2015 Genitourinary Cancers Symposium

simon-hughes-thumbThe underlying theme for this year’s multidisciplinary symposium on genitourinary cancers, held in Orlando, Florida, USA, was ‘Integrating biology into patient-centric care’. The first half of the meeting was dedicated to carcinomas of the prostate and bladder; the key points are summarised below.

Prostate cancer

The European Randomised Study of Screening for Prostate Cancer (Schroder et al., NEJM 2009) demonstrated that PSA screening for prostate cancer could reduce prostate-cancer specific mortality. However, in order to save one man’s life we need to screen 1068 men and treat 48 – in other words many men need to undergo unnecessary testing, including biopsies of which 75% reveal either no cancer or small volume low-risk disease unlikely to affect the individual’s quantity or quality of life. What is needed is a better marker for aggressive prostate cancer that can enable biopsies to be performed only in men likely to have clinically significant cancer. Dr Punnen (University of Miami) presented data from the first prospective multi-institutional study assessing the ability of the 4K score to identify men with at least Gleason grade 7 (Gl7+) prostate cancer. The 4K score utilises four Kallikrein blood tests (total PSA, free PSA, intact PSA, hK2) in addition to clinical information (digital rectal examination, prior biopsy results, age). They found that the 4K score demonstrated excellent accuracy in predicting Gl7+ prostate cancer, providing a personalised risk for each patient. This is a promising tool for selecting men likely to have high-grade disease and therefore most likely to benefit from a biopsy, versus those men without cancer, or with indolent disease.

Bicalutamide monotherapy has been shown to be inferior to castration in patients with metastatic prostate cancer (Tyrrell et al., Eur Urol 1998). However, in the non-metastatic setting the two treatment modalities are comparable (Iversen et al., J Urol 2000), although bicalutamide is thought to have a more favourable toxicity profile. The SPCG 6 Study (Scandanavian Prostate Cancer Group) randomised 1218 men with hormone-naïve non-metastatic prostate cancer to receive either bicalutamide 150mg daily or placebo. After 7 years’ follow-up, bicalutamide was found to be associated with a significant improvement in progression-free survival (HR 0.65; 0.55-0.76), but there was no difference in overall survival (HR 0.91; 0.76-1.09). At the meeting Dr Fred Thomsen (Copenhagen Prostate Centre) presented the updated long-term survival data from this study, after 14.6 years median follow-up. Once again, there was no difference in overall survival between the two study arms (HR 0.99; 0.87-1.13). However, on subset analysis there was a trend in favour of the placebo arm for localised disease (HR 1.19; 1.00-1.43), whilst men with locally advanced prostate cancer had a significant improvement in overall survival with the addition of bicalutamide (HR 0.77; 0.63-0.94). This survival benefit increased with higher baseline PSA.

Dr Philip Kantoff (Dana-Farber Cancer Institute) presented preliminary data on the membrane transporter protein SLCO2B1, one of a family of sodium independent transport systems for hormones and drugs. Castration-resistant prostate cancer cells overexpress members of the SLCO family, of which SLCO2B1 is the main transporter for DHEAS (dehydroepiandrosterone – the precursor of testosterone and dihydrotestosterone). Statins also utilise this transport system, and in vitro have been found to compete with DHEAS, reducing its transport. Dr Kantoff’s group analysed a cohort of 926 patients treated with ADT to determine whether statin use at the time of initiation of ADT might interfere with time to progression (TTP). 30.6% of patients were taking statins at initiation, and experienced a 12-month longer TTP than statin-negative patients (27.5 months versus 17.4 months; p=0.0005). This remained statistically significant even after adjusting for predefined prognostic clinical markers (HR 0.83; 0.69-0.99), and applied to patients with both metastatic and non-metastatic disease. These results need to be validated in prospective studies, but highlight that we need to be more aware of the potential interactions of non-cancer-related medications with our cancer therapies.

A small non-randomised prospective study from Johns Hopkins (presented by Dr Emmanuel Antonarakis) looked at whether detection of androgen receptor splice variant 7 (ARV7) in circulating tumour cells could predict response to taxanes in men with metastatic castration-resistant prostate cancer. ARV7 is a truncated form of the AR that lacks the ligand-binding domain, but remains constitutively active. Its presence has been associated with resistance to enzalutamide and abiraterone. They found ARV7-positive men might retain sensitivity to taxanes, which may therefore be a more efficacious treatment modality in these patients than AR-targeted therapies. In ARV7-negative men taxanes appeared to have comparable efficacy to AR-targeted agents. This work requires confirmation in larger biomarker-driven randomised studies.

At the 2014 Genitourinary Cancers Symposium Dr Chris Sweeney (Dana Faber Cancer Centre) presented landmark data from the ECOG 3805 study, demonstrating a survival benefit in hormone-naïve metastatic prostate cancer for the combination of ADT with docetaxel chemotherapy, over ADT alone. To date, subset analyses indicate that this benefit applies only to men with high-volume metastatic disease. At this meeting Dr Gwenaelle Gravis presented long-term data from the GETUG-AFU 15 study, addressing a similar question to ECOG 3805. Whilst the GETUG-AFU 15 study did not demonstrate a statistically significant survival benefit, the measured 14.4 month benefit in favour of docetaxel is directionally similar to that from the ECOG 3805 study (13.6 months). When looking at high-volume metastatic disease only, the survival in the GETUG-AFU 15 study was 10 months shorter than in the ECOG 3805 study. This may reflect the shorter follow-up for the latter, less use to date of subsequent docetaxel, and the fact that patients on the earlier GETUG-AFU 15 study would not have had access to drugs such as enzalutamide or abiraterone, whose activity in this setting (post-chemotherapy in the hormone-naïve setting) is yet to be evaluated.

Regarding radiotherapy dose escalation in prostate cancer, Dr Jeff Michalski (Washington University, St Louis) assessed external beam radiotherapy (EBRT) dose escalation from 70.2Gy (39 fractions) to 79.2Gy (44 fractions) in men with localised low–intermediate risk prostate cancer. They found a statistically significant improvement in biochemical disease-free survival (ie PSA control) with the higher dose (HR 0.59), but no difference in overall survival or prostate-cancer-specific mortality. There was, however, an increase in Grade 3+ gastrointestinal toxicities of 1% at 10 years (4% versus 5%), with no difference in 10-year Grade 3+ genitourinary toxicity (3%). Dr James Morris (University of Toronto) presented data on adding a brachytherapy boost to EBRT (ASCENDE-RT) in patients with intermediate–high risk prostate cancer. All patients received ADT, and 46Gy EBRT to the prostate and pelvic lymph nodes. The EBRT arm then received a 32Gy boost to the prostate, whilst the brachytherapy arm received an 115Gy low dose rate brachytherapy boost to the prostate. Again they found a large benefit in terms of biochemical disease-free survival (HR 0.49; p=0.001) at the expense of increased toxicity, but no survival fit has been demonstrated to date. However, increased biochemical control reduces the need for salvage treatments with their associated toxicities.

Bladder cancer

The bladder cancer sessions focused on early data from genomic profiling, demonstrating a potential role in predicting the response to systemic therapy in both the metastatic and neoadjuvant settings.

Regarding current clinical practice, Dr Matthew Galsky (Mount Sinai) discussed the role of adjuvant chemotherapy versus observation for locally advanced bladder cancer (pT3 and/or pN+ M0) post-cystectomy. Three randomised controlled trials addressing this question have failed to recruit, so whilst this would be the gold standard approach, population-based observational studies offer an alternative insight. Such a study was performed using the US National Cancer Database, minimising for bias using a propensity scoring system. Of 5633 subjects identified, 1293 received adjuvant chemotherapy. Investigators found that with a median follow-up of 6 years there was a significant survival benefit for adjuvant chemotherapy (HR ranging from 0.62-0.72 depending on the propensity adjustment technique used). This was irrespective of age (<70 years versus >70 years), gender or node positivity. Therefore, although neoadjuvant chemotherapy remains the standard of care, for patients who have not received this approach there is growing evidence to support the use of adjuvant chemotherapy in high-risk disease.

The other significant focus was on the role of angiogenesis inhibition in urothelial carcinoma. Angiogenesis is associated with increased stage and poor prognosis for urothelial carcinoma. It is predominantly mediated by VEGF, and in preclinical models the addition of VEGF inhibitors to cytotoxic chemotherapy increases anti-tumour efficacy. In the metastatic setting, the combination of paclitaxel and pazopanib (VEGF receptor TKI inhibitor) in refractory urothelial cancer showed excellent response rates of 50%, with a progression-free survival of 6 months and overall survival of 8 months (even for patients with more aggressive disease). There was significant myelosuppression in this single-arm phase-2 study, indicating that when progressing to phase 3 the drug dosages need to be reviewed. In the non-muscle-invasive setting, Dr Alexander Helfand (University of Michigan) presented data on consolidation therapy with sunitinib (VEGF Receptor TKI inhibitor) following intravesical BCG therapy. Promising clinical activity was demonstrated for 3-month control rates, and a 2-year relapse-free survival of 77% is encouraging. However, toxicity did result in only one third of patients tolerating the full course of sunitinib without dose alterations or cessation, indicating that in future studies it may be advisable to use a lower dose of this agent.

Simon Hughes
Consultant Clinical Oncologist, Guy’s and St Thomas’ NHS Trust; Honorary Senior Lecturer, King’s College London

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