PCa Commentary. Volume 83 September October 2013

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1 1221 Madison Street, First Floor Seattle, WA P ww.seattleprostate.com PCa Commentary Volume 83 September October 2013 Table of Contents Alpharadin, Xofigo Page 1 PTEN gene Page 3 ALPHARADIN (Radium-233); trade name, Xofigo Is now FDA approved for use in men with castrate-resistant prostate cancer without symptomatic bone metastases. Xofigo is now in position to become a standard therapy for men with prostate cancer metastatic to bone. Prostate cancer has a strong predilection to spread to bone in 90% of patients, and if men are not cured of their disease and don't succumb from other causes, it is likely that they might benefit from Xofigo somewhere in the course of their disease. Xofigo is the only bone-directed radiotherapeutic treatment that combines the several desired effects of: - slowing the progression of bony disease - contributing to pain relief, and - prolonging survival while producing a low level of adverse effects. The PCa Commentary has followed this radioisotope during its 7 years of clinical development with interest and anticipation. The PCa Commentary, Vol. 78, Nov/Dec summarized the results of the ALSYMPCA trial on which the FDA approval was based, and discussed the mode of action, side effects, and schedule of administration. Eligibility into the ALSYMPCA trial required progressive disease in at least 2 sites of bone metastasis, but many patients had more, i.e. 40% had >20 metastatic sites. Hafeez and Parker offered their summary of Alpharadin in Expert Opinion on Investigational Drugs, Mar 2013: "Radium-223 is set to become a new standard of care for the treatment of bony metastatic CRPC. It improves both survival and quality of life, delays skeletal events and is well tolerated. Its optimal use in the evolving treatment strategies for men with CRPC and bone metastases is yet to be determined. The pharmacology of Xofigo is unique in that radium-223, a calcium mimetic, targets only osteoblastic bone lesions and the osteoblastic components of osteolytic lesions. The highly destructive alpha particles preferentially concentrate in cancer sites and much less so in normal bone. Its lethal effect extends only over a distance of 2-10 cell diameters. One to 10 radiation hits are lethal to cells. The limited range of the alpha radiation explains the relatively minor suppressive effect or normal hematopoesis. This low level of myelosuppression allows the agent to be repeated, a feature that confers a definite advantage over the prior radioisotopes for the treatment of bone metastases. The treatment is given intravenously in an outpatient setting and the current regimen is six monthly administrations.

2 PCa COMMENTARY Vol. 83 September October 2013 Page 2 Xofigo continued: A brief summary of the results of the ALSYMPCA trial: (Xofigo, 641 men; placebo, 307) 1) Median overall survival: Xofigo, 14.9 months vs 11.3 months for placebo. 2) "Ra-223 significantly delayed time to first SRE [skeletal related event] versus placebo by a median increase of 5.8 months: 15.6 vs 9.8 mo; P<0.001; HR 0.66." A SRE was defined as a pathologic bone fracture (occurring in 5% of men treated with Ra-223 vs 7%, placebo), spinal cord compression --50% reduction (i.e. 4% vs 7%), use of external beam radiotherapy (30% vs 34%), or surgical intervention (2% for both)." (updated analysis, J Clin Oncol 31, 2013 (suppl 6; abst 11) 3) Median overall survival for men taking Xofigo who had not had prior Docetaxel was 16.1 months vs 14.1 months for those with prior Docetaxel exposure or those men unable to take chemotherapy. 4) The level of total alkaline phosphatase was inversely related to overall survival. 5) Hematologic side effects constituted the major category of adverse events: Neutropenia grade 1 and 2 - Xofigo, 4% vs placebo, 1% grade 3 and 4 - Xofigo, 2% vs placebo, 1% (2% of patients on Xofigo experienced ongoing pancytopenia vs none on placebo; and 2/614 receiving Xofigo died of bone marrow failure. Four percent of patients in the Xofigo and 2% in the placebo arm discontinued therapy due to myelosuppression.) Thrombocytopenia, grade 3/4, Xofigo, 6% v. placebo, 2% Anemia, grade 3/4, Xofigo, 13% vs placebo, 13% Prior Docetaxel therapy was a strong predictor of neutropenia and thrombocytopenia. The Xofigo product announcement sets forth the suggested requirements for baseline hematologic values and monitoring BOTTOM LINE: Xofigo "is an effective therapy with a highly favorable safety profile and may provide a new standard of care of treatment of CRPC patients with bone mets," Oliver Sartor, ASCO, Abst 9, 2012 GU Symposium.

3 PCa COMMENTARY Vol. 83 September October 2013 Page 3 PTEN A currently hot gene that carries prognostic significance in prostate cancer. [Tissue testing for PTEN loss is now available through CellNetix Laboratory in Seattle. For information contact Tom Lee, M.D. at ; tlee@cellnetix.com] The loss of the PTEN gene confers a poorer outcome for men with prostate cancer compared to those having an intact functional copy. Disabling mutations or the silencing of the PTEN gene are seen in a wide variety of cancers -- breast, colon, lung, endometrium, thyroid, brain, and kidney. Even an association with autism is under investigation. The focus of this article will be on the adverse effects of the loss of function of this gene in prostate cancer and how a clinician's awareness of this loss might influence clinical management. PTEN is a vital tumor suppressor. Its gene product suppresses key cellular processes involved in tumor progression. The loss of PTEN (phosphatase and tensin homologue located on chromosome ten) increases cellular proliferation and tumor angiogenesis, decreases cell death (apoptosis), and enhances cell migration. Each of these mechanisms contributes to cancer aggressiveness. Hence, PTEN loss is recognized as an informative biomarker predictive of adverse clinical outcome. Men are in the precarious position of having only a single diploid copy (i.e. two alleles) of this vital tumor suppressing gene, and a substantial number of men lose one allele early in the disease. However, even the loss of one allele confers liability and the subsequent loss of the second allele further increases its adverse effect. An excellent review by Logothetis et al.: "Molecular Classification of Prostate Cancer Progression: Foundation for Marker-Driven Treatment of Prostate Cancer," CANCER DISCOVERY, 2013 Aug, states: "Loss of the PTEN tumor suppressor gene, leading to the activation of the phosphoinositide 3-kinase/Akt pathway is one of the earliest genetic changes during prostate cancer progression." A hypothetical sequence of genomic events in prostate cancer progression was suggested by Bismar, BJU Int, Their hypothesis: the loss of one of our two alleles for this gene can disrupt proliferative control and lead to high-grade intraepithelial neoplasia (HGPIN) and increased genomic instability, which in turn promotes the acquisition of additional genomic abnormalities Complete loss of PTEN function resulting from inactivation of the second allele increases the "dose" of the loss and is associated with invasive prostate cancer. As stated in Bismar (ibid): others have confirmed a significant association of loss of PTEN [in association with the oncogenic TMPRSS2/ERG fusion gene] with lymph node metastases hormone-refractory PCA and cancer-specific death. Noted also was that a more extensive dose of PTEN loss as associated with increasing Gleason score, higher tumor stage, shorter time to cancer occurrence, and cancer aggressiveness. Increasing "dose" of PTEN loss is associated with increasing Gleason score, higher tumor stage, shorter time to cancer recurrence, and cancer aggressiveness.

4 PCa COMMENTARY Vol. 83 September October 2013 Page 4 PTEN continued: Various studies suggest that optimal prognostic information is best obtained by combining PTEN loss with other activated oncogenes, e.g. over-expression of MYC, the ERG fusion gene, and Akt. What management decisions might result from knowledge of PTEN loss? Currently there are no reported prospectively randomized comparisons wherein PTEN loss is the single variable. The most clinically applicable study is by Cuzick et al., British Journal of Cancer, June 2013: "Prognostic value of PTEN loss in men with conservatively managed localized prostate cancer." They reported on prostate cancer-specific death in 675 men whose cancer was diagnosed by TURP and compared prostate cancer-specific death for those with PTEN loss vs those having the intact gene. Cytoplasmic identification of PTEN was evaluated by immunohistochemical staining and also by FISH [fluorescent in situ hybridization, the test used by CellNetix ]. The authors searched 40 potentially prognostic biomarkers and concluded the PTEN was the most informative. Their Findings: The 18% of men with loss had 3.5X greater risk of PC-specific death compared to those with a functional gene. The total group was categorized by Gleason score, PSA, Ki-67 [a measure of cell proliferation] and extent of disease (based on number of positive chips in the TURP specimen). The men were treated with either surgery or radiation. Cuzick's analysis found that PTEN loss "was highly predictive of prostate cancer death (7.4X more risk; P=0.012) in the 50% of patients with low risk score based on a composite of Gleason score, PSA, Ki-67 and extent of disease, but had no prognostic value in the higher risk patients." The loss was more common in cases with Gleason score >7, Ki-67 score >5% or baseline PSA >10 ng/ml. The increased risk in the low-risk group with PSA of <10 ng/ml is especially relevant for men with Gleason 6 pathology where additional prognostic markers are particularly needed. Their graph displaying survival data shows that the 302 low-risk men with normal PTEN had a ~97% 10 year survival whereas survival for the 206 lowrisk men with PTEN loss was ~60%. This study should be considered as hypothesis generating for future studies because of its retrospective design. It is unwarranted to equate their metric of "number of positive TURP chips" with (say) % positive biopsy cores, which might be used to represent extent of disease in a future study. Possible Areas for Clinical Application Active Surveillance: Cuzick's data suggests that PTEN loss could be the variable studied, either prospectively or retrospectively, in candidates for active surveillance. His study has shown that among men with Gleason score 6, PSA <10, there will be some with PTEN loss. If a future study confirms, as suggested by Cuzick, that the outcome of these men is likely to be compromised by the loss, then in the future these men might be counseled that their projected duration of freedom from progression might be shorter than anticipated.

5 PCa COMMENTARY Vol. 83 September October 2013 Page 5 PTEN continued: Post Radical Prostatectomy: Lotan et al. (Clin Cancer Res October) studied the surgical specimens of 217 men and detected PTEN loss in between 75% and 86% [they used FISH and IHC]. "PTEN protein loss was associated with decreased time to metastases." A Johns Hopkins group lead by Chaux reported on 451 men who recurred and 451 who did not recur after radical prostatectomy: "Loss of PTEN expression is associated with increased risk of recurrence after prostatectomy for clinically localized prostate cancer," Modern Pathology, June 2012." "Men who recurred had a higher proportion of PTEN loss ( 40 vs 31%, P=0.02) than controls. Their conclusion: In patients with clinically localized prostate cancer treated by prostatectomy, '"Men with markedly decreased PTEN staining had a higher risk of recurrence (odds ratio 1.67) than controls [and this was] independent of known clinicopathological factors." [Emphasis mine] BOTTOM LINE: The use of the tumor suppressor PTEN (alone or in combination) as a biomarker in clinical studies is at an early stage of development. However, in the current era of the emerging importance of biomarkers for individualizing patient management, the PTEN gene will surely play an important role. COMMENT by Tom Lee, M.D., pathologist at CellNetix Laboratory, Seattle: At CellNetix, we feel that the PTEN test by FISH offers important information in clinical management decision for patients under consideration for active surveillance. PTEN is a novel marker that offers the only potentially applicable prognostic information in prostate cancer. Although some laboratories may suggest utilizing PTEN testing in cases of HGPIN or "atypical" diagnosis, we feel that the results of this test do not significantly change management decisions and the clinical utility in these scenarios has not been addressed in studies. PTEN testing would be beneficial in men with low volume Gleason 6-7 disease with PSA <10 ng/ml, who might otherwise be excellent candidates for active surveillance. The homozygous loss of PTEN would potentially indicate a more aggressive disease suggesting that additional imaging studies and/or additional biopsies might be appropriate if active surveillance is still in consideration. As additional studies become available, we will be modifying our recommendations for PTEN testing and potentially use it in combination with additional tests. Ed Weber, M.D., Editor Visit us at: News & Events This month s issue plus a compilation of past articles is available online. Your comments and requests for information on a specific topic are welcome at ecweber@nwlink.com "I want to thank Dawn Scott, Staffperson, Seattle Prostate Institute, and Mike Scully, Librarian, Swedish Medical Center for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible."