Men who are diagnosed with prostate cancer at later stages of the disease are more likely to say that their disease has affected several aspects of their life, including their self-esteem, how they share feelings with others, and how they feel about their sexual health, a survey found. Read the full article here: Patient Survey
Radioligand therapy (RLT) – i.e. PSMA directed endoradiation with Lutetium-177 – has been developed to the extent that it is a realistic option for men with late stage, heavily pretreated metastatic castration-resistant prostate cancer. The national protocol sponsored by Endocyte is open for enrollment at 66 sites in the United States.
The June 2018 Commentary, also posted on the Prostate Cancer Free Website and titled ‘Radioligard Therapy, An Update,” discussed the basic biology underlying this emerging treatment.
In very brief, the treatment involves the intravenously administered radioactive isotope, Lutetium-177, joined with an antibody (identified as ‘617’) that targets the PSMA antigen expressed on the surface of nearly all cancerous prostate cells. It is internalized into the cell and emits lethal beta radiation over its 6.5 day half-life. The radionuclide concentrates around the cell nucleus and directly damages DNA. Among prostate cancer cells there is a heterogeneity of intensity of PSMA expression with best treatment results seen in those men with the greatest PSMA expression.
This therapy has been extensively studied in many trials with the general consensus that the treatment is safe with minimal adverse effects and consistently has led to a > 50% decline in PSA in a range of ~40 to 60% of the men. Three examples will be highlighted below.
⇒ A typical example of study results were those published by Rahbar et al., “German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer,” J Nucl Med, 2017. Of the 145 men treated in 12 centers with 1 – 4 six week cycles “The overall biochemical response rate was 45% (i.e. >50% decline in PSA) after all cycles, whereas 40% of patients had already responded after a single cycle.” Significant (i.e. grade 3 -4) adverse effects were: anemia, 16%; reduced platelets, 4%; and low white blood cell counts, 3%. This represents fewer adverse effect than following second-line chemotherapy (e.g., most times cabazitaxel) and Radium-223 (Xofigo). Prior exposure to chemotherapy did not influence the likelihood of response.
Metastases in this study were present in bone, 87%; lymph nodes, 77%; liver 20%; and lung, 14%. Xerostomia, (dry mouth) was common since the salivary glands exhibit the PSMA antigen. Predictors of poor response were visceral disease and elevation of the enzyme alkaline phosphatase, an indication of heavier bone involvement.
⇒ The largest review of RLT was presented by Calopedos et al. Prostate Cancer and Prostatic Diseases, 2017. Ten trials were analyzed; 37% of 369 patients had a >50% decline in PSA. Their opinion: “PSMA-targeted RLT is a novel and promising concept, which provides a highly targeted systemic therapy for mCRPC, especially after exhausting [the available] conventional therapies.”
⇒ The FDA’s approval of RLT incorporated into the ‘VISION’ protocol was based on the ASCO GU 2019 Symposium report by Hoffman et al. (Melbourne, Australia), based on the prospective LuPSMA treatment of 50 heavily retreated patients. A PSA decline of >50% occurred in 62%; in 44% the PSAs declined 80% or more; median survival after treatment, 13.3 months. The median overall survival in those men with a > 50% PSA response was 18 months vs those with a lesser PSA response, i.e. 8.7 months.
Adverse effects: Low grade dry mouth in 66%; anemia, 10%; decreased platelets, 8%; and low white blood cell count, 6%. Retreatment was offered to those responders who later progressed (n=14) and in this group the median overall survival was 33 months. The authors stated: “we recorded a rapid and clinically meaningful improvement in quality of life.”
Their conclusion was that their data “provides proof of concept that 177Lu-PSMA-617 has promising anti-tumor activity, low toxicity and improves quality of life in patients with mCRPC who have not responded to most conventional treatment and exhibit high PSMA expression on PSMA PET/CT.” A multicenter Australian randomized phase 2 trial is ongoing comparing LuPSMA to cabazitaxel chemotherapy (NCT03392428) in men with very advanced disease.
The VISION Protocol (Clinicaltrials.gov, NCT03511664): “Study of 177Lu-PSMA-617 in Metastatic Castrate-Resistant Prostate Cancer.”
“The study population includes patients with progressive PSMA-positive mCRPC who received at least one novel anti-androgen axis drug (such as enzalutamide or abiraterone) and were previously treated with 1 – 2 taxane regimens.” The aim is to enroll 750 men. Participants are randomized in a 2:1 ratio between receiving the study treatment or ‘best supportive care’ as defined by their physicians. Six cycles of therapy at six-week intervals are planned with a re-evaluation after 4 cycles. Prior treatment with Xofigo (Rad-223) is an exclusion criteria. A pretreatment positive PSMA scan is a requirement. The primary objective of this study is to compare overall survival in the two cohorts.
The study is sponsored by Endocyte, the manufacturer of the study agent. The trial is currently available in 66 locations listed in the ClinicalTrial.gov web page. In the Western USA sites are recruiting in Arizona, California, and Colorado. The national study coordinator is Richard Messmann, MD, 765-476-1070, email@example.com.
In men under treatment for metastatic CRPC the effectiveness of current drugs targeting the androgen axis, e.g., abiraterone and enzalutamide, is limited by eventual resistance. An alternative therapy is clearly needed. Radioligand therapy such as 177Lutetium PSMA-617 is emerging as a safe and effective treatment. Participation in the VISION protocol offers a promising treatment opportunity for men at an advanced stage of the disease.
The commonly cited goal of ‘personalized medicine’ in regards to treatment selection based on genomic testing is early in the ‘work in progress’ stage. Breathtaking advances in next generation sequencing are very promising, but currently there are only limited options for therapeutic guidance. This was acknowledged by Dr. Oliver Sartor in the recent NEJM review, Metastatic Prostate Cancer, Feb 2018: “The use of advanced genomic analysis is now feasible to a greater extent than ever before. Whether its use improves treatment decisions is not yet clear.”
The intent of this Commentary is to highlight where in the course of cancer progression genomic information might have a beneficial impact on clinical management. The focus will be on ‘predictive biomarkers’, i.e., those which indicate the likelihood that a certain treatment will provide benefit … or no benefit.
Currently the predominant clinically informative mutations are BRCA1/2, ATM, CHEK2, PALB2 and a few others whose function is to repair damaged DNA. A second group is the androgen receptor splice-variants, predominantly AR-V7, overexpression of which predicts for little or no responses to agents targeting the androgen receptor (AR), e.g., Zytiga and Xtandi and others. A third class is the family of ‘mismatch repair genes’ (MMR) and CDK12. These mutations increase responsiveness to immunotherapy.
All of these mutations are found at low levels at the onset of the disease, but their expression increases significantly during the course of progressive cancer as an adaptive response to the pressure of treatment, i.e., androgen deprivation therapy and chemotherapy.
*Testing for germline (inherited) and somatic (acquired) mutations:
Germline mutations can be diagnosed from blood, saliva, scrapings of buccal mucosa or skin biopsies. Currently, somatic mutations are diagnosed by sequencing circulating tumor cells. Tests using blood plasma assaying for cell-free DNA are available and being refined. Multiple tests are available to identify mutations in MMR genes.
*Genomic testing in men with low- or favorable intermediate-risk prostate cancer:
Currently there is little utility in germline genomic analysis for men in this category. The low percentages of predictive markers, such as mutations in BRCA 2 (~6%) and in the family of mismatch repair genes (MMR) (~1.5%), do not merit the search. It is unlikely that at this early stage, knowledge about predictive mutations would change standard therapy.
Of note, mutated BRCA2 is both predictive and prognostic – prognostic for greater disease aggressiveness; predictive as to response to PARP inhibitors and platinum-based chemotherapy.
*Germline genomic testing in men with high-risk and locally advanced and metastatic disease:
Men in this group (i.e. Gleason 8-10, PSA>20 ng/mL, locally advanced tumor stage or nodal spread, >50% positive cores) may well benefit from foreknowledge of their mutational landscape since they are at risk for shorter durations of response to standard androgen suppression, earlier development of CRPC and metastasis. Knowledge of a man’s genomic status will then be on record to guide future therapy choices.
The National Cooperative Cancer Network recommends germline testing of men with these characteristics and those with metastatic disease.
*Genomic testing for germline mutations in DNA damage repair genes:
~BRCA2 and other members of the DNA damage repair gene family predict for more aggressive disease. Recently reported results (J Clin Oncol. Feb 2019, Castro et al.) from the PROREPAIR-B protocol found that in men with metastatic CRPC germline mutations in BRCA 1/2 and ATM conferred a significant negative impact on treatment outcome compared to non-carriers.
~When a man has developed metastatic castration-resistant prostate cancer (mCRPC) and already had been found on germline testing to have mutated BRCA1/2 (or mutations in ATM, CHEK2,RAD51D and PALB2) he then is a candidate for the many protocols open for treatment with PARP inhibitors. In the metastatic state the likelihood of being positive for DNA damage repair mutations increases to ~12 % (16% if ATM and BRCA1 are included).
In a small study of 50 men, heavily pretreated and unselected for mutations, Mateo et al., NEJM 2015 Oct, reported a >50% decline in PSA in 33%; in 16 men showing mutations in the DNA repair genes the response was 88%.
In another study 6 of 8 men carrying a BRCA2 mutation showed a >50% decline in PSA within 12 weeks when treated with carboplatin/Taxotere).
~ When a man has developed mCRPC it becomes informative to submit blood for assessment of somatic mutations, i.e., those mutations that have evolved in adaptation to suppressed testosterone. Assays for somatic mutations increased the total number of mutations in DNA repairs genes to ~25%, thereby expanding the eligibility for protocol-based PARP inhibition.
* Testing for overexpression of the splice-variant AR-V7:
AR-V7 is a modified form of the basic androgen receptor. It is continuously active in promoting tumor growth, and is not suppressed by agents targeting the AR such as Zytiga and Xtandi. Although AR-V7 is minimally expressed at the onset of prostate cancer, in the metastatic setting AR-V7 expression increases so that it is found in ~30 – 40% of men. A positive assay for acquired (i.e., ‘somatic’) overexpression of the AR-V7 splice variant predicts the unlikelihood of a response to drugs such as these.
-~A study by Antonarakis et.al. (J Clin Oncol. 2017 Jul) examined the clinical significance of ARV7 found in the circulating tumor cells (CTC) of 202 men with mCRPC progressing on ADT and were about to start therapy in either Zytiga or Xtandi. Three cohorts were established: those who were CTC negative (and therefore not testable for cellular AR-V7); those CTC+ and AR-V7 negative and those both CTC+ and AR-V7 positive. Before therapy with either drug 36 men (17.8%) were already CTC+ and AR-V7+ and those men were more likely to have Gleason score > 8, a higher PSA and metastases at diagnosis. In men who had previously received Zytiga or Xtandi 27% were CTC+ and AR-V7+.
~Response to treatment was defined as a >50% decline in PSA. Only 14% of CTC+/AR-V7+ group met that criteria for response. After first-line therapy the PSA median progression-free survival in this group was 2.9 months; after second-line hormone therapy and 4.1 months, compared to >21.6 months and 6.2 months, respectively, for the CTC- group. The Antonarakis study did not have chemotherapy treatment arm, however the superiority of taxane therapy over (say) Zytiga and Xtandi in men CTC+/ARV7+ was indicated in the study by Scher et al., (JAMA Oncology Nov 2016).
~Knowledge of the CTC/AR-V7 status in men newly diagnosed with metastatic disease has therapy implications. Currently treatment in this group of men is customarily an LHRH inhibitor (Lupron or Firmagon) combined with Zytiga, Xtandi, or chemotherapy. A positive test of AR-V7 might favor chemotherapy. In men who have progressed to mCRPC after initial hormone suppression, knowledge of the AR-V7 status could influence the choice of the next therapy and also the choice of the subsequent second-line therapy after progression.
~ Unfortunately testing for AR-V7 is limited by the cost: QIAGEN’s AdnaTest ProstateCancerPanel AR-V7 lists at $2784. Epic Sciences OncotypeDx Nuclear Detect employs a different technology and is commercially available through Genomic Health (included into the NCCN Guidelines for MCRPC and Medicare is covering it List price, $3950). It is still available at Johns Hopkins. The recent PROPHESY study found both assays to be equivalent. ‘Liquid Biopsy’ tests for AR-V7 are already available.
*Mismatch repair gene mutations – A predictive biomarker for response to immunotherapy:
Although minimally expressed in the primary tumor, as with other mutations, mutations in these genes (MSH2, MSH6, MLH1, PSM2) increase in metastatic disease, e.g. to 5 to 10%. “Clinically, due to the high number of neoantigens generated by this hypermutation phenotype, patients with mismatch repair defects are prime candidates for checkpoint blockade…,” Isaac et al., Asian J of Urol Nov 2018.
In 2018 the FDA approved the PD-1 blocker pembrolizumab, KETRUDA, for treatment of metastatic prostate cancer exhibiting these mutations. Men expressing PD-1 In the Keynote study had a 17% response to KETRUDA.
Genomic research for clinical relevant mutations is producing an immense quantity of data. Currently for efficiency, the practicing clinician and interested patients can focus on identifying mutations in three important genomic areas: the mutations in the DNA repair family of genes, overexpression of the AR-V7 splice variant, and mutations in MMR genes. These data can have important bearing on treatment choices.Your content goes here. Edit or remove this text inline or in the module Content settings. You can also style every aspect of this content in the module Design settings and even apply custom CSS to this text in the module Advanced settings.
Black men diagnosed with prostate cancer are 2 times more likely to actually have a more aggressive, fatal form of the disease than those of other races, suggesting that the current prostate cancer score method may be underestimating the risk of death among black patients, study suggests. Read full article here: Prostate Cancer Scoring Method
Ever since the first orchiectomy for metastatic prostate cancer in 1941 researchers and clinicians have been determinedly trying to restrain the androgen receptor (AR) by manipulating its hormone environment. But this wily adversary, like Houdini, after initial suppression wriggles a bit then escapes — transitioning prostate cancer into a castration-resistant state. Alterations in the AR eventually frustrate the beneficial gains from the LHRH inhibitors, and Zytiga, Xtandi, Erleada and others. This escape is accomplished by a variety of different mechanisms, presenting the challenge of anticipating and circumventing the persistence of AR signaling.
Mechanisms of resistance: The androgen receptor is the principle driver of castration-resistant prostate cancer (CRPC). Alterations in this pivotal signaling protein are the primary source of this resistance to the drugs used to suppress its function. The various mechanisms include:
an increase in the number of AR gene copies (‘amplification’);
development of point mutations (i.e., changing the AR ligand binding pocket to allow stimulation by other steroids such as glucocorticoids and progesterone);
increased expression of variant AR forms (i.e., AR-V7 and family that are self-stimulating independent of androgens);
synthesis of intraprostatic androgens from adrenally sourced DHEA;
overexpression of the enzyme inhibited by abiraterone (CYP17A); and
transdifferentiation to neuroendocrine cancer.
Managing the adverse mutations in the androgen receptor.
Signals from the tumor microenvironment (TME) influence AR alterations and contribute to the development of resistance. Microenvironmental elements — collagen matrix, fibroblasts, tumor infiltrating lymphocytes and myloid-derived cells, which lie in close proximity to the tumor, respond to depressed androgen levels and alter the cancer cell genome. One recognized consequence from this interaction is activation of the ‘epithelial mesenchymal transition’ (EMT) which leads to CRPC and promotes cancer aggressiveness, invasion and metastases. Recent studies have shown that signals (i.e. a cytokine, IL-23) arising from myeloid-derived suppressor cells in the microenvironment in the diminished androgen state activate the AR pathway and promote cell survival and resistance (in this study, resistance to enzalutamide). Under research are anti-bodies to IL-23 to restore enzalutamide’s effectiveness (Calcinotto et al., Nature, July 2018.) Taken together these factors comprise the basis of eventual resistance to the commonly employed drugs to control the progression of prostate cancer.
The primary concern: Challenging as these subjects are for research, the practical concern for the prostate cancer patients is whether this information can be applied to improve treatment outcome — prolongation of progression-free, metastases-free and overall survival.
* Research has shown that during therapy the AR adapts to a low androgen environment by generating mutations that predispose to castration resistance. This raises the very basic issue as to when to institute androgen depression in the face of a rising PSA after primary treatment. Spratt et.al., ASCO.org/edbook, 2018, cited three studies showing no benefit in overall or cancer-specific survival for immediate ADT (within 2 months after biochemical recurrence) except in instances of a rapid (<6 – 9 months) PSA doubling time, which is associated the early development of metastases. As a generalization, a good response to hormone suppression is unlikely when the PSA doubling time < 12 months. Recent studies have shown that men in that category are better candidates for combined therapy with an LHRH inhibitor and one of the newer agents, i.e. abiraterone, apalutamide or enzalutamide.
* Resistance to abiraterone (‘Zytiga’) and enzalutamide (’Xtandi’): About one third of men are resistant to both of these drugs at first exposure. Therapy with both agents over time induce the overexpression of the AR splice variant AR-V7 — a major source of resistance. Antonarakis et al., NEJM, 2014 Sept, demonstrated that when circulating tumor cells in men with metastatic disease tested positive for AR-V7 none responded to either agent. (Other studies report infrequent responses.) A study by Scher et al. (JAMA Oncology. 2016 June) found that docetaxel retains effectiveness when confronting AR-V7 overexpression. Taken together this data suggests that after the failure of either drug, and before instituting the alternative, a blood test for AR-V7 can provide guidance in the choice of the next treatment. The AR-V7 assay is available commercially at Quigen (AdnaTest ProstatePanel AR-V7) and with OncotypeDx’s Nuclear Detect test and continues to be offered at Johns Hopkins.
* Sequencing: Enzalutamide or abiraterone as 1st line therapy in CRPC? After progression to CRPC the frequently arising decision is which drug, abiraterone (AA) or enzalutamide (ENZ), provides the better initial outcome. This issue was addressed at ASCO June 2017, “A randomized phase II cross-over study of abiraterone + prednisone vs enzalutamide for patients  with castration-resistant prostate cancer, Mattie Annala et al., clinical trial NCT02125357. The primary endpoints of the study were the response rate to the first drug and the time to progression after 2nd-line therapy. The study patients had metastases to bone, liver and lung in 83%, 6%, and 10%, respectively. Findings: First line ENZ showed a PSA of >50% at 12 weeks of 77% vs 55% for AA. Because of the study’s small size, the difference in the median time to PSA progression on 1st line ENZ (14.9 months) vs 1st-line AA (10.2 months) was statistically insignificant. Following either drug as 2nd-line, the median time to progression was 7.4 months for both drugs. Among all the patients 10% to 20% showed no response to either drug. “Not surprisingly, circulating tumor DNA biomarkers suggest the patients with TP53 and BRCA2 alterations identify patients with a poor prognosis.”
*Steroid switch – prednisone to decadron upon AA/prednisone failure: A Phase II pilot study (Romero-Laorden et. al., British Journal of Cancer, 2018 Aug) reported that of 26 men with metastatic CRPC progressing on abiraterone/prednisone, when switched to a regimen of abiraterone/decadron (0.5 mg/day), 46.2 % of men showed a >30% drop in PSA and in 34.6% the PSA declined > 50% (as tested at 12 weeks). “Median time to biochemical and radiographic progression was 5.3 and 11.8 months respectively.” No man whose circulating tumor cells showed a gain in AR copy numbers responded.
* Is there an enzalutamide withdrawal response after initial benefit? Enzalutamide over time can induce a conformational change in its target, the ligand pocket of the AR, and activate the AR as opposed to inhibiting it. However, the PSA ‘withdrawal’ response to stopping ENZ was insignificant as opposed to up to ~30% of men who show a clinically meaningful PSA response upon the withdrawal of bicalutamide after initially responding to the drug
* Recapture of enzalutamide effectiveness with the BAT regimen: The ‘BAT’ (bipolar androgen therapy) trial studied 30 asymptomatic men with metastatic CRPC who showed progression on enzalutamide. The BAT regimen employs intramuscular testosterone cypionate 400 mg every 28 days (yielding supraphysiological T levels of ~1500 ng/dL) while continuing LHRH suppression (ADT). A median of 6 cycles were administered (range 1- 26). In Lancet Oncology Teply et al., Jan 2018, reported that 30% of men (9/30) responded with a 50% decline in PSA. Upon rechallenge with ENZ 52% (11/21) achieved a PSA 50% response, suggesting that the BAT regimen can resensitize the AR to re-exposure to ENZ. BAT was considered safe — 3% of men experienced significant side effects. “These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistance prostate cancer) are ongoing.”(NCT02090114)
*Darolutamide, another anti-androgen, joins the team — Does it offer features not available with enzalutamide or apalutamide? On February 14th the NEJM published the results of the randomized phase 3 trial, “Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. (Fizazi et al). Eligibility required a PSA doubling time of less than 10 months (the median was 4.4 months), the same requirement as in the studies of apalutamide and enzalutamide when tested in the nonmetastatic setting. Metastases-free survival was the end point in all the trials of three agents: for darolutamide, 40.4 months; for enzalutamide, 36.6 months; and for apalutamide, 40.5 months. Adverse events were also quite similar in kind and frequency in these three trials — all about 25%. The orally administered darolutamide was associated with fatigue in 11.4%; hypertension, 5.2%; cognitive disorders, 0.2%; and seizures, 0.2%. Fatigue – up to 15%, has been a common adverse event for all three agents. Only a head-to-head comparison among these drugs will provide detailed data about the effectiveness and side effects among these treatments.
* A heads-up toward the future: In early 2019 a phase I clinical trial will test a new drug, ARV-110, which employs a markedly different approach to suppressing the AR — its total destruction. A small molecule, orally administered, has been crafted that attaches to the AR protein and tags it for on-site degradation. Preclinical studies have suggested it is effective against AR mutants, AR overexpression; and in mice resistant to enzalutamide. The drug has been cleared by the FDA for Phase I testing.
BOTTOM LINE: Resistance to androgen receptor-targeted therapies regularly develops during therapy. The mechanisms underlying this resistance are varied. Research is ongoing in an effort to devise regimens to counter this liability.
Radiation Therapy approaches — including brachytherapy and external beam radiation therapy (EBRT) — lead to better 10-year survival rates than prostate surgery in young patients with low- and intermediate-risk prostate cancer, a study shows.
The longest screening study on prostate cancer shows blood test measuring the levels of PSA, a well-known marker of prostate cancer, cuts deaths from the disease by nearly 30%. The study followed 20,000 men in Sweden for more than two decades and was featured in Maria Franlund’s PhD thesis.