Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Patient self-reporting of tolerability using PRO-CTCAE: A randomized double-blind placebo controlled phase II trial comparing gemcitabine in combination with adavosertib or placebo in women with platinum resistant epithelial ovarian cancer.

5541 Background: A 4 month improvement in OS was demonstrated when Wee1 inhibitor adavosertib (Ad) and gemcitabine (G; arm A) was compared to G and placebo (P; arm B) in a phase 2 trial in recurrent ovarian cancer (NCT02151292). The patient reported outcome version of the CTCAE (PRO-CTCAE) was used to capture self-report of the frequency, severity and/or interference (scored 0-4; higher scores indicating worse symptomatic adverse events [syAEs]). Methods: Ad/P was given orally on D1-2, D8-9, D15-16 with G D1, D8, D15 in a 28-day cycle. English speaking pts in 2 centres completed PRO-CTCAE items electronically in clinic at baseline, D1 and D15 of each cycle and off treatment. An exploratory objective was to characterize syAEs in the first 3 months of therapy. We calculated 12-week area under the curve (AUC12w) as a measure of syAE over time and incremental AUC12w (iAUC12w) for adjustment to baseline syAEs and compared arms A and B using an independent samples t-test. We assessed proportion of scores 3-4 at 6 time-points and compared them using Fisher’s Exact Test at each survey. Results: 51 pts were enrolled and completed ≥1 survey, 47 were evaluable for primary outcome (arm A: 28, B: 19). ECOG status was ≤1 in 44/47 pts. Median number of cycles of therapy were 5 (1-16) in arm A, and 2 (1-16) in B. Survey completion rates were high (arm A 93%, B 95%). Mean AUC12w fatigue severity (A 152 [standard error 9] vs B 112 [10]; p = 0.005) and interference (A 144 [11] vs 98 [15]; p = 0.018), diarrhea frequency (A 70 [12] vs B 33 [9]; p = 0.014), mucositis (A 23 [6] vs B 6 [3]; p = 0.012) and difficulty swallowing severity (A 10 [3] vs B 2 [2]; p = 0.023) were higher in arm A (any grade). There were no statistically significant between-arm differences in abdominal pain, bloating, nausea, vomiting and anxiety. The iAUC12w was significantly higher in arm A vs B for difficulty swallowing severity (A 10.1 [3] vs B -2.7 [4.7]; p = 0.02), mucositis severity (A 19.9 [6.6] vs B -3.1 [6.9]; p = 0.02) and fatigue severity (A 35.2 [8.2] vs B -3.1 [9.8]; p = 0.005). Proportions with high scores (3-4) were only significantly higher at C1D15 for fatigue severity in arm A (A 55% vs B 19%, p = 0.044). No significant differences were seen in other 3-4 scores per survey time. Conclusions: This is the first study evaluating pts self-reported toxicity with adavosertib in a randomized setting, allowing pts self-evaluation of toxicity in the context of improved PFS and OS. Greater fatigue, diarrhea, mucositis and difficulty swallowing were experienced by pts receiving adavosertib and gemcitabine, but score 3-4 reached significance on C1D15 fatigue only. No significant differences were detected in syAE profile for nausea, vomiting, abdominal pain, bloating and anxiety. This approach allows objective assessment of pts perception of toxicity with complex therapy. Clinical trial information: NCT02151292. </jats:p

Pembrolizumab, maveropepimut-S, and low-dose cyclophosphamide in advanced epithelial ovarian cancer: Results from phase 1 and expansion cohort of PESCO trial.

5505 Background: Platinum-resistant ovarian cancer (PROC) continues to have a poor prognosis. Maveropepimut-S (MVP-S, namely DPX-Survivac) leverages the lipid-based DPX delivery platform to educate a specific and persistent T cell-based immune response to 5 HLA-restricted peptides from survivin, a cancer-related protein commonly upregulated in several cancers. MVP-S in combination with Pembrolizumab (Pemb) and low-dose Cyclophosphamide (CPA) is expected to enhance immune response. This trial aims to assess the safety and efficacy of this regimen in patients (pts) with PROC. Methods: Phase 1 escalation cohort allowed all PROC subtypes and comprised 2 dose levels (DL) of MVP-S with 1 initial dose 0.25 mL followed by boosters of 0.25 mL (DL1) or 0.5mL (DL2) SC q6w, combined with CPA (50 mg BID every other week) and Pemb (200 mg q3w). Dose escalation was performed using 3+3 design. Dose-limiting toxicities (DLT) were defined as G4 non-hematologic, ≥G3 persistent non-hematologic toxicity, laboratory value or febrile neutropenia; ≥G2 persistent injection site skin ulceration ( &gt; 1wk) or allergic/immune reactions by CTCAE v4.03. DL was considered safe if ≤1 DLT occurred in 6 pts until 21 days after initial and first boosting dose. Pts with high-grade serous (HGSOC) or endometrioid ovarian cancer were allowed in the Phase 2 expansion cohort (P2EC) and treated with the Recommended Phase 2 Dose (RP2D). Response was assessed every 6 wks. Activity in P2EC was defined as at least 2/10 partial response (PR) or stable disease (SD) for 12 wks according to RECIST 1.1. Primary endpoint is overall response rate (ORR), and secondary includes safety, PFS, and OS. Biopsies and blood draws were performed prior to and on treatment for genomic analysis, immune profiling and ctDNA. Results: Twenty-six pts were enrolled, 24 were evaluable for safety (8 DL1, 6 DL2, and 10 in P2EC). HGSOC represented 62% of phase I and 100% of P2EC. Median age was 61y (49-78). Pts received a median of 4 (1-7) prior lines of therapy. Median cycles of MVP-S were 2 (1-8). Toxicity G4/G3/G2 occurred in 1/3/7 pts of DL1 and 0/3/6 of DL2. G3/G2 immune-related AE (irAE) and injection site reactions (ISR) were observed in 1/1 and 1/3 pts treated at DL1, and in 1/0 and 2/2 pts at DL2, respectively. DL1 was selected as RP2D due to the occurrence of nephritis and ISR G3 at DL2. No AEs were qualified as DLT. On the P2EC, 5 G3 (1 irAE, 0 ISR) and 28 G2 (0 irAE, 3 ISR) toxicities were observed. At Phase 1, one pt with MSI-High clear cell subtype has ongoing CR after 26 mos of follow-up, 2 pts had PR and 6 SD.There were 1 PR and 3 SD on P2EC, of which 1 and 2, respectively, achieved response &gt; 12wks. Conclusions: The combination of MVP-S, low-dose CPA, and Pemb was tolerable and met the efficacy endpoint in the expansion cohort in heavily treated PROC. Immuno-genomic correlative analyses are ongoing. Clinical trial information: NCT03029403. [Table: see text] </jats:p

Out of the shadows : violent conflict and the real economy of Mindanao /

A deadly cocktail? Illicit drugs, politics and violent conflict in Lanao del sur and Maguindanao / Rufa Cagoco-Guiam and Steven SchoofsBandits, villains and bosses: kidnappers of the southern Philippines / Eric GutierrezBorrowing money and violence: the pagsanda credit system in Sulu / Jamail A. KamlianConclusions and policy implications / Francisco J. Lara, Jr. and Steven SchoofsCross-border illicit trade in Sulu and Tawi-tawi: the coexistence of economic agendas and violent conflict / Starjoan D. VillanuevaForeword / Teresita Quintos DelesInformal land markets and conflict in Maguindanao / Judy T. GulaneIntroduction / Steven Schoofs and Francisco J. Lara Jr.Robustness in data and methods: scoping the real economy of Mindanao / Francisco J. Lara, Jr. and Nikki P. dela RosaShadow economy or shadow state? The illicit gun trade in conflict-affected Mindanao / Eddie L. QuitorianoAdam, Jeroe