Tag: Prostate Cancer

NUBEQA® Combination Improves Overall Survival in Metastatic Hormone Sensitive Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of Prostate cancer will be diagnosed in 2022 and 34,500 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention.

The first-generation NonSteroidal Anti-Androgen (NSAA) agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. CASODEX® is often prescribed along with GnRH (Gonadotropin-Releasing Hormone) agonists for metastatic disease, or as a single agent second line hormonal therapy for those who had progressed on LHRH agonists.

NUBEQA® (Darolutamide) is a potent second-generation Androgen Receptor (AR) inhibitor with a new chemical structure and has a high affinity to the AR. NUBEQA® does not cross the blood-brain barrier and for this reason has a favorable safety and tolerability profile in prespecified adverse events such as seizures, when compared with other second-generation AR inhibitors such as ERLEADA® (Apalutamide) and XTANDI® (Enzalutamide). It has been associated with increased Overall Survival (OS) among patients with non-metastatic Castration-Resistant Prostate Cancer (CRPC) and has been approved by the FDA for this indication. Whether a combination of NUBEQA®, in combination with Androgen Deprivation Therapy (ADT), and Docetaxel would increase survival among patients with metastatic Hormone-Sensitive Prostate Cancer, is unknown.

ARASENS is an international, randomized, double-blind, placebo-controlled, Phase III trial, which evaluated the efficacy and safety of NUBEQA® (Darolutamide) added to Androgen Deprivation Therapy (ADT) and Docetaxel in patients with metastatic Hormone Sensitive Prostate Cancer. In this study, a total of 1306 patients were randomly assigned 1:1 to receive NUBEQA® (N=651) or placebo (N=655), both in combination with ADT and Docetaxel. All the patients received ADT (either a Luteinizing Hormone Releasing Hormone (LHRH} agonist or antagonist) or underwent Orchiectomy within 12 weeks before randomization and received six cycles of Docetaxel 75 mg/m2 IV given on Day 1 every 21 days, with Prednisone or Prednisolone. Patients received LHRH agonists along with a first-generation anti-androgen agent for at least 4 weeks before randomization to help prevent a tumor flare, and the anti-androgen agent was discontinued before randomization. Patients were then randomly assigned to receive either NUBEQA® 600 mg orally twice daily or matched placebo, and treatment was continued until disease progression or unacceptable toxicities.

Eligible patients had biopsy proven prostate cancer with bone metastases and had to be candidates for ADT and Docetaxel. Patients with regional lymph node involvement only (N1, below the aortic bifurcation) or if they had received ADT more than 12 weeks before randomization, second-generation Androgen Receptor pathway inhibitors, chemotherapy, or immunotherapy for prostate cancer before randomization, or radiotherapy within 2 weeks before randomization, were excluded. The median age was 67 years and both treatment groups were well balanced. All patients had metastatic disease at baseline, 78% of the patients had a Gleason score of 8 or greater, about 80% had bone metastases (Stage M1b) and 18% had visceral metastases (Stage M1c). The Primary end point was Overall Survival (OS) and Secondary end points included were time to Castration-Resistant Prostate Cancer, time to pain progression, symptomatic Skeletal Event-Free Survival and time to initiation of subsequent systemic antineoplastic therapy, as well as Safety. The median follow up for Overall Survival was 43 months.

The median Overall Survival was not estimable in the NUBEQA® group versus 48.9 months in the placebo group. The addition of NUBEQA® to the combination with ADT and Docetaxel reduced the risk of death by 32%, compared to the placebo group (HR=0.68; P<0.001). This OS benefit was noted across most subgroups. Further, the significant OS benefit with the addition of NUBEQA® was observed, despite receipt of subsequent life-prolonging systemic therapies such as different Androgen-Receptor pathway inhibitors by 75.6% of patients in the placebo control group. The OS at 4 years was 62.7% in the NUBEQA® group and 50.4% in the placebo group.

With regard to Secondary endpoints, the addition of NUBEQA® to ADT and Docetaxel demonstrated consistent benefits. The time to development of Castration-Resistant Prostate Cancer was significantly longer in the NUBEQA® group (HR=0.36; P<0.001), the time to pain progression was also significantly longer in the NUBEQA® group (HR=0.79; P=0.01), as well as symptomatic Skeletal Event-Free Survival (HR=0.61; P<0.001). Further, the time to the initiation of subsequent systemic antineoplastic therapy was also significantly longer in the NUBEQA® group (HR=0.39; P<0.001). Adverse events were similar in the two groups.

The authors concluded that among patients with metastatic Hormone Sensitive Prostate Cancer, the addition of NUBEQA® to Androgen Deprivation Therapy and Docetaxel resulted in significantly longer Overall Survival, as well as improvement in key Secondary end points, with no increase in adverse events.

Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. Smith MR, Hussain Saad F, et al. for the ARASENS Trial Investigators. N Engl J Med 2022;386:1132-1142.

Late Breaking Abstract – ESMO 2022: Apalutamide Plus Androgen Deprivation Therapy in Biochemically Relapsed Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of prostate cancer will be diagnosed in 2022, and 34,500 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.

The major source of PSA (Prostate Specific Antigen) is the prostate gland, and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy there is a gradual decline in PSA, before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent disease. Patient’s with biochemically relapsed prostate cancer following local therapy, and a short PSA doubling time, are at risk for distant metastases.

ERLEADA® (Apalutamide) is an orally administered Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. Apalutamide is presently approved for the treatment of patients with metastatic Castration Sensitive Prostate Cancer and non-metastatic Castration Resistant Prostate Cancer. ZYTIGA® (Abiraterone) is a selective, irreversible inhibitor of CYP 17A1 enzyme and decreases androgen biosynthesis in the testes, adrenal glands, and prostate-tumor tissue. Both Apalutamide and Abiraterone plus prednisone have been shown to prolong Overall Survival in the metastatic prostate cancer.

The purpose of this study was to evaluate if intensification of Androgen Deprivation Therapy (ADT) prolongs biochemical Progression Free Survival (PFS), in patients with biochemically relapsed prostate cancer. PRESTO is a randomized, open-label Phase III trial, in which 504 prostate cancer patients who had radical prostatectomy were included. Study patients had biochemical recurrence (PSA more than 0.05 ng/mL), a PSA doubling time of 9 months or less, and without distant metastases on conventional imaging (CT and Bone scan). Patients were randomized 1:1:1 to receive a finite 52-week treatment course with ADT alone (N=167), ADT plus Apalutamide (N=168), or ADT plus Apalutamide plus Abiraterone/Prednisone (N=169). Patients were stratified by PSA doubling time (less than 3 months versus 3-9 months) and patients were followed up following treatment completion with mostly lab assessment until PSA progression, at which point, treatment was per investigator discretion. Patient and disease characteristics at baseline were well balanced among the 3 study groups. The median age was 67 years and 84% of patients were white. The median PSA at baseline was 1.77 ng/mL. The PSA doubling time was less than 3 months for 26% of patients and between 3 and 9 months for 74% of patients. The median time between radical prostatectomy and baseline was 4.4 years. Overall, 85% of patients had prior radiation and 42% of patients had prior ADT. The Primary endpoint of the study was to compare biochemical Progression Free Survival (defined as increase in serum PSA of more than 0.2 ng/mL following treatment) in each experimental group with ADT alone. Secondary endpoints included safety, patient-reported Quality of Life (QOL), time to testosterone recovery (more than 50 ng/dL following treatment completion), Metastasis-Free Survival, and time to castration resistance.

The first planned interim analysis at a median follow-up of 21.5 months showed that both study groups significantly prolonged biochemical PFS compared to the control group. The median biochemical (PSA) PFS was 24.9 months with Apalutamide plus ADT versus 20.3 months with ADT alone (HR=0.52; P=0.00047). The median biochemical PFS was 26.0 months with ADT plus Apalutamide plus Abiraterone/Prednisone versus 20.0 months with ADT alone (HR=0.48; P=0.00008). A preplanned subgroup analysis based on stratification by PSA doubling time showed a consistent benefit in both study groups, compared to the control group, regardless of the length of PSA doubling time. The median time to testosterone recovery following treatment completion was 3.9 months with ADT alone, 3.8 months with Apalutamide plus ADT and 4.7 months with ADT plus Apalutamide plus Abiraterone/Prednisone. There was an increase in the incidence of adverse events with the addition of Abiraterone.

It was concluded that intensifying Androgen Receptor blockade with Apalutamide plus Androgen Deprivation Therapy prolongs biochemical PFS with a manageable safety profile and without impacting time to testosterone recovery, following a finite duration of treatment. The authors added that intensification of Androgen Receptor blockade should be considered in high-risk biochemically relapsed prostate cancer.

LBA63 – PRESTO: A phase III, open-label study of androgen annihilation in patients (pts) with high-risk biochemically relapsed prostate cancer (AFT-19). Aggarwal R, Heller G, Hillman D, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089

LYNPARZA® Superior to Next-Generation Hormonal Drug in CRPC Patients with Homologous Recombination Repair Gene Alterations

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of Prostate cancer will be diagnosed in 2022 and 34,500 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The malignant transformation of prostatic epithelial cell as well as the development of CRPC has been attributed to deleterious alterations in a variety of genes including loss-of-function alterations in Homologous Recombination Repair (HRR) genes.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes that recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1, BRCA2, PALB2, CHEK2 and ATM genes. Mutations in these genes predispose an individual to develop malignant tumors. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death. LYNPARZA® (Olaparib) is a first-in-class PARP inhibitor and blocks DNA damage response in tumors harboring a deficiency in Homologous Recombination Repair, as is noted in those with mutations such as BRCA1 and/or BRCA2. LYNPARZA® showed promising results in a Phase II trial (TOPARP), when given as monotherapy, in patients with BRCA1/2 or ATM gene-mutated mCRPC, who had received a prior Taxane-based chemotherapy, and at least one newer hormonal agent (ZYTIGA® or XTANDI®).

PROfound is a prospective, multicentre, randomized, open-label, Phase III trial in which the efficacy and safety of LYNPARZA® was compared with physician’s choice of either XTANDI® or ZYTIGA® in two groups of patients with mCRPC, who had progressed on prior treatment with new hormonal anticancer treatments, and had a qualifying tumor mutation in one of 15 genes involved in the Homologous Recombination Repair (HRR) pathway. Patients in Cohort A (N=245) had alterations in BRCA1, BRCA2 or ATM genes while those in Cohort B (N=142) had alterations in any one of 12 other genes known to be involved in DNA repair which included BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L. Patients were randomized 2:1 within each cohort to receive LYNPARZA® 300 mg orally BID or physician’s choice of XTANDI® 160 mg orally QD or ZYTIGA® 1000 mg orally QD along with Prednisone 5 mg orally BID. Patient characteristics were well-balanced between arms in each treatment group, median patient age was 68 years, approximately 25% of patients had de novo metastatic disease, about 65% of patients received prior Taxane therapy and more than 20% had received two lines of chemotherapy. Patients were allowed to cross over to LYNPARZA® upon progression. The Primary endpoint was radiographic Progression-Free Survival (rPFS) in Cohort A, assessed by Blinded Independent Central Review (BICR).

The authors had previously reported that in Cohort A, the median PFS was 7.4 months with LYNPARZA®, compared to 3.5 months in the control group (HR=0.34, P<0.0001). This represented a 66% greater delay in disease progression compared to hormonal therapy. The interim Overall Survival analysis in Cohort A showed that median OS was 18.5 months with LYNPARZA® compared to 15 months with control drug treatment (HR=0.64, P=0.0173). In Cohort A, the Objective Response Rate (ORR) was 33.3% with LYNPARZA® compared with 2.3% with control drug therapies (P<0.0001).

The authors in this publication reported the results of the prespecified Secondary endpoints, which included pain, Health-Related Quality of Life (HRQOL), symptomatic Skeletal-Related Events, and time to first opiate use for cancer-related pain in Cohort A group of patients. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Cohort A included 245 patients with alterations in BRCA1, BRCA2, or ATM genes, of whom 162 patients received the investigational agent LYNPARZA®, and 83 patients received control drug. The median duration of follow up at data cutoff was 6.2 months for all LYNPARZA® group patients and 3.5 months for the control group patients. The median time to pain progression was significantly longer with LYNPARZA® and was Not Reached in the LYNPARZA® group versus 9.92 months in the control group (HR=0.44; P=0.019). Pain interference scores were also significantly better in the LYNPARZA® group (difference in overall adjusted mean change from baseline score −0.85; nominal P=0.0004). Median time to progression of pain severity was Not Reached in either group. Among patients who had not used opiates at baseline (113 in the LYNPARZA® group, 58 in the control group), median time to first opiate use for cancer-related pain was 18.0 months in the LYNPARZA® group versus 7.5 months in the control group (HR=0.61; nominal P=0.044).

The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the LYNPARZA® group than the control group (10% versus 1% respectively; odds ratio=8.32; nominal P=0.0065). The median time to first symptomatic Skeletal-Related Event was not reached for either treatment group and the proportions of patients remaining free of symptomatic Skeletal-Related Events were 89.5% versus 77.1% at 6 months and 77.6% versus 53.6% at 12 months, in the LYNPARZA® and control groups respectively.

It was concluded that LYNPARZA® was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs, in patients with metastatic Castration-Resistant Prostate Cancer and Homologous Recombination Repair gene alterations, who had disease progression after a previous next-generation hormonal drug. The authors added that the study findings support the clinical benefit of improved radiographical Progression Free Survival and Overall Survival identified in PROfound trial.

Pain and health-related quality of life with olaparib versus physician’s choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial. Thiery-Vuillemin A, de Bono J, Hussain M, et al. The Lancet Oncology March 2022;23:393-405.

Genetically Adjusted PSA Values May Improve the Accuracy of Prostate Cancer Detection

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of prostate cancer will be diagnosed in 2022 and 34,500 men will die of the disease.

PSA is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on Prostate Specific Antigen (PSA) levels remains controversial and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer with PSA should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer. PSA elevation can be associated with several non-malignant conditions such as older age, infection, inflammation and Benign Prostatic Hypertrophy.

The researchers in this study hypothesized that the accuracy of PSA screening for prostate cancer could be improved by accounting for genetic factors that cause changes in PSA levels not associated with prostate cancer. The aim of this study was to characterize genetic determinants of PSA levels in cancer-free men, in order to personalize prostate cancer screening.

The researchers conducted a large Genome Wide Association Study of PSA, to improve Prostate cancer screening, by accounting for genetic factors that cause noncancer-related variations in PSA levels, thereby personalizing prostate cancer screening. This study involved 95,768 men without a diagnosis prostate cancer from the US, UK and Sweden. The researchers identified 128 PSA-related variants across the genome, including 82 novel variants that were not previously recognized, and created a polygenic score for PSA levels. This polygenic score provided a cumulative measure of each individual’s genetic predisposition to high PSA levels.

The authors validated the polygenic score by applying the score to PSA values of 5,725 individuals enrolled in the Prostate Cancer Prevention Trial (PCPT) and the 25,917 individuals enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The analysis showed that the score explained 7.3% of variation in baseline PSA values in PCPT trial and 8.8% of variation in baseline PSA values in the SELECT cohort, and the polygenic score was not associated with prostate cancer in both the prevention trials, confirming that the score reflected benign PSA variation.

The researchers next tested the ability of the polygenic score’s ability to improve detection of clinically significant prostate cancer and reduce over diagnosis among a real-world cohort at Kaiser Permanente. They adjusted each individual’s PSA values based on his unique polygenic score and estimated the impact of this adjustment on the PSA thresholds that trigger biopsy referrals. The authors estimated that by substituting the patient’s polygenic score for measured PSA values, 19.6% of negative biopsies in men without prostate cancer potentially could have been avoided, and 15.7% of biopsies could have been avoided in men who had indolent, low-grade prostate cancer (Gleason score <7), which represented 71% of all men.

The researchers then evaluated whether genetically adjusted polygenic score would better detect aggressive prostate cancer (Gleason score 7, PSA 10 ng/mL, T3-T4 stage and/or distant nodal metastases). It was noted that in both the PCPT and the SELECT cohorts, polygenic score was more strongly associated with aggressive prostate cancer than measured unadjusted PSA values. The polygenic score also exceeded the performance of the 269-variant genetic risk score.

The authors from this study concluded that genetically adjusted PSA (polygenic score) could reduce unnecessary testing and overdiagnosis of low-risk prostate cancer, and increase detection of aggressive tumors and thus make PSA a more useful and accurate screening biomarker. The researchers pointed out that the population studied, were primarily European descent, and the polygenic score will need to be validated in more diverse populations.

Genetic determinants of PSA levels improve prostate cancer screening. Kachuri L, Graff RE, Berndt SI, et al. Presented at: AACR Annual Meeting 2022; April 8-13; New Orleans, Louisiana. Abstract 1441/8.

FDA Approves PSMA Targeted Therapy for Metastatic Castrate Resistant Prostate Cancer

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SUMMARY: The FDA on March 23, 2022, approved PLUVICTO® (Lutetium Lu 177 vipivotide tetraxetan) for the treatment of adult patients with Prostate-Specific Membrane Antigen (PSMA)-positive metastatic Castration-Resistant Prostate Cancer (mCRPC), who had been treated with Androgen Receptor (AR) pathway inhibition and Taxane-based chemotherapy. The FDA also approved LOCAMETZ® (Gallium Ga 68 gozetotide), a radioactive diagnostic agent for Positron Emission Tomography (PET) of PSMA-positive lesions, including selection of patients with metastatic prostate cancer for whom PLUVICTO® PSMA-directed therapy is indicated. LOCAMETZ® is the first radioactive diagnostic agent approved for patient selection in the use of a radioligand therapeutic agent.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. Among those patients without metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. Progression to Castration Resistant Prostate Cancer (CRPC) often manifests itself with a rising PSA (Prostate Specific Antigen) and the estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

Prostate-Specific Membrane Antigen (PSMA) is a Type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer.

PLUVICTO® is a radiopharmaceutical that targets PSMA. It is comprised of Lutetium-177, a cytotoxic radionuclide , linked to the ligand PSMA-617, a small molecule designed to bind with high affinity to PSMA. Radioligand therapy with PLUVICTO® targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell. The antitumor activity and safety PLUVICTO® have been established previously in a Phase II study (Lancet Oncol. 2018;19:825-833).

VISION is an international, randomized, open-label Phase III study in which the benefit of PLUVICTO® was evaluated in men with PSMA-positive mCRPC, previously treated with second generation Androgen Receptor signaling pathway inhibitor (XTANDI® -Enzalutamide or ZYTIGA®-Abiraterone acetate), and 1 or 2 taxane chemotherapy regimens. In this trial, 831 patients were randomized 2:1 to receive PLUVICTO® 7.4 GBq (200 mCi) every 6 weeks for up to a total of 6 cycles plus Standard of Care as determined by the treating physician (N=551), or Standard of Care only (N=280). Both treatment groups were well balanced and this trial excluded patients treated with XOFIGO® (Radium-223). All enrolled patients received a GnRH analog or had prior bilateral orchiectomy and had a castrate level or serum/plasma testosterone of lower than 50ng/dL. PET imaging with LOCAMETZ® was used to determine PSMA positivity by central review. PSMA-positive mCRPC was defined as having at least one tumor lesion with LOCAMETZ® uptake greater than normal liver. Patients were excluded from enrollment if any lesions exceeding certain size criteria in the short axis had uptake less than or equal to uptake in normal liver. The Primary endpoints were radiographic Progression Free Survival (rPFS) by Independent Central Review (ICR) and Overall Survival (OS). Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), and time to first Symptomatic Skeletal Event (SSE). The median study follow up was 20.9 months.

Treatment with the combination of PLUVICTO® plus Standard of Care resulted in a statistically significant improvement in the Primary endpoints of Overall Survival and radiographic Progression Free Survival. PLUVICTO® plus Standard of Care significantly improved rPFS by 60%, compared to Standard of Care alone (median rPFS 8.7 versus 3.4 months, HR=0.40; P<0.001). The median OS was also significantly improved by 38% in the study group (median OS 15.3 versus 11.3 months, HR=0.62; P<0.001). All key secondary endpoints including Objective Response Rate, Disease Control Rate, and time to first Symptomatic Skeletal Event were statistically significant, and in favor of PLUVICTO® plus Standard of Care. The most common adverse reactions in patients receiving PLUVICTO® were fatigue, dry mouth, nausea, decreased appetite, constipation, anemia, lymphopenia, thrombocytopenia, hypocalcemia and hyponatremia.

It was concluded that radioligand therapy with PLUVICTO® significantly improved radiographic Progression Free Survival and Overall Survival when added to Standard of Care, compared with Standard of Care alone, in men with PSMA-positive metastatic Castration Resistant Prostate Cancer.

Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. Sartor O, de Bono J, Chi KN, et al. N Engl J Med 2021; 385:1091-1103.

LYNPARZA® Superior to Next-Generation Hormonal Drug in CRPC Patients with Homologous Recombination Repair Gene Alterations

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of Prostate cancer will be diagnosed in 2022 and 34,500 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The malignant transformation of prostatic epithelial cell as well as the development of CRPC has been attributed to deleterious alterations in a variety of genes including loss-of-function alterations in Homologous Recombination Repair (HRR) genes.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes that recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1, BRCA2, PALB2, CHEK2 and ATM genes. Mutations in these genes predispose an individual to develop malignant tumors. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

LYNPARZA® (Olaparib) is a first-in-class PARP inhibitor and blocks DNA damage response in tumors harboring a deficiency in Homologous Recombination Repair, as is noted in those with mutations such as BRCA1 and/or BRCA2. LYNPARZA® showed promising results in a Phase II trial (TOPARP), when given as monotherapy, in patients with BRCA1/2 or ATM gene-mutated mCRPC, who had received a prior Taxane-based chemotherapy, and at least one newer hormonal agent (ZYTIGA® or XTANDI®).

PROfound is a prospective, multicentre, randomized, open-label, Phase III trial in which the efficacy and safety of LYNPARZA® was compared with physician’s choice of either XTANDI® or ZYTIGA® in two groups of patients with mCRPC, who had progressed on prior treatment with new hormonal anticancer treatments, and had a qualifying tumor mutation in one of 15 genes involved in the Homologous Recombination Repair (HRR) pathway. Patients in Cohort A (N=245) had alterations in BRCA1, BRCA2 or ATM genes while those in Cohort B (N=142) had alterations in any one of 12 other genes known to be involved in DNA repair which included BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L. Patients were randomized 2:1 within each cohort to receive LYNPARZA® 300 mg orally BID or physician’s choice of XTANDI® 160 mg orally QD or ZYTIGA® 1000 mg orally QD along with Prednisone 5 mg orally BID. Patient characteristics were well-balanced between arms in each treatment group, median patient age was 68 years, approximately 25% of patients had de novo metastatic disease, about 65% of patients received prior Taxane therapy and more than 20% had received two lines of chemotherapy. Patients were allowed to cross over to LYNPARZA® upon progression. The Primary endpoint was radiographic Progression-Free Survival (rPFS) in Cohort A, assessed by Blinded Independent Central Review (BICR).

The authors had previously reported that in Cohort A, the median PFS was 7.4 months with LYNPARZA®, compared to 3.5 months in the control group (HR=0.34, P<0.0001). This represented a 66% greater delay in disease progression compared to hormonal therapy. The interim Overall Survival analysis in Cohort A showed that median OS was 18.5 months with LYNPARZA® compared to 15 months with control drug treatment (HR=0.64, P=0.0173). In Cohort A, the Objective Response Rate (ORR) was 33.3% with LYNPARZA® compared with 2.3% with control drug therapies (P<0.0001).

The authors in this publication reported the results of the prespecified Secondary endpoints, which included pain, Health-Related Quality of Life (HRQOL), symptomatic Skeletal-Related Events, and time to first opiate use for cancer-related pain in Cohort A group of patients. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Cohort A included 245 patients with alterations in BRCA1, BRCA2, or ATM genes, of whom 162 patients received the investigational agent LYNPARZA®, and 83 patients received control drug. The median duration of follow up at data cutoff was 6.2 months for all LYNPARZA® group patients and 3.5 months for the control group patients.

The median time to pain progression was significantly longer with LYNPARZA® and was Not Reached in the LYNPARZA® group versus 9.92 months in the control group (HR=0.44; P=0.019). Pain interference scores were also significantly better in the LYNPARZA® group (difference in overall adjusted mean change from baseline score −0.85; nominal P=0.0004). Median time to progression of pain severity was Not Reached in either group. Among patients who had not used opiates at baseline (113 in the LYNPARZA® group, 58 in the control group), median time to first opiate use for cancer-related pain was 18.0 months in the LYNPARZA® group versus 7.5 months in the control group (HR=0.61; nominal P=0.044).

The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the LYNPARZA® group than the control group (10% versus 1% respectively; odds ratio=8.32; nominal P=0.0065). The median time to first symptomatic Skeletal-Related Event was not reached for either treatment group and the proportions of patients remaining free of symptomatic Skeletal-Related Events were 89.5% versus 77.1% at 6 months and 77.6% versus 53.6% at 12 months, in the LYNPARZA® and control groups respectively.

It was concluded that LYNPARZA® was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs, in patients with metastatic Castration-Resistant Prostate Cancer and Homologous Recombination Repair gene alterations, who had disease progression after a previous next-generation hormonal drug. The authors added that the study findings support the clinical benefit of improved radiographical Progression Free Survival and Overall Survival identified in PROfound trial.

Pain and health-related quality of life with olaparib versus physician’s choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial. Thiery-Vuillemin A, de Bono J, Hussain M, et al. Published:February 11, 2022. DOI:https://doi.org/10.1016/S1470-2045(22)00017-1

NUBEQA® Combination Improves Overall Survival in Metastatic Hormone Sensitive Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of Prostate cancer will be diagnosed in 2022 and 34,500 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention.

The first-generation NonSteroidal Anti-Androgen (NSAA) agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. CASODEX® is often prescribed along with GnRH (Gonadotropin-Releasing Hormone) agonists for metastatic disease, or as a single agent second line hormonal therapy for those who had progressed on LHRH agonists.

NUBEQA® (Darolutamide) is a potent second-generation Androgen Receptor (AR) inhibitor with a new chemical structure and has a high affinity to the AR. NUBEQA® does not cross the blood-brain barrier and for this reason has a favorable safety and tolerability profile in prespecified adverse events such as seizures, when compared with other second-generation AR inhibitors such as ERLEADA® (Apalutamide) and XTANDI® (Enzalutamide). It has been associated with increased Overall Survival (OS) among patients with non-metastatic Castration-Resistant Prostate Cancer (CRPC) and has been approved by the FDA for this indication. Whether a combination of NUBEQA®, in combination with Androgen Deprivation Therapy (ADT), and Docetaxel would increase survival among patients with metastatic Hormone-Sensitive Prostate Cancer, is unknown.

ARASENS is an international, randomized, double-blind, placebo-controlled, Phase III trial, which evaluated the efficacy and safety of NUBEQA® (Darolutamide) added to Androgen Deprivation Therapy (ADT) and Docetaxel in patients with metastatic Hormone Sensitive Prostate Cancer. In this study, a total of 1306 patients were randomly assigned 1:1 to receive NUBEQA® (N=651) or placebo (N=655), both in combination with ADT and Docetaxel. All the patients received ADT (either a Luteinizing Hormone Releasing Hormone (LHRH} agonist or antagonist) or underwent Orchiectomy within 12 weeks before randomization and received six cycles of Docetaxel 75 mg/m2 IV given on Day 1 every 21 days, with Prednisone or Prednisolone. Patients received LHRH agonists along with a first-generation anti-androgen agent for at least 4 weeks before randomization to help prevent a tumor flare, and the anti-androgen agent was discontinued before randomization. Patients were then randomly assigned to receive either NUBEQA® 600 mg orally twice daily or matched placebo, and treatment was continued until disease progression or unacceptable toxicities.

Eligible patients had biopsy proven prostate cancer with bone metastases and had to be candidates for ADT and Docetaxel. Patients with regional lymph node involvement only (N1, below the aortic bifurcation) or if they had received ADT more than 12 weeks before randomization, second-generation Androgen Receptor pathway inhibitors, chemotherapy, or immunotherapy for prostate cancer before randomization, or radiotherapy within 2 weeks before randomization, were excluded. The median age was 67 years and both treatment groups were well balanced. All patients had metastatic disease at baseline, 78% of the patients had a Gleason score of 8 or greater, about 80% had bone metastases (Stage M1b) and 18% had visceral metastases (Stage M1c). The Primary end point was Overall Survival (OS) and Secondary end points included were time to Castration-Resistant Prostate Cancer, time to pain progression, symptomatic Skeletal Event-Free Survival and time to initiation of subsequent systemic antineoplastic therapy, as well as Safety. The median follow up for Overall Survival was 43 months.

The median Overall Survival was not estimable in the NUBEQA® group versus 48.9 months in the placebo group. The addition of NUBEQA® to the combination with ADT and Docetaxel reduced the risk of death by 32%, compared to the placebo group (HR=0.68; P<0.001). This OS benefit was noted across most subgroups. Further, the significant OS benefit with the addition of NUBEQA® was observed, despite receipt of subsequent life-prolonging systemic therapies such as different Androgen-Receptor pathway inhibitors by 75.6% of patients in the placebo control group. The OS at 4 years was 62.7% in the NUBEQA® group and 50.4% in the placebo group.

With regard to Secondary endpoints, the addition of NUBEQA® to ADT and Docetaxel demonstrated consistent benefits. The time to development of Castration-Resistant Prostate Cancer was significantly longer in the NUBEQA® group (HR=0.36; P<0.001), the time to pain progression was also significantly longer in the NUBEQA® group (HR=0.79; P=0.01), as well as symptomatic Skeletal Event-Free Survival (HR=0.61; P<0.001). Further, the time to the initiation of subsequent systemic antineoplastic therapy was also significantly longer in the NUBEQA® group (HR=0.39; P<0.001). Adverse events were similar in the two groups.

The authors concluded that among patients with metastatic Hormone Sensitive Prostate Cancer, the addition of NUBEQA® to Androgen Deprivation Therapy and Docetaxel resulted in significantly longer Overall Survival, as well as improvement in key Secondary end points, with no increase in adverse events.

Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. Smith MR, Hussain Saad F, et al. for the ARASENS Trial Investigators. NEJM. February 17, 2022. DOI: 10.1056/NEJMoa2119115.

Initial Management of Noncastrate Prostate Cancer: ASCO Guideline Update

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 248,530 new cases of prostate cancer will be diagnosed in 2021 and 34,130 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second generation anti-androgen agents, which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis.

This recent ASCO guideline, updates all preceding ASCO guidelines on initial hormonal management of noncastrate advanced, recurrent, or metastatic prostate cancer. This guideline was developed by a multidisciplinary expert panel and recommendations were made based on a systemic review of 4 clinical practice guidelines, 1 endorsement of a clinical practice guideline, 19 systematic reviews, 47 Phase III randomized controlled trials, 9 cohort studies, and 2 review papers.

Guideline Questions
CLINICAL QUESTION 1: What are the standard initial treatment options for metastatic noncastrate prostate cancer?
Recommendation 1: Docetaxel, Abiraterone, Enzalutamide, or Apalutamide, each when administered with Androgen Deprivation Therapy (ADT), represent four separate Standards of Care for noncastrate metastatic prostate cancer. The use of any of these agents in any particular combination or in any particular series cannot yet be recommended.
ADT Plus Docetaxel
Recommendation 1.1. For men with metastatic noncastrate prostate cancer with high-volume disease as defined per CHAARTED trial who are candidates for treatment with chemotherapy, the addition of Docetaxel to ADT should be offered.
Recommendation 1.2. For patients with low-volume metastatic disease as defined per CHAARTED trial who are candidates for chemotherapy, Docetaxel plus ADT should NOT be offered.
Recommendation 1.3. The recommended regimen of Docetaxel for men with metastatic noncastrate prostate cancer is six doses administered at 3-week intervals at 75 mg/m2 either alone (per CHAARTED trial) or with prednisolone.
ADT Plus Abiraterone
Recommendation 1.4. For men with high-risk de novo metastatic noncastrate prostate cancer, the addition of Abiraterone to ADT should be offered per LATITUDE trial.
Recommendation 1.5. For men with low-risk de novo metastatic noncastrate prostate cancer, ADT plus Abiraterone may be offered per STAMPEDE trial.
Recommendation 1.6. The recommended regimen for men with metastatic noncastrate prostate cancer is Abiraterone 1,000 mg with either prednisolone or prednisone 5 mg once daily until progressive disease is documented.
ADT Plus Enzalutamide
Recommendation 1.7. ADT plus Enzalutamide should be offered to men with metastatic noncastrate prostate cancer including both those with de novo metastatic disease and those who have received prior therapies, such as Radical Prostatectomy (RP) or RadioTherapy (RT) for localized disease. Enzalutamide plus ADT has demonstrated short-term survival benefits (PSA progression-free, clinical progression-free, and overall) when compared with ADT alone for men with metastatic noncastrate prostate cancer as a group per ENZAMET trial.
Recommendation 1.8. The recommended regimen for men with metastatic noncastrate prostate cancer is enzalutamide 160 mg per day with ADT.
ADT Plus Apalutamide
Recommendation 1.9. ADT plus Apalutamide should also be offered to men with metastatic noncastrate prostate cancer, including those with de novo metastatic disease or those who have received prior therapy, such as RP or RT for localized disease per TITAN trial.
Recommendation 1.95. The recommended regimen for men with metastatic noncastrate prostate cancer is Apalutamide 240 mg per day with ADT.
CLINICAL QUESTION 2: Are combination therapies such as combined androgen blockade (castration plus a nonsteroidal antiandrogen) better than castration alone, for men with noncastrate locally advanced nonmetastatic prostate cancer?
Recommendation 2.1. ADT plus Abiraterone and prednisolone should be considered for men with noncastrate locally advanced nonmetastatic prostate cancer, rather than castration monotherapy, because of the failure-free survival benefit per STAMPEDE trial. RT to the primary was mandated in STAMPEDE trial for patients with newly diagnosed node-negative, nonmetastatic disease and encouraged in patients with newly diagnosed node-positive, nonmetastatic disease. Failure-Free Survival (time to the earliest of biochemical failure, DP, or death) was significantly improved for patients with nonmetastatic disease treated with ADT plus Abiraterone and prednisolone compared with those treated with ADT alone, although ADT plus Abiraterone was administered for 2 or less years to men with nonmetastatic disease.
Recommendation 2.2. In resource-constrained settings where drugs such as Abiraterone may not be available, combined androgen blockade using ADT plus a first-generation antiandrogen, such as Flutamide, Nilutamide, or Bicalutamide, may be offered to men with locally advanced nonmetastatic prostate cancer, rather than castration monotherapy, based on recent meta-analyses.
CLINICAL QUESTION 3: Does early (immediate) Androgen Deprivation Therapy improve outcomes over deferred therapy for men with noncastrate locally advanced nonmetastatic disease?
Recommendation 3.1. Early (immediate) ADT may be offered to men who initially present with noncastrate locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo RT based on evidence in one meta-analysis of a modest, but statistically significant benefit in terms of both Overall Survival (OS) and Cancer-Specific Survival (CSS) among the larger population of men with locally advanced nonmetastatic disease.
CLINICAL QUESTION 4: Is Intermittent Androgen Deprivation Therapy better than continuous Androgen Deprivation Therapy for men with biochemically recurrent nonmetastatic disease?
Recommendation 4.1. Intermittent therapy may be offered to men with high-risk biochemically recurrent nonmetastatic prostate cancer after RP and/or RT based on evidence in meta-analyses of the noninferiority of Intermittent Androgen Deprivation Therapy (IADT) when compared with Continuous Androgen Deprivation Therapy (CADT) with respect to OS. This is further supported by evidence from four meta-analyses testing superiority. Low-risk biochemical recurrence after RP is defined as a PSA doubling time more than 1 year and pathologic Gleason score less than 8. Low-risk biochemical recurrence after RT is defined as an interval to biochemical recurrence more than 18 months and clinical Gleason score less than 8. High-risk biochemical recurrence after RP is defined as a PSA doubling time less than 1 year or a pathologic Gleason score of 8-10. High-risk biochemical recurrence after RT is defined as an interval to biochemical recurrence less than 18 months or a clinical Gleason score of 8-10. Active surveillance may be offered to men with low-risk biochemically recurrent nonmetastatic prostate cancer.

Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update. Virgo KS, Rumble RB, de Wit R, et al. J Clin Oncol 2021;39:1274-1305.