatic prostate cancer recurrence concluded that local control was excellent, with minimal severe or late toxicity, and among the ve studies reporting this outcome, the average duration of ADT-free survival was approximately 5-6 20 months. ADT-free survival UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE

14 Genetic and genomic classication, DNA biomarkers and circulating tumor DNA may add to the management pathway of oligometastatic prostate carcinoma. A sub-analysis was conducted on pooled data from STOMP and ORIOLE trials to assess the effectiveness of a high-risk mutational signature in stratifying outcomes after MDT, which was dened as the presence of pathogenic somatic mutations within ATM, BRCA1/2, Rb1, and TP53. Long-term results showed that metastasis directed therapy (MDT) benetted both patients with and without a high-risk mutation, although those individuals without a high-risk mutation treated with MDT had superior outcomes (median PFS 13.4 11 months versus 7.5 months. These ndings suggest that selected patients with oligometastatic or oligorecurrent disease lacking a high-risk mutation could potentially de-escalate treatment using MDT alone. Conversely, patients with high-risk mutations should be contemplated for an intensied targeted approach. Currently, several phase II and phase III studies recruit patients with recurrent OMPC to assess combinations of MDT and systemic therapy options, 12 such as ADT plus abiraterone + apalutamide. POSTCARD will determine the effect of durvalumab 13 in addition to MDT and Stereotactic Body Radiotherapy with or without darolutamide for OligoRecurrent Prostate Cancer (DART), which will 14 study the combination of darolutamide with SBRT. A phase III trial will test the role of apalutamide alone or in combination with MDT in patients with recurrent 15 hormone sensitive prostate cancer. Common SBRT recommended fractionations used are 35 Gy in 5 fractions for spinal lesions and 30 Gy in 3 fractions for extra spinal bone metastases. For the treatment of nodal disease, elective nodal irradiation (45 Gy in 25 fractions ) with a boost to suspicious lymph nodes ( 2.2-2.7Gy per fraction) or SBRT doses of 35 Gy in 5 fractions are 16-17 recommended. Study STOMP ORIOLE SABECOMET N 62 54 16 Nodal Recurrence Number of mets Treatment arms Type of treatment Type of imaging Media follow-up Results 55% <3 extracranial Observation vs. metastasesdirected therapies SBRT (n=25) sLND (n=6) Choline PET/CT 5.3 years Improved ADT-free survival (HR: 0.53: p,0.05) 61% Observation vs. metastasesdirected therapies SBRT Conventional imaging (for study includion) = PSMA PET/CT 18.8 months SBRT improved progression -free survival 4 1-5 SOC vs. SOC+ SABR SBRT Conventional imaging + PET 51 months SBRT improved overall survival <3 Example of (A) a patient with solitary oligorecurrent pelvic nodal relapse detected via PSMA-PET and (B) the corresponding imaging matched SBRT plan capture (30 Gy in 3 fractions) C) a patient with multiple (3) oligorecurrent pelvic and low paraaortic nodal disease in PSMA-PET and (D) the matched radiotherapy to the extended eld pelvic nodes (45 Gy in 25 fractions) with a simultaneous integrated boost to 65 Gy UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE

15 References: 1. NCCN Clinical Practice Guidelines in Oncology, National ComprehensiveCancer Network, 2022. Available at: https://www.nccn.org 2. Supiot S, Vaugier L, Pasquier D, et al. OLIGOPELVIS GETUG P07, a multicenter phase II trial of combined high-dose salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses in prostate cancer. Eur Urol 2021;80:405–414. 3. HellmanS, WeichselbaumRR. Oligometastases. J Clin Oncol. 1995 Jan;13(1):8–10. 4. Ost P, Jereczek-Fossa BA, Van As N, et al. Pattern of Progression after Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Nodal Recurrences. Clin Oncol (R Coll Radiol) 2016;28:e115–20. 5. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6(5):650. 6. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial.J Clin Oncol. 2020;38(25):2830. Epub 2020 Jun 2. 7. Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Recurrence: A Meta-analysis.Am J Clin Oncol. 2020;43(2):73. 8. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): Fiveyear results of a randomized phase II trial J Clin Oncol. 2020;38S:ASCO #10. 9. Curative-intent Metastasis-directed Therapies for Molecularlydened Oligorecurrent Prostate Cancer: A Prospective Phase II Trial Testing the Oligometastasis Hypothesis.Eur Urol. 2021;80(3):374. Epub 2021 Mar 6. 10. OLIGOPELVIS GETUG P07, a Multicenter Phase II Trial of Combined High-dose Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Node Relapses in Prostate Cancer. Eur Urol. 2021;80(4):405. Epub 2021 Jul 8. 11. Deek, M.P et al. Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials. J. Clin. Oncol. 2022, 40, 3377–3382 12. NCT03902951 Antiandrogen Therapy and SBRT in Treating Patients with Recurrent Metastatic Prostate Cancer. Available onlinehttps://clinicaltrials.gov/ct2/show/NCT03902951 13. NCT03795207 Prostate Cancer with Oligometastatic Relapse: Combining Stereotactic Ablative Radiotherapy and Durvalumab (MEDI4736) (POSTCARD)Available online: https://clinicaltrials.gov/ct2/show/NCT0379527 14. NCT04641078 Stereotactic Body Radiotherapy with or without Darolutamide for OligoRecurrent Prostate Cancer (DART)Available online https://clinicaltrials.gov/ct2/ show/NCT04641078 15. Ct04423211 Treating Prostate Cancer that Has Come Back after Surgery with Apalutamide and Targeted Radiation Using PET/CT Imagi Available online: https://clinicaltrials.gov/ ct2/show/NCT04423211 16. Node Oligorecurrence in Prostate Cancer: A Challenge, Almudena Zapatero et al 17. Recommendations for radiation therapy in oligometastatic prostate cancer: ESTRO_ACROP Delphi consenus, October 2022 In conclusion, oligometastatic prostate cancer should be viewed as an opportunity to alter the disease trajectory of prostate carcinoma. These patients should be managed jointly in a multidisciplinary team setting for best outcomes. Radiotherapy has a proven role to offer cure and delay disease progression. UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE