Prostate Cancer 2020: “The Times They Are a’Changing”

Prostate cancer (PC) care is rapidly evolving, with improved treatment options and outcomes. Trials recently published in the New England Journal of Medicine report on an oral lutenizing-hormone-releasing hormone antagonist with superior endocrine and tolerability profiles and positive outcomes for non-metastatic PC with androgen receptor antagonists, respectively. Prostate cancer (PC) care is rapidly evolving, with improved treatment options and outcomes. Trials recently published in the New England Journal of Medicine report on an oral lutenizing-hormone-releasing hormone antagonist with superior endocrine and tolerability profiles and positive outcomes for non-metastatic PC with androgen receptor antagonists, respectively. Prostate cancer (PC) is the most common male malignancy and a leading cause of death, with dietary and hereditary risk factors including germline DNA repair defects. Targeting androgen receptor (AR) signaling is a mainstay of treatment; surgical and chemical castration, with luteinizing-hormone-releasing hormone (LHRH) analogs, and one next-generation AR signaling inhibitor including abiraterone, apalutamide, darolutamide, and enzalutamide are standards of care for all advanced disease (Sartor and de Bono, 2018Sartor O. de Bono J.S. Metastatic prostate cancer.N. Engl. J. Med. 2018; 378: 645-657Crossref PubMed Scopus (246) Google Scholar). PC molecular intra- and inter-patient heterogeneity remains, however, a challenge to improving treatment; deleterious genomic alterations of BRCA2 and other homologous-recombination defects (PALB2, RAD51) sensitize to poly(ADP)-ribose polymerase inhibitors (PARPi) and improve survival from this PC subset (de Bono et al., 2020de Bono J. Mateo J. Fizazi K. Saad F. Shore N. Sandhu S. Chi K.N. Sartor O. Agarwal N. Olmos D. et al.Olaparib for metastatic castration-resistant prostate cancer.N. Engl. J. Med. 2020; 382: 2091-2102Crossref PubMed Scopus (827) Google Scholar). Mismatch repair and CDK12 aberrations sensitize to immunotherapy, with some having durable responses (Wu et al., 2018Wu Y.M. Cieślik M. Lonigro R.J. Vats P. Reimers M.A. Cao X. Ning Y. Wang L. Kunju L.P. de Sarkar N. et al.PCF/SU2C International Prostate Cancer Dream TeamInactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer.Cell. 2018; 173: 1770-1782.e14Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar; Nava Rodrigues et al., 2018Nava Rodrigues D. Rescigno P. Liu D. Yuan W. Carreira S. Lambros M.B. Seed G. Mateo J. Riisnaes R. Mullane S. et al.Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer.J. Clin. Invest. 2018; 128: 4441-4453Crossref PubMed Scopus (105) Google Scholar). Multiple other novel anticancer therapeutic strategies are showing promise, including PI3K/AKT inhibitors and PSMA targeting agents (Figure 1). While the search to identify novel PC therapeutic strategies continues, advances in endocrine treatment are also emerging. Two recent publications in the New England Journal of Medicine are of particular interest in this regard (Shore et al., 2020Shore N.D. Saad F. Cookson M.S. George D.J. Saltzstein D.R. Tutrone R. Akaza H. Bossi A. van Veenhuyzen D.F. Selby B. et al.HERO Study InvestigatorsOral relugolix for androgen-deprivation therapy in advanced prostate cancer.N. Engl. J. Med. 2020; 382: 2187-2196Crossref PubMed Scopus (174) Google Scholar; Sternberg et al., 2020Sternberg C.N. Fizazi K. Saad F. Shore N.D. De Giorgi U. Penson D.F. Ferreira U. Efstathiou E. Madziarska K. Kolinsky M.P. et al.PROSPER InvestigatorsEnzalutamide and survival in nonmetastatic, castration-resistant prostate cancer.N. Engl. J. Med. 2020; 382: 2197-2206Crossref PubMed Scopus (173) Google Scholar). These describe phase 3 clinical trials of an oral LHRH antagonist and of next-generation AR antagonism in non-metastatic prostate cancer (NMPC) with rising prostate-specific-antigen (PSA) blood levels but no detectable disease with current imaging modalities. Androgen deprivation therapy (ADT) by castration remains the standard of care for aggressive prostate cancers, both in the adjuvant setting for higher-risk locally advanced disease and for metastatic disease, with chemical castration by subcutaneous depot injection of an LHRH agonists (e.g., goserelin, leuprolide) every three months being most commonly utilized. The recently reported phase 3 HERO trial shows that the oral LHRH antagonist relugolix is significantly superior to leuprolide and results in rapid testosterone suppression when administered orally once a day without the initial testosterone surge seen with LHRH agonists (Shore et al., 2020Shore N.D. Saad F. Cookson M.S. George D.J. Saltzstein D.R. Tutrone R. Akaza H. Bossi A. van Veenhuyzen D.F. Selby B. et al.HERO Study InvestigatorsOral relugolix for androgen-deprivation therapy in advanced prostate cancer.N. Engl. J. Med. 2020; 382: 2187-2196Crossref PubMed Scopus (174) Google Scholar). Testosterone recovery upon discontinuation of relugolix is also faster than following leuprolide cessation (Shore et al., 2020Shore N.D. Saad F. Cookson M.S. George D.J. Saltzstein D.R. Tutrone R. Akaza H. Bossi A. van Veenhuyzen D.F. Selby B. et al.HERO Study InvestigatorsOral relugolix for androgen-deprivation therapy in advanced prostate cancer.N. Engl. J. Med. 2020; 382: 2187-2196Crossref PubMed Scopus (174) Google Scholar). Furthermore, critically, the incidence of major adverse cardiovascular events after 48 weeks of treatment is 2.9% in the relugolix group and 6.2% with leuprolide (Shore et al., 2020Shore N.D. Saad F. Cookson M.S. George D.J. Saltzstein D.R. Tutrone R. Akaza H. Bossi A. van Veenhuyzen D.F. Selby B. et al.HERO Study InvestigatorsOral relugolix for androgen-deprivation therapy in advanced prostate cancer.N. Engl. J. Med. 2020; 382: 2187-2196Crossref PubMed Scopus (174) Google Scholar). Strikingly, in the subgroup of men enrolled with a history of cardiovascular disease (CVD), the incidence is 3.6% in the relugolix group and 17.8% in the leuprolide group (Shore et al., 2020Shore N.D. Saad F. Cookson M.S. George D.J. Saltzstein D.R. Tutrone R. Akaza H. Bossi A. van Veenhuyzen D.F. Selby B. et al.HERO Study InvestigatorsOral relugolix for androgen-deprivation therapy in advanced prostate cancer.N. Engl. J. Med. 2020; 382: 2187-2196Crossref PubMed Scopus (174) Google Scholar). CVD is the principal non-cancer-related cause of death among men with PC (Sturgeon et al., 2019Sturgeon K.M. Deng L. Bluethmann S.M. Zhou S. Trifiletti D.M. Jiang C. Kelly S.P. Zaorsky N.G. A population-based study of cardiovascular disease mortality risk in US cancer patients.Eur. Heart J. 2019; 40: 3889-3897Crossref PubMed Scopus (302) Google Scholar). As PC survival improves, CVD morbidity and mortality from PC therapy is likely to become increasingly important, and these results may be very significant. Overall, relugolix appears to be superior to leuprolide in that it is oral and therefore easier to administer, and achieves better testosterone suppression with decreased CVD toxicity. Relugolix is therefore likely to become the new standard of care, although it has not been proved to date to have anticancer activity superior to established surgical or chemical castration treatments (Figure 1). The other significant development in endocrine therapy relates to next-generation AR antagonists for NMPC, with three trials with apalutamide (Small et al., 2019Small E.J. Saad F. Chowdhury S. Oudard S. Hadaschik B.A. Graff J.N. Olmos D. Mainwaring P.N. Lee J.Y. Uemura H. et al.Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.Ann. Oncol. 2019; 30: 1813-1820Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar), darolutamide (Fizazi et al., 2019Fizazi K. Shore N. Tammela T.L. Ulys A. Vjaters E. Polyakov S. Jievaltas M. Luz M. Alekseev B. Kuss I. et al.ARAMIS InvestigatorsDarolutamide in nonmetastatic, castration-resistant prostate cancer.N. Engl. J. Med. 2019; 380: 1235-1246Crossref PubMed Scopus (471) Google Scholar), and enzalutamide (Sternberg et al., 2020Sternberg C.N. Fizazi K. Saad F. Shore N.D. De Giorgi U. Penson D.F. Ferreira U. Efstathiou E. Madziarska K. Kolinsky M.P. et al.PROSPER InvestigatorsEnzalutamide and survival in nonmetastatic, castration-resistant prostate cancer.N. Engl. J. Med. 2020; 382: 2197-2206Crossref PubMed Scopus (173) Google Scholar) all showing significantly improved time to metastases and improved overall survival (Figure 1); none of these trials, however, directly tested whether early treatment is superior to later treatment. For example, the NMPC trial administers enzalutamide plus ADT, versus ADT alone, to men with worse prognosis disease indicated by a rapidly rising PSA with a doubling-time of <10 months (Sternberg et al., 2020Sternberg C.N. Fizazi K. Saad F. Shore N.D. De Giorgi U. Penson D.F. Ferreira U. Efstathiou E. Madziarska K. Kolinsky M.P. et al.PROSPER InvestigatorsEnzalutamide and survival in nonmetastatic, castration-resistant prostate cancer.N. Engl. J. Med. 2020; 382: 2197-2206Crossref PubMed Scopus (173) Google Scholar). Enzalutamide significantly lowers the risk of metastasis or death without radiological progression, with enzalutamide improving median overall survival (67.0 versus 56.3 months), with a 27% reduction in the risk of death (Sternberg et al., 2020Sternberg C.N. Fizazi K. Saad F. Shore N.D. De Giorgi U. Penson D.F. Ferreira U. Efstathiou E. Madziarska K. Kolinsky M.P. et al.PROSPER InvestigatorsEnzalutamide and survival in nonmetastatic, castration-resistant prostate cancer.N. Engl. J. Med. 2020; 382: 2197-2206Crossref PubMed Scopus (173) Google Scholar). Similar survival benefit has also been seen with both apalutamide (Small et al., 2019Small E.J. Saad F. Chowdhury S. Oudard S. Hadaschik B.A. Graff J.N. Olmos D. Mainwaring P.N. Lee J.Y. Uemura H. et al.Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.Ann. Oncol. 2019; 30: 1813-1820Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar) and darolutamide (Fizazi et al., 2019Fizazi K. Shore N. Tammela T.L. Ulys A. Vjaters E. Polyakov S. Jievaltas M. Luz M. Alekseev B. Kuss I. et al.ARAMIS InvestigatorsDarolutamide in nonmetastatic, castration-resistant prostate cancer.N. Engl. J. Med. 2019; 380: 1235-1246Crossref PubMed Scopus (471) Google Scholar). Together, these three trials indicate, but do not prove, that earlier initiation of AR blockade on development of castration resistance (CR), but prior to the detection of metastases, improves clinical outcomes. Cell population statistical analyses may explain these findings, with lower tumor cell burden in NMPC making resistant lethal clones less likely to emerge. It remains unclear, however, whether the men dying on the control arms of these trials ever received a next-generation AR inhibitor; it is therefore not possible to unequivocally claim from these data that earlier is better, and trials are now needed randomizing patients to earlier (NMPC) versus later (metastatic CRPC) treatment. NMPC is a disease state defined by the sensitivity of medical imaging (Mateo et al., 2019Mateo J. Fizazi K. Gillessen S. Heidenreich A. Perez-Lopez R. Oyen W.J.G. Shore N. Smith M. Sweeney C. Tombal B. et al.Managing nonmetastatic castration-resistant prostate cancer.Eur. Urol. 2019; 75: 285-293Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar); new imaging methodologies, including whole-body magnetic resonance imaging (MRI) and PSMA-positron-emission-tomography (PET) scans, often identify missed metastases in men in whom NMPC was defined by conventional imaging (computerized-tomography scans and bone scans). This makes it likely that the NMPC state may diminish. Another important finding from the NMPC trials is that while the three agents in question (apalutamide, darolutamide, and enzalutamide) are all well-tolerated, there are important toxicities associated with their use, including fatigue, fractures, falls, and cognitive impairment (Small et al., 2019Small E.J. Saad F. Chowdhury S. Oudard S. Hadaschik B.A. Graff J.N. Olmos D. Mainwaring P.N. Lee J.Y. Uemura H. et al.Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.Ann. Oncol. 2019; 30: 1813-1820Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar; Sternberg et al., 2020Sternberg C.N. Fizazi K. Saad F. Shore N.D. De Giorgi U. Penson D.F. Ferreira U. Efstathiou E. Madziarska K. Kolinsky M.P. et al.PROSPER InvestigatorsEnzalutamide and survival in nonmetastatic, castration-resistant prostate cancer.N. Engl. J. Med. 2020; 382: 2197-2206Crossref PubMed Scopus (173) Google Scholar; Fizazi et al., 2019Fizazi K. Shore N. Tammela T.L. Ulys A. Vjaters E. Polyakov S. Jievaltas M. Luz M. Alekseev B. Kuss I. et al.ARAMIS InvestigatorsDarolutamide in nonmetastatic, castration-resistant prostate cancer.N. Engl. J. Med. 2019; 380: 1235-1246Crossref PubMed Scopus (471) Google Scholar). These appear to be least frequent with darolutamide, which may be less likely to penetrate the blood-brain barrier. Moreover, further patient follow-up is needed to determine the risk of fatal cardiovascular adverse events from these agents, with the enzalutamide NMPC trial reporting a significant increase in adverse events leading to death in the enzalutamide group (n = 57 [2/100 patient years]) compared to the controls (n = 3 [<1/100 patient years]) (Sternberg et al., 2020Sternberg C.N. Fizazi K. Saad F. Shore N.D. De Giorgi U. Penson D.F. Ferreira U. Efstathiou E. Madziarska K. Kolinsky M.P. et al.PROSPER InvestigatorsEnzalutamide and survival in nonmetastatic, castration-resistant prostate cancer.N. Engl. J. Med. 2020; 382: 2197-2206Crossref PubMed Scopus (173) Google Scholar). In conclusion, PC care is changing for the better, with improved diagnosis, superior imaging, molecular stratification, and novel endocrine and non-endocrine therapies targeting key tumor cell vulnerabilities, including DNA repair defects that are either present at diagnosis or emerge with endocrine resistance. Further advances are eagerly anticipated and may include the study of circulating biomarkers elucidating disease evolution, novel treatments targeting AR splice variants, PI3K/AKT signaling, and PSMA. We envision that the next decade of PC research will continue to transform care, with PC sufferers living longer and better. The J.S.d.B. laboratory is funded by the Prostate Cancer UK and Movember to the London Movember Prostate Cancer Centre of Excellence at The Institute of Cancer Research and Royal Marsden (CEO013-2-002), the U.S. Department of Defense, the Prostate Cancer Foundation, Cancer Research UK (CRM108X-A25144), and the UK Department of Health through an Experimental Cancer Medicine Centre grant (ECMC-CRM064X). A.P. is funded by a CRUK Centre Clinical Training Award (CRM120X). J.S.d.B. has served on advisory boards and received fees from companies including Astra Zeneca, Astellas, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech/Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, QIAGEN, Sanofi Aventis, Sierra Oncology, Taiho, and Vertex Pharmaceuticals. J.S.d.B. is an employee of The ICR, which has received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, and Vertex and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers, and PI3K/AKT pathway inhibitors (no personal income). J.S.d.B. was named as an inventor, with no financial interest, for patent 8,822,438. J.S.d.B. has been the CI/PI of many industry sponsored clinical trials. J.S.d.B. is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.